June 2024 – Page 88 – 1stOncology™: Cancer Intelligence Service

Minghui Pharmaceutical Presents Phase 1/2 Clinical Data of MHB088C (B7-H3 ADC) as Monotherapy for the Treatment of Patients with Recurrent or Metastatic Solid Tumors at the 2024 ASCO Annual Meeting

On June 3, 2024 Minghui Pharmaceutical, Inc., a late-stage clinical biopharmaceutical company, reported that the preliminary Phase 1/2 clinical data of MHB088C (B7-H3 ADC) was presented at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in an oral presentation (Press release, Minghui Pharmaceutical, JUN 3, 2024, View Source [SID1234644042]).

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Abstract #: 3012

Results of a Phase 1/2 Study of MHB088C: a Novel B7-H3 Antibody-Drug Conjugate (ADC) Incorporating a Potent DNA Topoisomerase I Inhibitor in Recurrent or Metastatic Solid Tumors

In this Phase 1/2 study, the safety/tolerability, pharmacokinetics, and efficacy of MHB088C in patients (pts) with recurrent or metastatic solid tumors were evaluated. The study results were as follows:

At data cutoff, MHB088C was well tolerated. The most common TRAEs were hematological toxicities. 4 mg/kg Q3W was the DLT dose and 3 mg/kg Q3W was defined as the MTD. 1.6 mg/kg Q2W, 2.0 mg/kg Q3W and 2.4 mg/kg Q3W demonstrated favorable safety profiles with low single-digit Grade ≥3 hematological AEs for the two lower doses. No interstitial lung disease (ILD) was reported as of the data cutoff.
Of 98 efficacy evaluable pts with different tumor types at doses ranging from 0.8 mg/kg to 4.0mg/kg, ORR was 33.7% (33/98) and DCR was 83.7% (82/98), with DoR not reached yet. The majority of pts remain on the treatment.
Of 31 efficacy evaluable pts with small cell lung cancer (SCLC), ORR was 61.3% (19/31) and DCR was 93.5% (29/31). 24 pts (77.4%) remain on the treatment, and 6 pts (19.4%) achieved 60% or more tumor reduction, with 2 CRs of target lesion at 3.0 mg/kg. Among 10 pts at 1.6 mg/kg Q2W, ORR was 80% and DCR was 90%.
Of 7 efficacy evaluable pts with esophageal squamous cell carcinoma (ESCC), ORR was 42.9% and DCR was 85.7%. The median follow-up was over 3.0 months.
Professor Lin Shen from the Beijing Cancer Hospital stated: "MHB088C represents an innovative advancement in cancer treatment as a novel B7-H3 ADC equipped with a potent DNA Topo I inhibitor. The preliminary data are highly encouraging, showcasing clinically meaningful and durable antitumor activities at very safe doses across multiple cancer types. We are optimistic about the ongoing study and anticipate further positive clinical outcomes."

Dr. Guoqing Cao, CEO of Minghui Pharmaceutical, stated: "We are excited to share the results of Phase 1/2 study of MHB088C at the 2024 ASCO (Free ASCO Whitepaper). MHB088C is a well-differentiated B7-H3 ADC, conjugating an optimal anti-human B7-H3 antibody with our Proprietary SuperTopoiTM payload. We are seeing robust efficacy at very safe doses without major hematological toxicity or ILD. Particularly, in SCLC, 9 out of 10 patients experienced tumor shrinkage at 1.6 mg/kg Q2W, with an ORR of 80%. The durability of responses was also notable in ESCC, with an ORR of 43% and median follow-up over 3 months.

The safety profile of MHB088C is consistent with that of our other program MHB036C, a TROP-2 ADC, without major hematological toxicity or ILD either. Between the two clinical programs, with data from more than 250 patients, we are confident that we now have one of the best ADC platforms in the industry. Efficacy in other cancer types has also been observed and will be reported in future conferences. We look forward to initiating registrational trials of the monotherapy for selected tumor types by the end of 2024 and exploring the IO combination in earlier line settings for both ADC assets in the near future."

About MHB088C
MHB088C is a novel B7-H3 ADC generated through Minghui’s SuperTopoiTM ADC platform. Minghui’s proprietary payload is 5 to 10 times more potent than DXd, retaining key advantages such as bystander effect while eliminating the risk of interstitial lung disease. Conjugated with Minghui’s proprietary B7-H3 antibody, which has superior binding and internalization compared to the competitor’s antibodies, MHB088C has demonstrated remarkable anti-tumor efficacy across various cancer types. It was 3 to 10 times more potent in killing tumor cells than the competitor’s compound in xenograft models.

Leading Cancer Researchers from NYU Langone’s Perlmutter Cancer Center Present Latest Clinical Findings & Research at ASCO 2024 Annual Conference

On June 3, 2024 Researchers from NYU Langone Health’s Perlmutter Cancer Center reported their latest findings and research at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Conference, held May 31 to June 4 at Chicago’s McCormick Place (Press release, NYU Langone Health, JUN 3, 2024, View Source;research-at-asco-2024-annual-conference-302162148.html [SID1234644041]).

Among these presentations:

a three-year update on the long-term efficacy of an mRNA vaccine for use in patients being treated for metastatic melanoma
a retrospective look at treatment patterns and outcomes in patients with advanced endometrial cancer
a look at the safety and efficacy of a noninvasive combination treatment for patients with recurrent glioblastoma
"This year’s crop of presentations is a showcase of the Perlmutter Cancer Center’s commitment to delivering the highest level of research and clinical care," said Alec Kimmelman, MD, PhD, the center’s director.

Late-Breaker Rapid Oral Abstract: Three-year update on the long-term efficacy of an mRNA vaccine for use in patients being treated for metastatic melanoma
Monday, June 3, 10:15AM CT

In a follow-up presentation at ASCO (Free ASCO Whitepaper) to the recently published clinical trial describing the effectiveness of combining the immunotherapy drug pembrolizumab with V940—an investigational individualized neoantigen mRNA vaccine for people with high-risk, surgically removed melanoma—this three-year update looks at the longer-term recurrence rates of treated patients.

The primary analysis of the phase 2 trial, led by Jeffrey S. Weber, MD, PhD, deputy director of Perlmutter Cancer Center, and sponsored by Moderna and Merck, assessed patients who received the vaccine, called mRNA-4157/V940, and the immunotherapy drug pembrolizumab, comparing their risk of recurrence and development of distant metastases to those who had received only pembrolizumab.

This three-year follow-up analysis showed a higher percentage of durable and meaningful long-term recurrence-free survival or survival without distant spread of cancer in patients who received both treatments (74.8 percent) compared to those who received only pembrolizumab (55.6 percent). The patients’ overall survival also improved with combination treatment, at 96.0 percent compared to 90.2 percent with pembrolizumab alone.

"This additional information continues to support the potential of mRNA-4156/V940 in combination with pembrolizumab for patients with metastatic melanoma," said Dr. Weber. "We have followed up this work with a randomized phase 3 trial in more than a thousand patients, which we hope will provide a definitive assessment of the efficacy of the combination of V940 and pembrolizumab compared to pembrolizumab alone."

Poster: A retrospective look at treatment patterns and outcomes in patients with advanced endometrial cancer
Monday, June 3, 9AM

This retrospective study, led by Bhavana Pothuri, MD, director of gynecologic oncology research at Perlmutter Cancer Center and a professor in the Department of Obstetrics and Gynecology, assesses testing for treatment options, treatment patterns, and outcomes among patients with advanced endometrial cancer. In the past decade, newer therapies have been introduced for advanced endometrial cancer. Molecular profiling of mismatch repair/microsatellite instability (MMR/MSI) status has become an important testing tool to determine treatment, but real-world data on the prevalence of its use is limited.

Researchers looked at 1,441 deidentified patients with advanced endometrial cancer who started therapy between January 2018 and June 2023, analyzing patient characteristics, treatment patterns, and testing patterns.

While MMR/MSI testing was common, less than 50 percent of patients were receiving new therapies, and further study with implementation science may aid in increased adoption.

"Advanced endometrial cancer is the fourth most common cancer affecting women in the United States, and it is the only gynecologic malignancy with increasing incidence—and increasing mortality that is soon expected to surpass that of ovarian cancer," said Dr. Pothuri. "Despite increasing trends, there may be outstanding barriers to the adoption of new therapies. We need further studies to assess these changes in outcomes over a longer time frame, along with continued education to increase awareness and access to newer FDA-approved treatments."

Poster: The safety and efficacy of a noninvasive combination treatment for patients with recurrent glioblastoma
Saturday, June 1, 9AM

Dimitris G. Placantonakis, MD, PhD, an associate professor in the Department of Neurosurgery, is presenting an ongoing, multicenter phase1/2 study that explores if sonodynamic therapy is safe and can help patients with recurrent or progressive glioblastoma live longer.

Recurrent glioblastoma is a lethal brain tumor that has an extremely poor prognosis and no effective therapies. Sonodynamic therapy is a noninvasive combination treatment that uses a drug, aminolevulinic acid HCL (SONALA-001), and a device, the Exablate 4000 Type 2.0, to deliver focused ultrasound to target glioblastoma cells. This has been shown in previous studies to lead to tumor cell death and improved survival in animal models.

People enrolled in this trial are receiving different dosage levels in order to determine the maximum tolerable dose for further study. The phase 2 portion will further characterize safety, along with evaluation of the efficacy of this treatment, with other key endpoints, including overall survival and recurrence rate.

"We are very excited about this study because, as a new therapy, it offers hope for people with this disease," said Dr. Placantonakis. "This is also exciting because it offers a noninvasive treatment approach that pulses ultrasound waves from a device that is outside the head, so there is no need to surgically remove the tumor, and it eliminates the risk of side effects that are inherent in conventional brain surgery."

Late-breaking results from PALOMA-2 study of subcutaneous amivantamab in combination with lazertinib show clinically meaningful antitumor response and improved safety profile in patients with EGFR-mutated non-small cell lung cancer

On June 3, 2024 Johnson & Johnson reported new data from the Phase 2 PALOMA-2 study evaluating subcutaneous (SC) amivantamab combined with lazertinib as a first-line treatment in patients with advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletion (ex19del) or L858R mutations (Press release, Johnson & Johnson, JUN 3, 2024, View Source [SID1234644040]). These data, which were featured in a late-breaking poster presentation at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Abstract #LBA8612), showed a comparable response rate in patients treated with SC amivantamab and lazertinib compared to those treated with the intravenous (IV) formulation in the MARIPOSA study, which established the combination of amivantamab and lazertinib as superior to osimertinib. SC amivantamab was associated with significantly lower rates of infusion-related reactions (IRRs) and shorter treatment time compared with the IV formulation.1

"These encouraging data show similar response rates in patients treated with the subcutaneous administration of amivantamab compared with the IV formulation," said Professor Nicolas Girard, Head of Medical Oncology, Institut Curie, and Professor of Thoracic Oncology and Respiratory Medicine at the Paris Saclay University, France, and study author.* "With favorable tolerability based on fewer infusion-related reactions, this formulation has the potential to address a current unmet need in the treatment of EGFR-mutant lung cancer."

In the PALOMA-2 study, Cohorts 1 and 6 enrolled patients with treatment-naïve, EGFR ex19del or L858R-mutated advanced NSCLC, a patient population similar to the MARIPOSA study population. In Cohort 1 prophylactic anticoagulation use was recommended, and in Cohort 6 it was required. As of January 6, 2024, 68 and 58 patients were enrolled in Cohorts 1 and 6, respectively. At a median follow-up of 8.6 months, across all patients, SC amivantamab combined with lazertinib demonstrated an overall response rate (ORR) of 77 percent (95 percent Confidence Interval [CI], 68-84) as assessed by the investigator per RECIST v1.1.** (primary endpoint) and 79 percent (95 percent CI, 70-86) as assessed by blinded independent central review. A similar ORR of 86 percent (95 percent CI, 83-89) was observed with IV amivantamab in combination with lazertinib, as determined by a blinded independent central review in the Phase 3 MARIPOSA study. Average administration time was approximately five minutes versus the IV administration of 2-4 hours. Median duration of response was not estimable in both cohorts.1

The pooled analysis from Cohort 1 and Cohort 6 showed the safety profile for SC amivantamab was consistent with previous reports, with no new safety signals identified. The most common treatment-emergent adverse events (AEs) (≥ 20 percent) across all patients were paronychia (71 percent), rash (61 percent) and hypoalbuminemia (48 percent). IRRs were reported in 15 percent of patients across the two cohorts. Discontinuation of all medicines due to treatment-related AEs occurred in approximately nine percent of all patients. Prophylactic anticoagulation was administered to 71 percent of patients in Cohort 1 and 100 percent of those in Cohort 6. Venous thromboembolic events (VTEs) were reported in 18 and seven percent of patients in Cohorts 1 and 6, respectively, with no dose reductions or discontinuations reported due to VTEs. These findings suggest prophylactic anticoagulation can be safely implemented and reduce the incidence of VTEs with the combination of amivantamab plus lazertinib.1

"The safety and tolerability data from the PALOMA-2 study highlight the potential of subcutaneous amivantamab as an important therapy in the first-line treatment of patients with EGFR-mutant lung cancer," said Kiran Patel, M.D., Vice President, Clinical Development, Solid Tumors, Johnson & Johnson Innovative Medicine. "As we advance our robust pipeline and portfolio for patients with lung cancer, we remain dedicated to developing safe and effective therapies that offer distinct benefits in the treatment of this disease."

About the PALOMA-2 Study

PALOMA-2 (NCT05498428) is an open-label Phase 2 study evaluating the efficacy, safety, and pharmacokinetics (PK) of first-line SC amivantamab (administered via manual injection) combined with lazertinib and/or chemotherapy in patients with EGFR-mutated advanced or metastatic NSCLC. Sixty-eight and 58 patients were enrolled in Cohorts 1 and 6, respectively. Prophylactic anticoagulation for the first four months of treatment was recommended in Cohort 1 and mandatory in Cohort 6. The primary endpoint was objective response rate (ORR) as assessed by the investigator per RECIST v1.1.2

About RYBREVANT

RYBREVANT (amivantamab-vmjw), a fully-human bispecific antibody targeting EGFR and MET with immune cell-directing activity, is approved in the U.S., Europe, and in other markets around the world as monotherapy for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.3 In the subcutaneous formulation, amivantamab is co-formulated with recombinant human hyaluronidase PH20 (rHuPH20), Halozyme’s ENHANZE drug delivery technology.

RYBREVANT is also approved in the U.S. in combination with chemotherapy (carboplatin and pemetrexed) for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test. In October 2023, a type II extension of indication application was submitted to the European Medicines Agency (EMA) seeking approval of RYBREVANT for this indication.

In December 2023, Johnson & Johnson submitted a supplmental Biologics License Application (sBLA) together with a New Drug Application (NDA) to the U.S. FDA for RYBREVANT in combination with lazertinib for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or L858R substitution mutations, as detected by an FDA-approved test. This submission is based on the Phase 3 MARIPOSA study and was granted Priority Review in February 2024. A marketing authorization application (MAA) and type II extension of indication application were also submitted to the EMA seeking approval of lazertinib in combination with RYBREVANT based on the MARIPOSA study.

In November 2023, Johnson & Johnson submitted an sBLA to the U.S. FDA for RYBREVANT in combination with chemotherapy for the treatment of patients with EGFR-mutated NSCLC who progressed on or after osimertinib based on the MARIPOSA-2 study. A type II extension of indication application was also submitted to the EMA seeking approval of RYBREVANT for this indication.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for NSCLC§ prefer next-generation sequencing–based strategies over polymerase chain reaction–based approaches for the detection of EGFR exon 20 insertion variants. The NCCN Guidelines include:

Amivantamab-vmjw (RYBREVANT) plus carboplatin and pemetrexed as a preferred (Category 1 recommendation) first-line therapy in treatment-naive patients with newly diagnosed advanced or metastatic EGFR exon 20 insertion mutation-positive advanced NSCLC, or as a subsequent therapy option (Category 2A recommendation) for patients that have progressed on or after platinum-based chemotherapy with or without immunotherapy and have EGFR exon 20 insertion mutation-positive advanced NSCLC.4 †‡
Amivantamab-vmjw (RYBREVANT) plus chemotherapy as a preferred (Category 1 recommendation) subsequent therapy for patients with locally advanced or metastatic NCSLC with EGFR exon 19 deletions or exon 21 L858R mutations who experienced disease progression after treatment with osimertinib.4 †‡
Amivantamab-vmjw (RYBREVANT) as a subsequent therapy option (Category 2A recommendation) for patients that have progressed on or after platinum-based chemotherapy with or without an immunotherapy and have EGFR exon 20 insertion mutation-positive NSCLC.4 †‡
RYBREVANT is being studied in multiple clinical trials in NSCLC, including:

The Phase 1 PALOMA (NCT04606381) study assessing the feasibility of subcutaneous administration of amivantamab based on safety and pharmacokinetics and to determine a dose, dose regimen and formulation for amivantamab subcutaneous delivery.5
The Phase 2 PALOMA-2 (NCT05498428) study assessing subcutaneous amivantamab in patients with advanced or metastatic solid tumors including EGFR-mutated NSCLC.2
The Phase 3 PALOMA-3 (NCT05388669) study assessing lazertinib with subcutaneous amivantamab compared to intravenous amivantamab in patients with EGFR-mutated advanced or metastatic NSCLC.6
The Phase 3 PAPILLON (NCT04538664) study assessing RYBREVANT in combination with carboplatin-pemetrexed versus chemotherapy alone in the first-line treatment of patients with advanced or metastatic NSCLC with EGFR exon 20 insertion mutations.7
The Phase 3 MARIPOSA-2 (NCT04988295) study assessing the efficacy of RYBREVANT (with or without lazertinib) and carboplatin-pemetrexed versus carboplatin-pemetrexed alone in patients with locally advanced or metastatic EGFR ex19del or L858R substitution NSCLC after disease progression on or after osimertinib.8
The Phase 3 MARIPOSA (NCT04487080) study assessing RYBREVANT in combination with lazertinib versus osimertinib and versus lazertinib alone in the first-line treatment of patients with locally advanced or metastatic NSCLC with EGFR ex19del or L858R substitution mutations.9
The Phase 1 CHRYSALIS (NCT02609776) study evaluating RYBREVANT in patients with advanced NSCLC.10
The Phase 1/1b CHRYSALIS-2 (NCT04077463) study evaluating RYBREVANT in combination with lazertinib and lazertinib as a monotherapy in patients with advanced NSCLC with EGFR mutations.11
The Phase 1/2 METalmark (NCT05488314) study assessing RYBREVANT and capmatinib combination therapy in locally advanced or metastatic NSCLC.12
The Phase 1/2 PolyDamas (NCT05908734) study assessing RYBREVANT and cetrelimab combination therapy in locally advanced or metastatic NSCLC.13
The Phase 2 SKIPPirr (NCT05663866) study exploring how to decrease the incidence and/or severity of first-dose infusion-related reactions with RYBREVANT in combination with lazertinib in relapsed or refractory EGFR-mutated advanced or metastatic NSCLC.14
For more information, visit: View Source

About Non-Small Cell Lung Cancer

Worldwide, lung cancer is one of the most common cancers, with NSCLC making up 80 to 85 percent of all lung cancer cases.15,16 The main subtypes of NSCLC are adenocarcinoma, squamous cell carcinoma, and large cell carcinoma.17 Among the most common driver mutations in NSCLC are alterations in EGFR, which is a receptor tyrosine kinase controlling cell growth and division.18 EGFR mutations are present in 10 to 15 percent of Western patients with NSCLC with adenocarcinoma histology and occur in 40 to 50 percent of Asian patients.17,18,19,20,21,22 EGFR ex19del or EGFR L858R mutations are the most common EGFR mutations.23 The five year survival rate for all people with advanced NSCLC and EGFR mutations treated with EGFR tyrosine kinase inhibitors (TKIs) is less than 20 percent.24,25 EGFR exon 20 insertion mutations are the third most prevalent activating EGFR mutation.26 Patients with EGFR exon 20 insertion mutations have a real-world five-year overall survival (OS) of eight percent in the frontline setting, which is worse than patients with EGFR ex19del or L858R mutations, who have a real-world five-year OS of 19 percent.27

RYBREVANT IMPORTANT SAFETY INFORMATION3

WARNINGS AND PRECAUTIONS

The safety population of RYBREVANT with carboplatin and pemetrexed described in Warnings and Precautions was based on 151 patients in the PAPILLON study.

The safety population of RYBREVANT as a single agent described in Warnings and Precautions was based on 129 patients in the CHRYSALIS study.

Infusion-Related Reactions

RYBREVANT can cause infusion-related reactions (IRR); signs and symptoms of IRR include dyspnea, flushing, fever, chills, nausea, chest discomfort, hypotension, and vomiting.

RYBREVANT with Carboplatin and Pemetrexed

RYBREVANT in combination with carboplatin and pemetrexed can cause infusion-related reactions. Based on the safety population, infusion-related reactions occurred in 42% of patients treated with RYBREVANT in combination with carboplatin and pemetrexed, including Grade 3 (1.3%) adverse reactions. The incidence of infusion modifications due to IRR was 40%, and 0.7% of patients permanently discontinued RYBREVANT.

RYBREVANT as a Single Agent

Based on the safety population, IRR occurred in 66% of patients treated with RYBREVANT. Among patients receiving treatment on Week 1 Day 1, 65% experienced an IRR, while the incidence of IRR was 3.4% with the Day 2 infusion, 0.4% with the Week 2 infusion, and cumulatively 1.1% with subsequent infusions. Of the reported IRRs, 97% were Grade 1-2, 2.2% were Grade 3, and 0.4% were Grade 4. The median time to onset was 1 hour (range 0.1 to 18 hours) after start of infusion. The incidence of infusion modifications due to IRR was 62%, and 1.3% of patients permanently discontinued RYBREVANT due to IRR.

Premedicate with antihistamines, antipyretics, and glucocorticoids, and infuse RYBREVANT as recommended. Administer RYBREVANT via a peripheral line on Week 1 and Week 2. Monitor patients for any signs and symptoms of infusion reactions during RYBREVANT infusion in a setting where cardiopulmonary resuscitation medication and equipment are available. Interrupt infusion if IRR is suspected. Reduce the infusion rate or permanently discontinue RYBREVANT based on severity.

Interstitial Lung Disease/Pneumonitis

RYBREVANT can cause interstitial lung disease (ILD)/pneumonitis.

RYBREVANT with Carboplatin and Pemetrexed

Based on the safety population, Grade 3 ILD/pneumonitis occurred in 2.6% of patients treated with RYBREVANT in combination with carboplatin and pemetrexed. All patients required permanent discontinuation.

RYBREVANT as a Single Agent

Based on the safety population, ILD/pneumonitis occurred in 3.3% of patients treated with RYBREVANT, with 0.7% of patients experiencing Grade 3 ILD/pneumonitis. Three patients (1%) discontinued RYBREVANT due to ILD/pneumonitis.

Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold RYBREVANT in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed.

Dermatologic Adverse Reactions

RYBREVANT can cause rash (including dermatitis acneiform), pruritus, and dry skin.

RYBREVANT with Carboplatin and Pemetrexed

RYBREVANT in combination with carboplatin and pemetrexed can cause dermatologic adverse reactions. Based on the safety population, rash occurred in 89% of patients treated with RYBREVANT in combination with carboplatin and pemetrexed, including Grade 3 (19%) adverse reactions. Rash leading to dose reductions occurred in 19% of patients; 2% permanently discontinued RYBREVANT, and 1.3% discontinued pemetrexed.

RYBREVANT as a Single Agent

Based on the safety population, rash occurred in 74% of patients treated with RYBREVANT, including Grade 3 rash in 3.3% of patients. The median time to onset of rash was 14 days (range: 1 to 276 days). Rash leading to dose reduction occurred in 5% of patients, and RYBREVANT was permanently discontinued due to rash in 0.7% of patients.

Toxic epidermal necrolysis occurred in one patient (0.3%) treated with RYBREVANT as a single agent.

Instruct patients to limit sun exposure during and for 2 months after treatment with RYBREVANT. Advise patients to wear protective clothing and use broad-spectrum UVA/UVB sunscreen. Alcohol-free emollient cream is recommended for dry skin.

If skin reactions develop, start topical corticosteroids and topical and/or oral antibiotics. For Grade 3 reactions, add oral steroids and consider dermatologic consultation. Promptly refer patients presenting with severe rash, atypical appearance or distribution, or lack of improvement within 2 weeks to a dermatologist. Withhold, dose reduce, or permanently discontinue RYBREVANT based on severity.

Ocular Toxicity

RYBREVANT can cause ocular toxicity including keratitis, dry eye symptoms, conjunctival redness, blurred vision, visual impairment, ocular itching, and uveitis.

RYBREVANT with Carboplatin and Pemetrexed

Based on the safety population, RYBREVANT in combination with carboplatin and pemetrexed can cause ocular toxicity including blepharitis, dry eye, conjunctival redness, blurred vision, and eye pruritus. All events were Grade 1-2.

RYBREVANT as a Single Agent

Based on the safety population, keratitis occurred in 0.7% and uveitis occurred in 0.3% of patients treated with RYBREVANT. All events were Grade 1-2. Promptly refer patients presenting with eye symptoms to an ophthalmologist. Withhold, dose reduce, or permanently discontinue RYBREVANT based on severity.

Embryo-Fetal Toxicity

Based on its mechanism of action and findings from animal models, RYBREVANT can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of RYBREVANT.

Adverse Reactions

RYBREVANT with Carboplatin and Pemetrexed

For the 151 patients in the PAPILLON clinical trial who received RYBREVANT in combination with carboplatin and pemetrexed, the most common adverse reactions (≥20%) were rash (90%), nail toxicity (62%), stomatitis (43%), infusion-related reaction (42%), fatigue (42%), edema (40%), constipation (40%), decreased appetite (36%), nausea (36%), COVID-19 (24%), diarrhea (21%), and vomiting (21%). The most common Grade 3 to 4 laboratory abnormalities (≥2%) were decreased albumin (7%), increased alanine aminotransferase (4%), increased gamma-glutamyl transferase (4%), decreased sodium (7%), decreased potassium (11%), decreased magnesium (2%), and decreases in white blood cells (17%), hemoglobin (11%), neutrophils (36%), platelets (10%), and lymphocytes (11%).

Serious adverse reactions occurred in 37% of patients who received RYBREVANT in combination with carboplatin and pemetrexed. Serious adverse reactions in ≥2% of patients included rash, pneumonia, ILD, pulmonary embolism, vomiting, and COVID-19. Fatal adverse reactions occurred in 7 patients (4.6%) due to pneumonia, cerebrovascular accident, cardio-respiratory arrest, COVID-19, sepsis, and death not otherwise specified.

RYBREVANT as a Single Agent

For the 129 patients in the CHRYSALIS clinical trial who received RYBREVANT as a single agent, the most common adverse reactions (≥20%) were rash (84%), IRR (64%), paronychia (50%), musculoskeletal pain (47%), dyspnea (37%), nausea (36%), fatigue (33%), edema (27%), stomatitis (26%), cough (25%), constipation (23%), and vomiting (22%). The most common Grade 3 to 4 laboratory abnormalities (≥2%) were decreased lymphocytes (8%), decreased albumin (8%), decreased phosphate (8%), decreased potassium (6%), increased alkaline phosphatase (4.8%), increased glucose (4%), increased gamma-glutamyl transferase (4%), and decreased sodium (4%).

Serious adverse reactions occurred in 30% of patients who received RYBREVANT. Serious adverse reactions in ≥2% of patients included pulmonary embolism, pneumonitis/ILD, dyspnea, musculoskeletal pain, pneumonia, and muscular weakness. Fatal adverse reactions occurred in 2 patients (1.5%) due to pneumonia and 1 patient (0.8%) due to sudden death.

Please read the full Prescribing Information for RYBREVANT.

DARZALEX® (daratumumab)-based regimens significantly improve clinical outcomes in both transplant-eligible and -ineligible patients who are newly diagnosed with multiple myeloma

On June 3, 2024 Johnson & Johnson reported data from the Phase 3 PERSEUS study showing deepening of responses and sustained minimal residual disease (MRD) negativity at both 10-5 and 10-6 levels with an induction regimen of DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) in combination with bortezomib, lenalidomide and dexamethasone (D-VRd) followed by a maintenance regimen of DARZALEX FASPRO plus lenalidomide (D-R) for the treatment of patients with transplant-eligible (TE) newly diagnosed multiple myeloma (NDMM) (Press release, Johnson & Johnson, JUN 3, 2024, View Source;ineligible-patients-who-are-newly-diagnosed-with-multiple-myeloma-302162312.html [SID1234644039]). The rates of deep and sustained MRD negativity were associated with improved progression-free survival (PFS) with DARZALEX FASPRO-based quadruplet induction, consolidation and doublet maintenance regimen in these patients versus VRd. The data are featured as oral presentations at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Abstract #7502) and the 2024 European Hematology Association (EHA) (Free EHA Whitepaper) Congress (Abstract #S201).

"MRD-negativity is an important measure in predicting long-term progression-free survival for patients with multiple myeloma," said Dr. Paula Rodriguez-Otero, Department of Hematology, Cancer Center Clínica Universidad de Navarra, Pamplona, Navarra, Spain.* "The higher rates of deep and sustained MRD negativity with this DARZALEX FASPRO-based regimen underscore the potential of D-VRd and D-R maintenance to shift the treatment paradigm for transplant-eligible patients with newly diagnosed multiple myeloma and bring us closer to the potential for a functional cure."

In the PERSEUS study, the D-VRd arm showed deeper responses and higher rates of MRD negativity over time at both 10-5 and 10-6 levels compared to the VRd arm (n=354), with higher rates of complete response at the end of consolidation (44.5 percent vs. 34.7 percent) and maintenance (87.9 percent vs. 70.1 percent). Rates of MRD negativity at 10-6 increased over time and were consistently higher in the D-VRd vs. VRd arm: 43.9 percent vs. 20.9 percent (P=0.0001) at 12 months; 57.7 percent vs. 27.4 percent (P=0.0001) at 24 months and 63.9 percent vs. 30.8 percent (P=0.0001) at 36 months.1

The D-VRd arm also demonstrated higher rates of sustained MRD negativity at 10-6 for at least 12 months compared to the VRd arm: 47.3 percent vs. 18.6 percent (P <0.0001). The PFS rate at 48 months was 84.3 percent for the D-VRd arm compared to 67.7 percent for the VRd arm (hazard ratio [HR], 0.42; 95 percent confidence interval [CI], 0.30-0.59; P<0.0001).1

Final survival analysis from Phase 3 MAIA study of DARZALEX-based regimen as a frontline combination therapy to be presented at EHA (Free EHA Whitepaper)

Follow-up data from MAIA showed a median overall survival of 7.5 years for DARZALEX plus lenalidomide and dexamethasone (D-Rd), with a 33 percent reduction in the risk of death versus lenalidomide plus dexamethasone (Rd) in transplant-ineligible patients with NDMM (HR, 0.67;95 percent CI,0.55-0.82; nominal P<0.0001).2 Median overall survival was 90.3 months with D-Rd vs. 64.1 months with Rd. The overall survival benefit with D-Rd vs. Rd was consistent across pre-specified subgroups.2 The median age of patients enrolled in MAIA was 73 (range: 45 to 90) years, with 43.6 percent of participants over the age of 75 years.2 Data will be presented in a poster at EHA (Free EHA Whitepaper) (Abstract #P968).

"The median overall survival of 7.5 years seen in the MAIA study reinforces the efficacy of DARZALEX as a foundational treatment in the frontline setting for patients with multiple myeloma who are not eligible for transplant," said Jordan Schecter, M.D., Vice President, Disease Area Leader, Multiple Myeloma, at Johnson & Johnson Innovative Medicine. "DARZALEX has shown an overall survival benefit across three studies in newly diagnosed multiple myeloma, supporting it as a standard-of-care. DARZALEX-based quadruplet and triplet regimens have advanced outcomes for newly diagnosed patients in the transplant-eligible and ineligible settings."

Long-term data from Phase 3 CASSIOPEIA study evaluating DARZALEX-based therapy and maintenance in TE patients with NDMM to be presented at EHA (Free EHA Whitepaper)

More than six years of follow-up data from CASSIOPEIA show that post-transplant maintenance with DARZALEX reduced the risk of disease progression or death by 51 percent vs. observation, with the median PFS not reached at six years with DARZALEX vs median PFS of less than four years (45.8 months) with observation (HR, 0.49; 95 percent CI, 0.40 – 0.59; P< 0.0001).3 The results will be presented in an oral presentation at EHA (Free EHA Whitepaper) (Abstract #S204).

In the PERSEUS, MAIA and CASSIOPEIA studies, the safety profiles were consistent with the known safety profiles for DARZALEX and DARZALEX FASPRO.1,2,3

* Dr. Paula Rodriguez-Otero, Department of Hematology, Cancer Center Clínica Universidad de Navarra, has provided consulting, advisory, and speaking services to Johnson & Johnson; she has not been paid for any media work.

About the PERSEUS study
The PERSEUS study (NCT03710603) is being conducted in collaboration with the European Myeloma Network as the sponsor. PERSEUS is an ongoing, randomized, open-label, Phase 3 study comparing the efficacy and safety of D-VRd and ASCT followed by D-R maintenance vs. VRd and ASCT followed by R maintenance in patients with transplant-eligible NDMM. The primary endpoint is PFS, and secondary endpoints include overall CR or better rate, overall MRD-negativity (in patients with CR or better), and overall survival. DARZALEX FASPRO was discontinued after at least 24 months of D-R maintenance therapy in patients who had a CR or better and had sustained MRD–negative status for at least 12 months.4 The median age is 61.0 (range, 32-70) years for patients in the D-VRd arm and 59.0 (range, 31-70) years for patients in the VRd arm. The study is being conducted in 14 countries in Europe and Australia.

Data from the PERSEUS study were featured as a late-breaking oral presentation (LBA-1) at the 2023 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and simultaneously published in The New England Journal of Medicine in 2023.

About the MAIA Trial
The randomized, open-label, multicenter Phase 3 (NCT02076009) study included 737 newly diagnosed patients with multiple myeloma ineligible for high-dose chemotherapy and autologous stem cell transplant (ASCT), aged 45-90 years (median age of 73).5 Patients were randomized to receive either D-Rd or Rd alone in 28-day cycles. In the D-Rd arm, patients received DARZALEX 16 milligrams per kilogram (mg/kg) IV weekly for cycles 1 – 2, every two weeks for cycles 3 – 6 and every four weeks for cycle 7 and thereafter.iv Patients in the D-Rd and Rd treatment arms received 25 mg of lenalidomide on days 1 – 21 of each 28-day cycle, and dexamethasone at 40 mg once a week for each cycle. Patients in both treatment arms continued until disease progression or unacceptable toxicity.6

Earlier results from the MAIA study supported the U.S. Food and Drug Administration (FDA) approval of DARZALEX in combination with Rd. These data were also published in The New England Journal of Medicine in 2019. An updated OS analysis was published in The Lancet Oncology in 2021.

About the CASSIOPEIA Trial
The randomized, open-label, multicenter, Phase 3 (NCT02541383) study is sponsored by the French Intergroupe Francophone du Myelome in collaboration with the Dutch-Belgian Cooperative Trial Group for Hematology Oncology and Janssen Research & Development, LLC. This Phase 3 study included 1,085 newly diagnosed patients with previously untreated, symptomatic multiple myeloma who were eligible for high-dose chemotherapy and stem cell transplant. Part one of the study compared DARZALEX (D) in combination with bortezomib, thalidomide and dexamethasone (VTd) versus VTd induction and consolidation therapy in patients with NDMM who were eligible for autologous stem cell transplantation (ASCT) and demonstrated that D-VTd yielded deeper responses and improved PFS. Part two of the study compared D-maintenance therapy given every 8 weeks (at a reduced frequency treatment schedule compared to the standard long-term dosing frequency of every 4 weeks) versus observation. The primary endpoint in this part of the study is the proportion of patients who achieve a sCR 100 days after transplant. In the second part of the study, which is ongoing, patients who achieved a partial response or better in part one will undergo a second randomization to receive maintenance treatment with DARZALEX 16 mg/kg every eight weeks for up to two years or will be observed with no further treatment. The primary endpoint in this part of the study is PFS.7

About Multiple Myeloma
Multiple myeloma is a blood cancer that affects a type of white blood cell called plasma cells, which are found in the bone marrow.8 In multiple myeloma, these malignant plasma cells proliferate and replace normal cells in the bone marrow.9 Multiple myeloma is the second most common blood cancer worldwide and remains an incurable disease.10 In 2024, it is estimated that more than 35,000 people will be diagnosed with multiple myeloma in the U.S. and more than 12,000 will die from the disease.11 People with multiple myeloma have a 5-year survival rate of 59.8 percent.7 While some people diagnosed with multiple myeloma initially have no symptoms, most patients are diagnosed due to symptoms that can include bone fracture or pain, low red blood cell counts, tiredness, high calcium levels, kidney problems or infections.12,13

About DARZALEX FASPRO and DARZALEX

DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) received U.S. FDA approval in May 2020 and is approved for eight indications in multiple myeloma, three of which are for frontline treatment in newly diagnosed patients who are transplant eligible or ineligible.14 It is the only subcutaneous CD38-directed antibody approved to treat patients with MM. DARZALEX FASPRO is co-formulated with recombinant human hyaluronidase PH20 (rHuPH20), Halozyme’s ENHANZE drug delivery technology.

DARZALEX (daratumumab) received U.S. FDA approval in November 2015 and is approved in eight indications, three of which are in the frontline setting, including newly diagnosed patients who are transplant eligible and ineligible.6

DARZALEX is the first CD38-directed antibody approved to treat multiple myeloma.5 DARZALEX-based regimens have been used in the treatment of more than 518,000 patients worldwide and more than 68,000 patients in the U.S. alone.

In August 2012, Janssen Biotech, Inc. and Genmab A/S entered a worldwide agreement, which granted Janssen an exclusive license to develop, manufacture and commercialize daratumumab.

Since 2020, the National Comprehensive Cancer Network (NCCN) has recommended daratumumab-based combination regimens for the treatment of newly diagnosed multiple myeloma and relapsed and refractory multiple myeloma.† For newly diagnosed multiple myeloma in non-transplant candidates, the NCCN guidelines recommend daratumumab in combination with lenalidomide and dexamethasone as a Category 1 preferred regimen; daratumumab in combination with bortezomib, melphalan, and prednisone as another recommended Category 1 regimen; and daratumumab in combination with bortezomib, cyclophosphamide, and prednisone as another recommended Category 2A regimen. For newly diagnosed multiple myeloma in transplant candidates, the NCCN guidelines recommend daratumumab in combination with bortezomib, lenalidomide and dexamethasone as another recommended Category 2A regimen; daratumumab in combination with bortezomib, thalidomide and dexamethasone as a Category 2A regimen useful in certain circumstances; daratumumab in combination with carfilzomib, lenalidomide and dexamethasone as a Category 2A regimen useful in certain circumstances; and daratumumab in combination with cyclophosphamide, bortezomib and dexamethasone as a Category 2A regimen useful in certain circumstances. For maintenance in transplant candidates, the NCCN guidelines recommend daratumumab in combination with lenalidomide as useful in certain circumstances. In relapsed/refractory myeloma, four daratumumab regimens are listed as Category 1 preferred regimens for early relapses (1-3 prior therapies): daratumumab in combination with lenalidomide and dexamethasone; daratumumab in combination with bortezomib and dexamethasone; daratumumab in combination with carfilzomib and dexamethasone; and daratumumab in combination with pomalidomide and dexamethasone [after one prior therapy including lenalidomide and a proteasome inhibitor (PI)]. The NCCN also recommends daratumumab in combination with cyclophosphamide, bortezomib and dexamethasone as another Category 2A regimen for early relapses (1-3 prior therapies) and as monotherapy as a Category 2A regimen useful in certain circumstances for early relapse patients after at least three prior therapies, including a PI and an immunomodulatory agent, or for patients who are double refractory to a PI and an immunomodulatory agent.

For more information, visit www.DARZALEX.com.

DARZALEX INDICATIONS AND IMPORTANT SAFETY INFORMATION

INDICATIONS

DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) is indicated for the treatment of adult patients with multiple myeloma:

In combination with bortezomib, melphalan, and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant
In combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy
In combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant
In combination with pomalidomide and dexamethasone in patients who have received at least one prior line of therapy including lenalidomide and a proteasome inhibitor
In combination with carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy
In combination with bortezomib and dexamethasone in patients who have received at least one prior therapy
As monotherapy in patients who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent
CONTRAINDICATIONS

DARZALEX is contraindicated in patients with a history of severe hypersensitivity (eg, anaphylactic reactions) to daratumumab or any of the components of the formulation.

WARNINGS AND PRECAUTIONS

Infusion-Related Reactions

DARZALEX can cause severe and/or serious infusion-related reactions including anaphylactic reactions. These reactions can be life–threatening, and fatal outcomes have been reported. In clinical trials (monotherapy and combination: N=2066), infusion-related reactions occurred in 37% of patients with the Week 1 (16 mg/kg) infusion, 2% with the Week 2 infusion, and cumulatively 6% with subsequent infusions. Less than 1% of patients had a Grade 3/4 infusion-related reaction at Week 2 or subsequent infusions. The median time to onset was 1.5 hours (range: 0 to 73 hours). Nearly all reactions occurred during infusion or within 4 hours of completing DARZALEX. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, tachycardia, headache, laryngeal edema, pulmonary edema, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting, and nausea. Less common signs and symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, hypotension and blurred vision.

When DARZALEX dosing was interrupted in the setting of ASCT (CASSIOPEIA) for a median of 3.75 months (range: 2.4 to 6.9 months), upon re-initiation of DARZALEX, the incidence of infusion-related reactions was 11% for the first infusion following ASCT. Infusion-related reactions occurring at re-initiation of DARZALEX following ASCT were consistent in terms of symptoms and severity (Grade 3 or 4: <1%) with those reported in previous studies at Week 2 or subsequent infusions. In EQUULEUS, patients receiving combination treatment (n=97) were administered the first 16 mg/kg dose at Week 1 split over two days, ie, 8 mg/kg on Day 1 and Day 2, respectively. The incidence of any grade infusion-related reactions was 42%, with 36% of patients experiencing infusion-related reactions on Day 1 of Week 1, 4% on Day 2 of Week 1, and 8% with subsequent infusions.

Pre-medicate patients with antihistamines, antipyretics, and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt DARZALEX infusion for reactions of any severity and institute medical management as needed. Permanently discontinue DARZALEX therapy if an anaphylactic reaction or life-threatening (Grade 4) reaction occurs and institute appropriate emergency care. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion.

To reduce the risk of delayed infusion-related reactions, administer oral corticosteroids to all patients following DARZALEX infusions. Patients with a history of chronic obstructive pulmonary disease may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease.

Ocular adverse reactions, including acute myopia and narrowing of the anterior chamber angle due to ciliochoroidal effusions with potential for increased intraocular pressure or glaucoma, have occurred with DARZALEX infusion. If ocular symptoms occur, interrupt DARZALEX infusion and seek immediate ophthalmologic evaluation prior to restarting DARZALEX.

Interference With Serological Testing

Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive indirect antiglobulin test (indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab infusion. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum. The determination of a patient’s ABO and Rh blood type is not impacted. Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX. Type and screen patients prior to starting DARZALEX.

Neutropenia and Thrombocytopenia

DARZALEX may increase neutropenia and thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. Consider withholding DARZALEX until recovery of neutrophils or for recovery of platelets.

Interference With Determination of Complete Response

Daratumumab is a human immunoglobulin G (IgG) kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.

Embryo-Fetal Toxicity

Based on the mechanism of action, DARZALEX can cause fetal harm when administered to a pregnant woman. DARZALEX may cause depletion of fetal immune cells and decreased bone density. Advise pregnant women of the potential risk to a fetus. Advise females with reproductive potential to use effective contraception during treatment with DARZALEX and for 3 months after the last dose.

The combination of DARZALEX with lenalidomide, pomalidomide, or thalidomide is contraindicated in pregnant women because lenalidomide, pomalidomide, and thalidomide may cause birth defects and death of the unborn child. Refer to the lenalidomide, pomalidomide, or thalidomide prescribing information on use during pregnancy.

ADVERSE REACTIONS

The most frequently reported adverse reactions (incidence ≥20%) were: upper respiratory infection, neutropenia, infusion–related reactions, thrombocytopenia, diarrhea, constipation, anemia, peripheral sensory neuropathy, fatigue, peripheral edema, nausea, cough, pyrexia, dyspnea, and asthenia. The most common hematologic laboratory abnormalities (≥40%) with DARZALEX are: neutropenia, lymphopenia, thrombocytopenia, leukopenia, and anemia.

Please click here to see the full Prescribing Information.

DARZALEX FASPRO INDICATIONS AND IMPORTANT SAFETY INFORMATION

INDICATIONS

DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) is indicated for the treatment of adult patients with multiple myeloma:

WARNINGS AND PRECAUTIONS 

Hypersensitivity and Other Administration Reactions 
Both systemic administration-related reactions, including severe or life-threatening reactions, and local injection-site reactions can occur with DARZALEX FASPRO. Fatal reactions have been reported with daratumumab-containing products, including DARZALEX FASPRO. 

Systemic Reactions 
In a pooled safety population of 898 patients with multiple myeloma (N=705) or light chain (AL) amyloidosis (N=193) who received DARZALEX FASPRO as monotherapy or in combination, 9% of patients experienced a systemic administration-related reaction (Grade 2: 3.2%, Grade 3: 1%). Systemic administration-related reactions occurred in 8% of patients with the first injection, 0.3% with the second injection, and cumulatively 1% with subsequent injections. The median time to onset was 3.2 hours (range: 4 minutes to 3.5 days). Of the 140 systemic administration-related reactions that occurred in 77 patients, 121 (86%) occurred on the day of DARZALEX FASPRO administration. Delayed systemic administration-related reactions have occurred in 1% of the patients.

Severe reactions included hypoxia, dyspnea, hypertension, tachycardia, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. Other signs and symptoms of systemic administration-related reactions may include respiratory symptoms, such as bronchospasm, nasal congestion, cough, throat irritation, allergic rhinitis, and wheezing, as well as anaphylactic reaction, pyrexia, chest pain, pruritus, chills, vomiting, nausea, hypotension, and blurred vision.

Pre-medicate patients with histamine-1 receptor antagonist, acetaminophen, and corticosteroids. Monitor patients for systemic administration-related reactions, especially following the first and second injections. For anaphylactic reaction or life-threatening (Grade 4) administration-related reactions, immediately and permanently discontinue DARZALEX FASPRO. Consider administering corticosteroids and other medications after the administration of DARZALEX FASPRO depending on dosing regimen and medical history to minimize the risk of delayed (defined as occurring the day after administration) systemic administration-related reactions.

Ocular adverse reactions, including acute myopia and narrowing of the anterior chamber angle due to ciliochoroidal effusions with potential for increased intraocular pressure or glaucoma, have occurred with daratumumab-containing products. If ocular symptoms occur, interrupt DARZALEX FASPRO and seek immediate ophthalmologic evaluation prior to restarting DARZALEX FASPRO.

Local Reactions 
In this pooled safety population, injection-site reactions occurred in 8% of patients, including Grade 2 reactions in 0.7%. The most frequent (>1%) injection-site reaction was injection-site erythema. These local reactions occurred a median of 5 minutes (range: 0 minutes to 6.5 days) after starting administration of DARZALEX FASPRO. Monitor for local reactions and consider symptomatic management. 

Neutropenia 
Daratumumab may increase neutropenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. Consider withholding DARZALEX FASPRO until recovery of neutrophils. In lower body weight patients receiving DARZALEX FASPRO, higher rates of Grade 3-4 neutropenia were observed. 

Thrombocytopenia 
Daratumumab may increase thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Consider withholding DARZALEX FASPRO until recovery of platelets. 

Embryo-Fetal Toxicity 
Based on the mechanism of action, DARZALEX FASPRO can cause fetal harm when administered to a pregnant woman. DARZALEX FASPRO may cause depletion of fetal immune cells and decreased bone density. Advise pregnant women of the potential risk to a fetus. Advise females with reproductive potential to use effective contraception during treatment with DARZALEX FASPRO and for 3 months after the last dose. 

The combination of DARZALEX FASPRO with lenalidomide, thalidomide, or pomalidomide is contraindicated in pregnant women because lenalidomide, thalidomide, and pomalidomide may cause birth defects and death of the unborn child. Refer to the lenalidomide, thalidomide, or pomalidomide prescribing information on use during pregnancy. 

Interference With Serological Testing 
Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive indirect antiglobulin test (indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab administration. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum. The determination of a patient’s ABO and Rh blood type are not impacted. 

Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX FASPRO. Type and screen patients prior to starting DARZALEX FASPRO. 

Interference With Determination of Complete Response 
Daratumumab is a human immunoglobulin G (IgG) kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and of disease progression in some DARZALEX FASPRO-treated patients with IgG kappa myeloma protein. 

ADVERSE REACTIONS 
In multiple myeloma, the most common adverse reaction (≥20%) with DARZALEX FASPRO monotherapy is upper respiratory tract infection. The most common adverse reactions with combination therapy (≥20% for any combination) include fatigue, nausea, diarrhea, dyspnea, insomnia, headache, pyrexia, cough, muscle spasms, back pain, vomiting, hypertension, upper respiratory tract infection, peripheral sensory neuropathy, constipation, pneumonia, and peripheral edema. 

The most common hematology laboratory abnormalities (≥40%) with DARZALEX FASPRO are decreased leukocytes, decreased lymphocytes, decreased neutrophils, decreased platelets, and decreased hemoglobin. 

Please click here to see the full Prescribing Information.

CARVYKTI® (ciltacabtagene autoleucel) significantly improved progression-free survival and deepened responses versus two standard therapies for patients with functional high-risk multiple myeloma

On June 3, 2024 Johnson & Johnson reported results from a subgroup analysis of the Phase 3 CARTITUDE-4 study. The data show CARVYKTI (ciltacabtagene autoleucel; cilta-cel) significantly improved progression-free survival (PFS) compared to standard therapies of pomalidomide, bortezomib and dexamethasone (PVd) or daratumumab, pomalidomide and dexamethasone (DPd) for patients with lenalidomide-refractory multiple myeloma after one prior line of therapy (LOT), including patients with functional high-risk (FHR) multiple myeloma (Press release, Johnson & Johnson, JUN 3, 2024, View Source [SID1234644038]). FHR was defined as progressive disease within 18 months after receiving autologous stem cell transplant (ASCT) or the start of initial frontline therapy in patients with no ASCT.1 These data were featured as an oral presentation at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Abstract #7504) and will also be shared at the 2024 European Hematology Association (EHA) (Free EHA Whitepaper) Congress (Abstract #P959).1,2

Data from the CARTITUDE-4 study supported the recent U.S. FDA approval of CARVYKTI, the first and only B-cell maturation antigen (BCMA)-targeted therapy approved for the treatment of patients with relapsed/refractory multiple myeloma as early as after first relapse.

A Phase 3 CARTITUDE-4 subgroup analysis included 136 patients (CARVYKTI, n=68; standard therapies, n=68) who received one prior LOT, including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), and were lenalidomide-refractory.1 After a median follow-up of 16 months (range, 0.1-27), median PFS was not reached (NR) (95 percent Confidence Interval [CI]; not estimable [NE]-NE) among patients who received CARVYKTI compared to 17 months (95 percent CI, 11-NE) for the control arm as a second-line treatment (hazard ratio [HR]=0.35 [95 percent CI, 0.2-0.7; P=.0007]).1

In an additional subgroup analysis of 79 patients with FHR multiple myeloma (CARVYKTI, n=40; standard therapies, n=39) median PFS was NR [18-NE] with CARVYKTI versus 12 months (8-NE) with standard therapies (HR=0.27 [95 percent CI, 0.1-0.6; P=.0006]).1 Patients treated with CARVYKTI had deeper overall response rates (88 percent; 80 percent), complete response (CR) or better (68 percent; 39 percent), minimal residual disease (MRD) negativity (65 percent; ten percent), and longer median duration of response (mDOR) (NR [16-NE]; 16 [8-NE]) compared to those treated with standard therapies.1

"Patients with functional high-risk myeloma whose disease progressed during the first 18 months of initial myeloma therapy are known to have poor prognosis, yet they have not been well represented in any clinical trial," said Luciano J. Costa, M.D., Ph.D., Professor of Medicine and Director of the Multiple Myeloma Program, University of Alabama at Birmingham, and principal study investigator.* "This subset analysis of CARTITUDE-4 provides strong evidence that these patients greatly benefit from cilta-cel and will help healthcare professionals better understand the potential of this therapy."

The proportion of patients with grade 3 or higher treatment-emergent adverse events (TEAEs) was comparable among patients who received CARVYKTI versus standard therapies as second-line treatment (96 percent, 96 percent) and those with one prior LOT and FHR multiple myeloma (100 percent, 97 percent), respectively.1 Overall, 11 patients in the CARVYKTI one prior LOT subgroup and 11 patients in the standard therapies one prior LOT subgroup died.1 Of patients with FHR multiple myeloma, seven patients from the CARVYKTI arm and nine who received standard therapies died.1 Of the seven deaths in patients with one prior LOT and FHR multiple myeloma, two did not receive CARVYKTI as study treatment and three received CARVYKTI as subsequent therapy.1

"Many patients with FHR multiple myeloma from the CARTITUDE-4 subgroup analysis experienced deep and durable responses following the single-infusion of CARVYKTI, further supporting the potential to treat a broader patient population," said Jordan Schecter, M.D., Vice President, Disease Area Leader, Multiple Myeloma, at Johnson & Johnson Innovative Medicine. "At Johnson & Johnson, we aspire to eliminate cancer and remain steadfast in our commitment to realizing the full potential of CARVYKTI to improve outcomes for patients."

CARTITUDE-2: Cilta-cel results in patients with suboptimal response to frontline autologous stem cell transplant ± lenalidomide maintenance (Abstract #7505)

Results from Cohort D of the CARTITUDE-2 study demonstrated deep and durable responses following a single infusion of cilta-cel with or without lenalidomide maintenance.3 This cohort evaluated patients who had a suboptimal response after ASCT frontline therapy.3 These data were presented as an oral presentation at the 2024 ASCO (Free ASCO Whitepaper) Annual Meeting (Abstract #7505).3

At a median follow-up of 22 months, patients treated with cilta-cel (n=17) demonstrated a 94 percent overall response rate, with 94 percent also achieving a CR or better.3 Of the 15 MRD-evaluable patients, 80 percent achieved MRD negativity at 10–5.3 The mDOR was NR.3 Eighteen-month PFS and OS rates were 94 percent each.3 Patients in Cohort D had robust CAR-T expansion, but numerically shorter persistence compared to patients with lenalidomide-refractory multiple myeloma and one to three prior LOT (CARTITUDE-4) and heavily pretreated patients (CARTITUDE-1).3

All patients had grade 3 or 4 TEAEs including any grade neutropenia (94 percent), lymphopenia (65 percent), thrombocytopenia (47 percent), leukopenia (41 percent), infections (71 percent), or cytokine release syndrome (CRS) (82 percent; median onset of eight days).3 One patient had a secondary malignancy of grade 3 myelodysplastic syndromes (MDS). No cases of movement and neurocognitive treatment-emergent (MNT) AEs/parkinsonism were observed.3

About CARTITUDE-4

CARTITUDE-4 (NCT04181827) is the first international, randomized, open-label Phase 3 study evaluating the efficacy and safety of cilta-cel versus pomalidomide, bortezomib and dexamethasone (PVd) or daratumumab, pomalidomide and dexamethasone (DPd) in adult patients with relapsed and lenalidomide-refractory multiple myeloma who received one to three prior lines of therapy.4 Results were presented at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting and published in The New England Journal of Medicine.

About CARTITUDE-2

CARTITUDE-2 (NCT04133636) is an ongoing, multi-cohort Phase 2 study evaluating the safety and efficacy of cilta-cel in patients with multiple myeloma.5 Cohort D evaluates cilta-cel with lenalidomide maintenance in patients who achieved less than complete response (CR) after autologous stem cell transplant (ASCT) frontline therapy.

About CARVYKTI (ciltacabtagene autoleucel; cilta-cel)

CARVYKTI (cilta-cel) received U.S. Food and Drug Administration approval in February 2022 for the treatment of adults with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. In April 2024, CARVYKTI was approved in the U.S. for the second-line treatment of adult patients with relapsed or refractory myeloma who have received at least one prior line of therapy including a proteasome inhibitor, an immunomodulatory agent, and who are refractory to lenalidomide, following a unanimous (11 to 0) FDA Oncologic Drugs Advisory Committee (ODAC) recommendation in support of this new indication. In April 2024, the European Medicines Agency (EMA) approved a Type II variation for CARVYKTI for the treatment of adults with relapsed and refractory multiple myeloma who have received at least one prior therapy, including an immunomodulatory agent and a proteasome inhibitor, have demonstrated disease progression on the last therapy, and are refractory to lenalidomide. In September 2022, Japan’s Ministry of Health, Labour and Welfare (MHLW) approved CARVYKTI for the treatment of adults with relapsed or refractory multiple myeloma in patients that have no history of CAR-positive T cell infusion therapy targeting BCMA and who have received three or more lines of therapies, including an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 monoclonal antibody, and in whom multiple myeloma has not responded to or has relapsed following the most recent therapy.

CARVYKTI is a BCMA-directed, genetically modified autologous T-cell immunotherapy, which involves reprogramming a patient’s own T-cells with a transgene encoding chimeric antigen receptor (CAR) that directs the CAR-positive T cells to eliminate cells that express BCMA. BCMA is primarily expressed on the surface of malignant multiple myeloma B-lineage cells, as well as late-stage B cells and plasma cells. The CARVYKTI CAR protein features two BCMA-targeting single domains designed to confer high avidity against human BCMA. Upon binding to BCMA-expressing cells, the CAR promotes T-cell activation, expansion, and elimination of target cells.

In December 2017, Janssen Biotech, Inc., a Johnson & Johnson company, entered into an exclusive worldwide license and collaboration agreement with Legend Biotech USA, Inc. to develop and commercialize CARVYKTI.

For more information, visit www.CARVYKTI.com.

About Multiple Myeloma

Multiple myeloma is an incurable blood cancer that affects a type of white blood cell called plasma cells, which are found in the bone marrow.6 In multiple myeloma, these plasma cells proliferate and spread rapidly and replace normal cells in the bone marrow with tumors.7 Multiple myeloma is the third most common blood cancer worldwide and remains an incurable disease.8 In 2024, it was estimated that more than 35,000 people will be diagnosed with multiple myeloma in the U.S. and more than 12,000 people would die from the disease.9 People living with multiple myeloma have a 5-year survival rate of 59.8 percent.10 While some people diagnosed with multiple myeloma initially have no symptoms, most patients are diagnosed due to symptoms that can include bone fracture or pain, low red blood cell counts, tiredness, high calcium levels and kidney problems or infections.11,12

CARVYKTI IMPORTANT SAFETY INFORMATION

INDICATIONS AND USAGE

CARVYKTI (ciltacabtagene autoleucel) is a B-cell maturation antigen (BCMA)-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory multiple myeloma, who have received at least 1 prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent, and are refractory to lenalidomide.

IMPORTANT SAFETY INFORMATION

WARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGIC TOXICITIES, HLH/MAS, PROLONGED and RECURRENT
CYTOPENIA, and SECONDARY HEMATOLOGICAL MALIGNANCIES

Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients following treatment
with CARVYKTI. Do not administer CARVYKTI to patients with active infection or inflammatory disorders. Treat severe or
life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), which may be fatal or life-threatening, occurred
following treatment with CARVYKTI, including before CRS onset, concurrently with CRS, after CRS resolution, or in the
absence of CRS. Monitor for neurologic events after treatment with CARVYKTI. Provide supportive care and/or
corticosteroids as needed.

Parkinsonism and Guillain-Barré syndrome (GBS) and their associated complications resulting in fatal or life-threatening
reactions have occurred following treatment with CARVYKTI.

Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS), including fatal and life-threatening
reactions, occurred in patients following treatment with CARVYKTI. HLH/MAS can occur with CRS or neurologic toxicities.

Prolonged and/or recurrent cytopenias with bleeding and infection and requirement for stem cell transplantation for
hematopoietic recovery occurred following treatment with CARVYKTI.

Secondary hematological malignancies, including myelodysplastic syndrome and acute myeloid leukemia, have occurred
in patients following treatment with CARVYKTI. T-cell malignancies have occurred following treatment of hematologic
malignancies with BCMA- and CD19-directed genetically modified autologous T-cell immunotherapies, including
CARVYKTI.

CARVYKTI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called
the CARVYKTI REMS Program.

WARNINGS AND PRECAUTIONS

Increased early mortality – In CARTITUDE-4, a (1:1) randomized controlled trial, there was a numerically higher percentage of early deaths in patients randomized to the CARVYKTI treatment arm compared to the control arm. Among patients with deaths occurring within the first 10 months from randomization, a greater proportion (29/208; 14%) occurred in the CARVYKTI arm compared to (25/211; 12%) in the control arm. Of the 29 deaths that occurred in the CARVYKTI arm within the first 10 months of randomization, 10 deaths occurred prior to CARVYKTI infusion, and 19 deaths occurred after CARVYKTI infusion. Of the 10 deaths that occurred prior to CARVYKTI infusion, all occurred due to disease progression, and none occurred due to adverse events. Of the 19 deaths that occurred after CARVYKTI infusion, 3 occurred due to disease progression, and 16 occurred due to adverse events. The most common adverse events were due to infection (n=12).

Cytokine release syndrome (CRS), including fatal or life-threatening reactions, occurred following treatment with CARVYKTI. Among patients receiving CARVYKTI for RRMM in the CARTITUDE-1 & 4 studies (N=285), CRS occurred in 84% (238/285), including ≥Grade 3 CRS (ASCT 2019) in 4% (11/285) of patients. Median time to onset of CRS, any grade, was 7 days (range: 1 to 23 days). CRS resolved in 82% with a median duration of 4 days (range: 1 to 97 days). The most common manifestations of CRS in all patients combined (≥10%) included fever (84%), hypotension (29%) and aspartate aminotransferase increased (11%). Serious events that may be associated with CRS include pyrexia, hemophagocytic lymphohistiocytosis, respiratory failure, disseminated intravascular coagulation, capillary leak syndrome, and supraventricular and ventricular tachycardia. CRS occurred in 78% of patients in CARTITUDE-4 (3% Grade 3 to 4) and in 95% of patients in CARTITUDE-1 (4% Grade 3 to 4).

Identify CRS based on clinical presentation. Evaluate for and treat other causes of fever, hypoxia, and hypotension. CRS has been reported to be associated with findings of HLH/MAS, and the physiology of the syndromes may overlap. HLH/MAS is a potentially life-threatening condition. In patients with progressive symptoms of CRS or refractory CRS despite treatment, evaluate for evidence of HLH/MAS.

Ensure that a minimum of two doses of tocilizumab are available prior to infusion of CARVYKTI.

Of the 285 patients who received CARVYKTI in clinical trials, 53% (150/285) patients received tocilizumab; 35% (100/285) received a single dose, while 18% (50/285) received more than 1 dose of tocilizumab. Overall, 14% (39/285) of patients received at least one dose of corticosteroids for treatment of CRS.

Monitor patients at least daily for 10 days following CARVYKTI infusion at a REMS-certified healthcare facility for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for at least 4 weeks after infusion. At the first sign of CRS, immediately institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids.

Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time.

Neurologic toxicities, which may be severe, life-threatening, or fatal, occurred following treatment with CARVYKTI. Neurologic toxicities included ICANS, neurologic toxicity with signs and symptoms of parkinsonism, GBS, immune mediated myelitis, peripheral neuropathies, and cranial nerve palsies. Counsel patients on the signs and symptoms of these neurologic toxicities, and on the delayed nature of onset of some of these toxicities. Instruct patients to seek immediate medical attention for further assessment and management if signs or symptoms of any of these neurologic toxicities occur at any time.

Among patients receiving CARVYKTI in the CARTITUDE-1 & 4 studies for RRMM, one or more neurologic toxicities occurred in 24% (69/285), including ≥Grade 3 cases in 7% (19/285) of patients. Median time to onset was 10 days (range: 1 to 101) with 63/69 (91%) of cases developing by 30 days. Neurologic toxicities resolved in 72% (50/69) of patients with a median duration to resolution of 23 days (range: 1 to 544). Of patients developing neurotoxicity, 96% (66/69) also developed CRS. Subtypes of neurologic toxicities included ICANS in 13%, peripheral neuropathy in 7%, cranial nerve palsy in 7%, parkinsonism in 3%, and immune mediated myelitis in 0.4% of the patients.

Immune Effector Cell-associated Neurotoxicity Syndrome (ICANS): Patients receiving CARVYKTI may experience fatal or life-threatening ICANS following treatment with CARVYKTI, including before CRS onset, concurrently with CRS, after CRS resolution, or in the absence of CRS.

Among patients receiving CARVYKTI in the CARTITUDE-1 & 4 studies, ICANS occurred in 13% (36/285), including Grade ≥3 in 2% (6/285) of the patients. Median time to onset of ICANS was 8 days (range: 1 to 28 days). ICANS resolved in 30 of 36 (83%) of patients with a median time to resolution of 3 days (range: 1 to 143 days). Median duration of ICANS was 6 days (range: 1 to 1229 days) in all patients including those with ongoing neurologic events at the time of death or data cut off. Of patients with ICANS 97% (35/36) had CRS. The onset of ICANS occurred during CRS in 69% of patients, before and after the onset of CRS in 14% of patients respectively.

Immune Effector Cell-associated Neurotoxicity Syndrome occurred in 7% of patients in CARTITUDE-4 (0.5% Grade 3) and in 23% of patients in CARTITUDE-1 (3% Grade 3). The most frequent ≥2% manifestations of ICANS included encephalopathy (12%), aphasia (4%), headache (3%), motor dysfunction (3%), ataxia (2%) and sleep disorder (2%).

Monitor patients at least daily for 10 days following CARVYKTI infusion at the REMS-certified healthcare facility for signs and symptoms of ICANS. Rule out other causes of ICANS symptoms. Monitor patients for signs or symptoms of ICANS for at least 4 weeks after infusion and treat promptly. Neurologic toxicity should be managed with supportive care and/or corticosteroids as needed.

Parkinsonism: Neurologic toxicity with parkinsonism has been reported in clinical trials of CARVYKTI. Among patients receiving CARVYKTI in the CARTITUDE-1 & 4 studies, parkinsonism occurred in 3% (8/285), including Grade ≥ 3 in 2% (5/285) of the patients. Median time to onset of parkinsonism was 56 days (range: 14 to 914 days). Parkinsonism resolved in 1 of 8 (13%) of patients with a median time to resolution of 523 days. Median duration of parkinsonism was 243.5 days (range: 62 to 720 days) in all patients including those with ongoing neurologic events at the time of death or data cut off. The onset of parkinsonism occurred after CRS for all patients and after ICANS for 6 patients.

Parkinsonism occurred in 1% of patients in CARTITUDE-4 (no Grade 3 to 4) and in 6% of patients in CARTITUDE-1 (4% Grade 3 to 4).

Manifestations of parkinsonism included movement disorders, cognitive impairment, and personality changes. Monitor patients for signs and symptoms of parkinsonism that may be delayed in onset and managed with supportive care measures. There is limited efficacy information with medications used for the treatment of Parkinson’s disease for the improvement or resolution of parkinsonism symptoms following CARVYKTI treatment.

Guillain-Barré syndrome: A fatal outcome following GBS occurred following treatment with CARVYKTI despite treatment with intravenous immunoglobulins. Symptoms reported include those consistent with Miller-Fisher variant of GBS, encephalopathy, motor weakness, speech disturbances, and polyradiculoneuritis.

Monitor for GBS. Evaluate patients presenting with peripheral neuropathy for GBS. Consider treatment of GBS with supportive care measures and in conjunction with immunoglobulins and plasma exchange, depending on severity of GBS.

Immune mediated myelitis: Grade 3 myelitis occurred 25 days following treatment with CARVYKTI in CARTITUDE-4 in a patient who received CARVYKTI as subsequent therapy. Symptoms reported included hypoesthesia of the lower extremities and the lower abdomen with impaired sphincter control. Symptoms improved with the use of corticosteroids and intravenous immune globulin. Myelitis was ongoing at the time of death from other cause.

Peripheral neuropathy occurred following treatment with CARVYKTI. Among patients receiving CARVYKTI in the CARTITUDE-1 & 4 studies, peripheral neuropathy occurred in 7% (21/285), including Grade ≥3 in 1% (3/285) of the patients. Median time to onset of peripheral neuropathy was 57 days (range: 1 to 914 days). Peripheral neuropathy resolved in 11 of 21 (52%) of patients with a median time to resolution of 58 days (range: 1 to 215 days). Median duration of peripheral neuropathy was 149.5 days (range: 1 to 692 days) in all patients including those with ongoing neurologic events at the time of death or data cut off.

Peripheral neuropathies occurred in 7% of patients in CARTITUDE-4 (0.5% Grade 3 to 4) and in 7% of patients in CARTITUDE-1 (2% Grade 3 to 4). Monitor patients for signs and symptoms of peripheral neuropathies. Patients who experience peripheral neuropathy may also experience cranial nerve palsies or GBS.

Cranial nerve palsies occurred following treatment with CARVYKTI. Among patients receiving CARVYKTI in the CARTITUDE-1 & 4 studies, cranial nerve palsies occurred in 7% (19/285), including Grade ≥3 in 1% (1/285) of the patients. Median time to onset of cranial nerve palsies was 21 days (range: 17 to 101 days). Cranial nerve palsies resolved in 17 of 19 (89%) of patients with a median time to resolution of 66 days (range: 1 to 209 days). Median duration of cranial nerve palsies was 70 days (range: 1 to 262 days) in all patients including those with ongoing neurologic events at the time of death or data cut off. Cranial nerve palsies occurred in 9% of patients in CARTITUDE-4 (1% Grade 3 to 4) and in 3% of patients in CARTITUDE-1 (1% Grade 3 to 4).

The most frequent cranial nerve affected was the 7th cranial nerve. Additionally, cranial nerves III, V, and VI have been reported to be affected.

Monitor patients for signs and symptoms of cranial nerve palsies. Consider management with systemic corticosteroids, depending on the severity and progression of signs and symptoms.

Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS): Among patients receiving CARVYKTI in the CARTITUDE-1 & 4 studies, HLH/MAS occurred in 1% (3/285) of patients. All events of HLH/MAS had onset within 99 days of receiving CARVYKTI, with a median onset of 10 days (range: 8 to 99 days) and all occurred in the setting of ongoing or worsening CRS. The manifestations of HLH/MAS included hyperferritinemia, hypotension, hypoxia with diffuse alveolar damage, coagulopathy and hemorrhage, cytopenia and multi-organ dysfunction, including renal dysfunction and respiratory failure.

Patients who develop HLH/MAS have an increased risk of severe bleeding. Monitor hematologic parameters in patients with HLH/MAS and transfuse per institutional guidelines. Fatal cases of HLH/MAS occurred following treatment with CARVYKTI.

HLH is a life-threatening condition with a high mortality rate if not recognized and treated early. Treatment of HLH/MAS should be administered per institutional standards.

CARVYKTI REMS: Because of the risk of CRS and neurologic toxicities, CARVYKTI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the CARVYKTI REMS.

Further information is available at View Source or 1-844-672-0067.

Prolonged and Recurrent Cytopenias: Patients may exhibit prolonged and recurrent cytopenias following lymphodepleting chemotherapy and CARVYKTI infusion.

Among patients receiving CARVYKTI in the CARTITUDE-1 & 4 studies, Grade 3 or higher cytopenias not resolved by day 30 following CARVYKTI infusion occurred in 62% (176/285) of the patients and included thrombocytopenia 33% (94/285), neutropenia 27% (76/285), lymphopenia 24% (67/285) and anemia 2% (6/285). After Day 60 following CARVYKTI infusion 22%, 20%, 5%, and 6% of patients had a recurrence of Grade 3 or 4 lymphopenia, neutropenia, thrombocytopenia, and anemia respectively, after initial recovery of their Grade 3 or 4 cytopenia. Seventy-seven percent (219/285) of patients had one, two or three or more recurrences of Grade 3 or 4 cytopenias after initial recovery of Grade 3 or 4 cytopenia. Sixteen and 25 patients had Grade 3 or 4 neutropenia and thrombocytopenia, respectively, at the time of death.

Monitor blood counts prior to and after CARVYKTI infusion. Manage cytopenias with growth factors and blood product transfusion support according to local institutional guidelines.

Infections: CARVYKTI should not be administered to patients with active infection or inflammatory disorders. Severe, life-threatening, or fatal infections, occurred in patients after CARVYKTI infusion.

Among patients receiving CARVYKTI in the CARTITUDE-1 & 4 studies, infections occurred in 57% (163/285), including ≥Grade 3 in 24% (69/285) of patients. Grade 3 or 4 infections with an unspecified pathogen occurred in 12%, viral infections in 6%, bacterial infections in 5%, and fungal infections in 1% of patients. Overall, 5% (13/285) of patients had Grade 5 infections, 2.5% of which were due to COVID-19. Patients treated with CARVYKTI had an increased rate of fatal COVID-19 infections compared to the standard therapy arm.

Monitor patients for signs and symptoms of infection before and after CARVYKTI infusion and treat patients appropriately. Administer prophylactic, pre-emptive and/or therapeutic antimicrobials according to the standard institutional guidelines. Febrile neutropenia was observed in 5% of patients after CARVYKTI infusion and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids and other supportive care, as medically indicated. Counsel patients on the importance of prevention measures. Follow institutional guidelines for the vaccination and management of immunocompromised patients with COVID-19.

Viral Reactivation: Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients with hypogammaglobulinemia. Perform screening for Cytomegalovirus (CMV), HBV, hepatitis C virus (HCV), and human immunodeficiency virus (HIV) or any other infectious agents if clinically indicated in accordance with clinical guidelines before collection of cells for manufacturing. Consider antiviral therapy to prevent viral reactivation per local institutional guidelines/clinical practice.

Hypogammaglobulinemia: can occur in patients receiving treatment with CARVYKTI. Among patients receiving CARVYKTI in the CARTITUDE-1 & 4 studies, hypogammaglobulinemia adverse event was reported in 36% (102/285) of patients; laboratory IgG levels fell below 500mg/dl after infusion in 93% (265/285) of patients. Hypogammaglobulinemia either as an adverse reaction or laboratory IgG level below 500mg/dl, after infusion occurred in 94% (267/285) of patients treated. Fifty six percent (161/285) of patients received intravenous immunoglobulin (IVIG) post CARVYKTI for either an adverse reaction or prophylaxis.

Monitor immunoglobulin levels after treatment with CARVYKTI and administer IVIG for IgG <400 mg/dL. Manage per local institutional guidelines, including infection precautions and antibiotic or antiviral prophylaxis.

Use of Live Vaccines: The safety of immunization with live viral vaccines during or following CARVYKTI treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during CARVYKTI treatment, and until immune recovery following treatment with CARVYKTI.

Hypersensitivity Reactions occurred following treatment with CARVYKTI. Among patients receiving CARVYKTI in the CARTITUDE-1 & 4 studies, hypersensitivity reactions occurred in 5% (13/285), all of which were ≤Grade 2. Manifestations of hypersensitivity reactions included flushing, chest discomfort, tachycardia, wheezing, tremor, burning sensation, non-cardiac chest pain, and pyrexia.

Serious hypersensitivity reactions, including anaphylaxis, may be due to the dimethyl sulfoxide (DMSO) in CARVYKTI. Patients should be carefully monitored for 2 hours after infusion for signs and symptoms of severe reaction. Treat promptly and manage patients appropriately according to the severity of the hypersensitivity reaction.

Secondary Malignancies: Patients treated with CARVYKTI may develop secondary malignancies. Among patients receiving CARVYKTI in the CARTITUDE-1 & 4 studies, myeloid neoplasms occurred in 5% (13/285) of patients (9 cases of myelodysplastic syndrome, 3 cases of acute myeloid leukemia, and 1 case of myelodysplastic syndrome followed by acute myeloid leukemia). The median time to onset of myeloid neoplasms was 447 days (range: 56 to 870 days) after treatment with CARVYKTI. Ten of these 13 patients died following the development of myeloid neoplasms; 2 of the 13 cases of myeloid neoplasm occurred after initiation of subsequent antimyeloma therapy. Cases of myelodysplastic syndrome and acute myeloid leukemia have also been reported in the post marketing setting. T-cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T-cell immunotherapies, including CARVYKTI. Mature T-cell malignancies, including CAR-positive tumors, may present as soon as weeks following infusions, and may include fatal outcomes.

Monitor life-long for secondary malignancies. In the event that a secondary malignancy occurs, contact Janssen Biotech, Inc. at 1-800-526-7736 for reporting and to obtain instructions on collection of patient samples.

Effects on Ability to Drive and Use Machines: Due to the potential for neurologic events, including altered mental status, seizures, neurocognitive decline or neuropathy, patients receiving CARVYKTI are at risk for altered or decreased consciousness or coordination in the 8 weeks following CARVYKTI infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery during this initial period, and in the event of new onset of any neurologic toxicities.

ADVERSE REACTIONS

The most common nonlaboratory adverse reactions (incidence greater than 20%) are pyrexia, cytokine release syndrome, hypogammaglobulinemia, hypotension, musculoskeletal pain, fatigue, infections-pathogen unspecified, cough, chills, diarrhea, nausea, encephalopathy, decreased appetite, upper respiratory tract infection, headache, tachycardia, dizziness, dyspnea, edema, viral infections, coagulopathy, constipation, and vomiting. The most common Grade 3 or 4 laboratory adverse reactions (incidence greater than or equal to 50%) include lymphopenia, neutropenia, white blood cell decreased, thrombocytopenia, and anemia.

Please read full Prescribing Information, including Boxed Warning, for CARVYKTI.

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