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

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"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
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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.