On June 4, 2022 TGen reported that PHOENIX Tumor DNA circulating in the bloodstream can help clinicians decide whether chemotherapy is right for their patients who have undergone surgery for stage II colon cancer, according to a breakthrough study published online in The New England Journal of Medicine and presented today at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Abstract LBA100) (Press release, TGen, JUN 4, 2022, View Source [SID1234615572]). An international team that included investigators from the Translational Genomics Research Institute (TGen), part of City of Hope, conducted the study to lend clarity to the role of adjuvant chemotherapy in this setting.

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Previous studies suggested that the presence of circulating tumor DNA (ctDNA), the small fragments of a cancer’s genetic material shed into the blood, predicted a recurrence of the cancer after surgery, while the absence of ctDNA predicted a low recurrence risk. The real-world study is thought to be the first to use ctDNA to guide follow-up chemotherapy decisions in stage II colon cancer patients after surgery to determine if certain patients can be spared from this form of treatment based.

A total of 455 patients in Australian centers were assigned to either ctDNA-guided care (n=302) or standard care (n=153) following their surgeries. Standard care follows traditional guidelines based on clinicopathological features that are associated with higher cancer risk. If patients in the study’s guided group still had ctDNA present in their blood samples four to seven weeks after surgery, they received one of two kinds of chemotherapy. If tumor DNA was not found, then those patients in the ctDNA-guided group were not treated with chemotherapy.

Of those receiving ctDNA-guided care, physicians were able to not only inform treatment, but actually reduce the number of patients who were treated with chemotherapy without compromising their recurrence-free survival.

"The study’s findings suggest a way to identify which patients can avoid unnecessary chemotherapy, with its potentially serious side effects and its expense. And for those who have undergone chemotherapy or know someone who has, and know what it means, I think this is really great news," said Dr. Cristian Tomasetti, the newly appointed Director of the Center for Cancer Prevention and Early Detection at City of Hope and TGen.

ctDNA can be a useful addition to traditional tissue-based features – like the size of the tumor – to determine risk of recurrence, since tumors themselves are so different from one another.

"For instance, sometimes the potential of a large tumor to be dangerous and invade tissues can actually be lower than a smaller cancer with the right combination of mutations," Dr. Kamel Lahouel, a first author on the paper explained.

In the follow-up 37 months later, patients under standard care were almost twice as likely as patients in the ctDNA-guided group to receive chemotherapy –27.9% compared to 15.3%. Despite the difference in treatment, two-year recurrence-free survival rates were not worse in the guided group (93.5%) compared to the standard care group (92.4%).

"The goal at the beginning of the study was to prove that ctDNA-guided therapy would not lead to worse outcomes than standard care," said Lahouel, "and we ended up with an estimate that is even better than the standard of care guidance. I think that is what is really impressive."

Among the patients in the guided group, those who had the circulating DNA and were treated with chemotherapy had an 86.4% three-year recurrence-free survival rate, compared to 92.5% for those who did not have ctDNA and did not receive chemotherapy.

"We wanted to come up with ways to tell whether therapy was needed, and this technology will also help in the future to determine whether a particular therapy isn’t working, or when we should switch to another therapy, or even when it is OK to stop chemotherapy in a patient. Based on further study we can think about further personalizing treatment with these technologies," said Tomasetti.

Finally, while these findings confirm that certain patients are not likely to need chemotherapy, they also confirm the importance of chemotherapy for those with detectable ctDNA after surgery, Lahouel and Tomasetti noted. In previous studies, scientists found an 80% risk of recurrence in stage II colon cancer patients with detectable ctDNA who did not receive chemotherapy.

This groundbreaking study was led by Dr. Bert Vogelstein and researchers at the Johns Hopkins Kimmel Cancer Center, Dr. Jeanne Tie and researchers at the Peter MacCallum Cancer Centre of the University of Melbourne, Australia, and Drs. Kamel Lahouel, and Cristian Tomasetti, now both at the Translational Genomics Research Institute (TGen) and City of Hope.

Drs. Tomasetti and Lahouel focus on mathematical prediction and advancements in technologies like ctDNA detection, as part of their work with the TGen and City of Hope alliance to transform the diagnosis, treatment and prevention of cancer and other life-threatening diseases.

These exciting results were achieved thanks to new technologies able to find tumor DNA in the blood. The same technologies are also very promising for detecting cancer much earlier.

"All drugs work better in patients with cancers that are detected relatively early, before they have given rise to large metastatic masses. However, new drugs are usually first tested in patients whose cancers are very advanced," said Bert Vogelstein, M.D., Clayton Professor of Oncology, co-director of the Ludwig Center at Johns Hopkins and a Howard Hughes Medical Institute investigator. "We hope that ctDNA analysis will enable testing of new drugs in patients with early-stage cancers and micrometastases, when the new drugs are most likely to save lives."

Research funding support came from The Australian National Health and Medical Research Council (NHMRC), the Marcus Foundation, the Virginia and D.K. Ludwig Fund for Cancer Research, Lustgarten Foundation, The Conrad R. Hilton Foundation, The Sol Goldman Charitable Trust, John Templeton Foundation, National Institutes of Health (CA62924, CA009071, GM136577 and CA06973) and the Eastern Health Research Foundation (Linda Williams Memorial Grant).

On June 13, 2022 Pfizer Inc. (NYSE:PFE) reported overall survival (OS) results from the Phase 3 PALOMA-2 trial, which evaluated IBRANCE (palbociclib) in combination with letrozole compared to placebo plus letrozole for the first-line treatment of postmenopausal women with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC) (Press release, Pfizer, JUN 4, 2022, View Source;Metastatic-Breast-Cancer [SID1234615571]). With a median follow-up of 90 months, patients receiving IBRANCE in combination with letrozole had numerically longer OS compared to placebo plus letrozole (median (95% CI) 53.9 months (49.8–60.8) vs median 51.2 months (43.7–58.9)); the results were not statistically significant (Hazard Ratio (HR)=0.956 [95% CI, 0.777–1.177]). The PALOMA-2 trial was designed for a primary endpoint of progression-free survival (PFS) with OS as one of the secondary endpoints. The results will be presented today as an oral presentation at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2022 Annual Meeting (LBA 1003).

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"Forward-Looking Information and Factors That May Affect Future Results"

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"IBRANCE continues to provide substantial benefit as a first-line treatment for adults with HR+, HER2- mBC based on strong progression-free survival data, which formed the basis of its worldwide approvals," said Chris Boshoff, M.D., Ph.D., Chief Development Officer, Oncology, Pfizer Global Product Development. "Interpretation of OS in PALOMA-2 is limited by the large and disproportionate censoring of patients with missing survival data between treatment arms. We remain confident in the compelling benefits that IBRANCE plus endocrine therapy offers to this patient population, which is underscored by data from PALOMA-2 showing delayed time to chemotherapy, maintenance of quality of life and a consistent safety profile. Pfizer continues to invest in expanding the treatment options for people living with metastatic breast cancer."

"IBRANCE transformed the treatment landscape for patients with HR+, HER2- MBC when it was approved in 2015, representing the first new treatment in this patient population in over a decade," said Richard Finn, M.D., Professor of Medicine at the UCLA David Geffen School of Medicine and Jonsson Comprehensive Cancer Center. "PALOMA-2 enrolled a diverse patient population including patients whose disease was first diagnosed in the metastatic stage as well as those with Disease Free Interval (DFI) less than 12 months from adjuvant treatment and those with greater than 12 months following adjuvant treatment. The median survival of over 50 months in this population represents a significant improvement in the natural history of HR+ breast cancer."

PALOMA-2 met its primary endpoint of PFS in 2016 and was published in The New England Journal of Medicine in November 2016. The results demonstrated IBRANCE plus letrozole resulted in an improved median PFS of 24.8 months when compared to 14.5 months with placebo plus letrozole (HR=0.580). The PALOMA-2 trial showed that in addition to substantially delaying progressive disease, IBRANCE as first-line treatment, in combination with letrozole, delayed time to chemotherapy (38.1 months vs 29.8 months; HR, 0.73), while maintaining quality of life with no new identified safety issues.

The OS analysis being presented at ASCO (Free ASCO Whitepaper) included a large proportion of patients with missing survival data (i.e. patients who withdrew consent or were lost to follow-up) and were censored (assumed to be alive) at the time of the analysis: 13% in the treatment arm versus 21% in the control arm. Also of note, 10% of IBRANCE plus letrozole and 2% of placebo plus letrozole patients were still on study treatment at the time of the final analysis. The most common adverse reactions in PALOMA-2 included neutropenia, leukopenia, infections, fatigue and nausea.

IBRANCE continues to be a leader in the CDK4/6 inhibitor class, prescribed to over 450,000 patients across more than 100 countries, and seven out of 10 patients in the U.S. who are prescribed a CDK4/6 inhibitor receiving an IBRANCE prescription.i

About the PALOMA-2 Study

PALOMA-2 is a randomized (2:1), multicenter, multinational, double-blind Phase 3 study designed to assess the efficacy (defined by PFS) and safety of IBRANCE (125 mg orally once daily for three out of four weeks in repeated cycles) in combination with letrozole (2.5 mg once daily continuously) versus letrozole plus placebo as a first-line treatment for postmenopausal women with ER+, HER2- metastatic breast cancer. PALOMA-2 evaluated a total of 666 women from 186 global sites in 17 countries. Patients were to be stratified by site of disease (visceral, non-visceral), by disease-free interval since completion of prior (neo)adjuvant therapy (de novo metastatic, ≤12 months, >12 months), and by the nature of prior (neo)adjuvant anti-cancer treatment received (prior hormonal therapy, no prior hormonal therapy). The primary endpoint was progression-free survival, as assessed by the investigators; secondary endpoints were overall survival, objective response, clinical benefit response, patient-reported outcomes, pharmacokinetic effects, and safety.

About the IBRANCE Real-World Evidence Program

The IBRANCE Real-World Evidence (RWE) program is generating data from multiple studies involving more than 8,000 patients around the world. These studies include diverse patient populations treated in everyday clinical practice and are collecting data related to clinical outcomes, translational data and quality of life endpoints, which complement the data generated from the PALOMA randomized clinical trials. Most recently, Pfizer reported results from a retrospective comparative effectiveness study of 2,888 men and postmenopausal women with HR+, HER2- mBC evaluating IBRANCE in the real-world, first-line setting in combination with aromatase inhibitors (AI) compared to AI alone. Pfizer will continue to share new data from these studies with the scientific community as results become available.

About IBRANCE (palbociclib) 125 mg tablets and capsules

IBRANCE is an oral inhibitor of CDKs 4 and 6,ii which are key regulators of the cell cycle that trigger cellular progression.iii,iv In the U.S., IBRANCE is indicated for the treatment of adult patients with HR+, HER2- advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine-based therapy in postmenopausal women or in men; or with fulvestrant in patients with disease progression following endocrine therapy.

The full U.S. Prescribing Information for the IBRANCE tablets and the IBRANCE capsules can be found here and here.

IMPORTANT IBRANCE (palbociclib) SAFETY INFORMATION FROM THE U.S. PRESCRIBING INFORMATION

Neutropenia was the most frequently reported adverse reaction in PALOMA-2 (80%) and PALOMA-3 (83%). In PALOMA-2, Grade 3 (56%) or 4 (10%) decreased neutrophil counts were reported in patients receiving IBRANCE plus letrozole. In PALOMA-3, Grade 3 (55%) or Grade 4 (11%) decreased neutrophil counts were reported in patients receiving IBRANCE plus fulvestrant. Febrile neutropenia has been reported in 1.8% of patients exposed to IBRANCE across PALOMA-2 and PALOMA-3. One death due to neutropenic sepsis was observed in PALOMA-3. Inform patients to promptly report any fever.

Monitor complete blood count prior to starting IBRANCE, at the beginning of each cycle, on Day 15 of first 2 cycles and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia.

Severe, life-threatening, or fatal interstitial lung disease (ILD) and/or pneumonitis can occur in patients treated with CDK4/6 inhibitors, including IBRANCE when taken in combination with endocrine therapy. Across clinical trials (PALOMA-1, PALOMA-2, PALOMA-3), 1.0% of IBRANCE-treated patients had ILD/pneumonitis of any grade, 0.1% had Grade 3 or 4, and no fatal cases were reported. Additional cases of ILD/pneumonitis have been observed in the post-marketing setting, with fatalities reported.

Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis (e.g. hypoxia, cough, dyspnea). In patients who have new or worsening respiratory symptoms and are suspected to have developed pneumonitis, interrupt IBRANCE immediately and evaluate the patient. Permanently discontinue IBRANCE in patients with severe ILD or pneumonitis.

Based on the mechanism of action, IBRANCE can cause fetal harm. Advise females of reproductive potential to use effective contraception during IBRANCE treatment and for at least 3 weeks after the last dose. IBRANCE may impair fertility in males and has the potential to cause genotoxicity. Advise male patients to consider sperm preservation before taking IBRANCE. Advise male patients with female partners of reproductive potential to use effective contraception during IBRANCE treatment and for 3 months after the last dose. Advise females to inform their healthcare provider of a known or suspected pregnancy. Advise women not to breastfeed during IBRANCE treatment and for 3 weeks after the last dose because of the potential for serious adverse reactions in nursing infants.

The most common adverse reactions (≥10%) of any grade reported in PALOMA-2 for IBRANCE plus letrozole vs placebo plus letrozole were neutropenia (80% vs 6%), infections (60% vs 42%), leukopenia (39% vs 2%), fatigue (37% vs 28%), nausea (35% vs 26%), alopecia (33% vs 16%), stomatitis (30% vs 14%), diarrhea (26% vs 19%), anemia (24% vs 9%), rash (18% vs 12%), asthenia (17% vs 12%), thrombocytopenia (16% vs 1%), vomiting (16% vs 17%), decreased appetite (15% vs 9%), dry skin (12% vs 6%), pyrexia (12% vs 9%), and dysgeusia (10% vs 5%).

The most frequently reported Grade ≥3 adverse reactions (≥5%) in PALOMA-2 for IBRANCE plus letrozole vs placebo plus letrozole were neutropenia (66% vs 2%), leukopenia (25% vs 0%), infections (7% vs 3%), and anemia (5% vs 2%).

Lab abnormalities of any grade occurring in PALOMA-2 for IBRANCE plus letrozole vs placebo plus letrozole were decreased WBC (97% vs 25%), decreased neutrophils (95% vs 20%), anemia (78% vs 42%), decreased platelets (63% vs 14%), increased aspartate aminotransferase (52% vs 34%), and increased alanine aminotransferase (43% vs 30%).

The most common adverse reactions (≥10%) of any grade reported in PALOMA-3 for IBRANCE plus fulvestrant vs placebo plus fulvestrant were neutropenia (83% vs 4%), leukopenia (53% vs 5%), infections (47% vs 31%), fatigue (41% vs 29%), nausea (34% vs 28%), anemia (30% vs 13%), stomatitis (28% vs 13%), diarrhea (24% vs 19%), thrombocytopenia (23% vs 0%), vomiting (19% vs 15%), alopecia (18% vs 6%), rash (17% vs 6%), decreased appetite (16% vs 8%), and pyrexia (13% vs 5%).

The most frequently reported Grade ≥3 adverse reactions (≥5%) in PALOMA-3 for IBRANCE plus fulvestrant vs placebo plus fulvestrant were neutropenia (66% vs 1%) and leukopenia (31% vs 2%).

Lab abnormalities of any grade occurring in PALOMA-3 for IBRANCE plus fulvestrant vs placebo plus fulvestrant were decreased WBC (99% vs 26%), decreased neutrophils (96% vs 14%), anemia (78% vs 40%), decreased platelets (62% vs 10%), increased aspartate aminotransferase (43% vs 48%), and increased alanine aminotransferase (36% vs 34%).

Avoid concurrent use of strong CYP3A inhibitors. If patients must be administered a strong CYP3A inhibitor, reduce the IBRANCE dose to 75 mg. If the strong inhibitor is discontinued, increase the IBRANCE dose (after 3-5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor. Grapefruit or grapefruit juice may increase plasma concentrations of IBRANCE and should be avoided. Avoid concomitant use of strong CYP3A inducers. The dose of sensitive CYP3A substrates with a narrow therapeutic index may need to be reduced as IBRANCE may increase their exposure.

For patients with severe hepatic impairment (Child-Pugh class C), the recommended dose of IBRANCE is 75 mg. The pharmacokinetics of IBRANCE have not been studied in patients requiring hemodialysis.

About Pfizer Oncology

At Pfizer Oncology, we are committed to advancing medicines wherever we believe we can make a meaningful difference in the lives of people living with cancer. Today, we have an industry-leading portfolio of 24 approved innovative cancer medicines and biosimilars across more than 30 indications, including breast, genitourinary, colorectal, blood and lung cancers, as well as melanoma.

On June 4, 2022 Kite, a Gilead Company (Nasdaq: GILD), reported longer-term follow-up results from two pivotal studies of the CAR T-cell therapy Tecartus (brexucabtagene autoleucel) (Press release, Kite Pharma, JUN 4, 2022, View Source [SID1234615569]). The three-year follow-up of ZUMA-2, a Phase 2 global, multi-center study evaluating the efficacy of Tecartus in patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL), and two-year follow-up of ZUMA-3, a global, multi-center, single-arm, open-label Phase 1/2 study evaluating Tecartus in adult patients (≥18 years old) with R/R B-cell acute lymphoblastic leukemia (B-ALL) were both presented today during a poster session at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Abstracts #7518 and #7010). Three-year follow-up data from ZUMA-2 were also simultaneously published in ASCO (Free ASCO Whitepaper)’s Journal of Clinical Oncology.

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"We are very encouraged by the totality of these data, which suggest a significant and sustained response with Tecartus for people living with difficult-to-treat blood cancers like MCL and B-ALL," said Frank Neumann, MD, PhD, SVP & Global Head of Clinical Development, Kite. "These longer-term results add to the growing maturity of data on Kite’s CAR T-cell therapies."

At nearly three years of follow-up (median 35.6 months) in the ZUMA-2 trial, the overall response rate (ORR) was 91%, with 68% of treated patients achieving a complete response (CR; 95% CI, 55.2–78.5). The median duration of response (DOR) was 28.2 months, with 37% of treated patients in ongoing response at data cut-off. Median overall survival (OS) among treated patients was 46.6 months. Among those patients who achieved a CR, the median OS has not yet been reached (30-month OS rate was 60.3%). Late relapse, classified as more than 24 months post-infusion, was infrequent (n=3).

"There remains a significant need among patients living with MCL for therapies that provide a long-term response, as many patients have high-risk disease that is more likely to relapse or progress following multiple lines of treatment," said Michael Wang, MD, ZUMA-2 Lead Investigator and Puddin Clarke Endowed Professor, Department of Lymphoma and Myeloma, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center. "The three-year data from ZUMA-2 represent the longest follow-up for a CAR T-cell therapy in MCL patients to date and are impressive in their demonstration of brexu-cel to elicit durable long-term responses."

In the ZUMA-3 trial, longer follow-up of the pivotal analysis and outcomes of a newly-conducted larger pooled analysis of Phase 1 and 2 patients by independent review who received the pivotal dose of Tecartus were reported. Most patients in the analysis were heavily pre-treated, with a median of two prior therapies, and 47% had received three or more prior therapies. At a median follow-up of 29.7 months for pooled Phase 1 and 2 patients, 73.1% of treated patients achieved a CR or CR with incomplete hematological recovery (CRi). Median OS was 25.4 months for both Phase 2 treated patients and pooled Phase 1 and 2 treated patients. At data cutoff, median OS had not yet been reached in Phase 2 patients who achieved a CR. Similar outcomes among Phase 2 treated patients (n=55) and the pooled analysis of Phase 1 and 2 patients (n=78) were observed.

"With two years of follow-up and an expanded data set in ZUMA-3 in a heavily pre-treated patient population, we’ve observed a high durable response rate, with the majority of the responses associated with undetectable minimal residual disease following treatment with brexu-cel," said Bijal Shah, MD, ZUMA-3 investigator and medical oncologist, Moffitt Cancer Center, Tampa, Florida. "For adult patients with B-ALL, this is a marked improvement relative to historical standards of care, so these treatment results are particularly important."

Across both trials, no new safety signal has been observed in this extended follow-up period. In ZUMA-2, 3% of treatment-emergent adverse events (AEs) of interest occurred since the primary report. The most frequent Grade ≥3 AE was neutropenia (1 [1%] Grade 3; 7 [10%] Grade 4). Two patients had treatment-related Grade 3 serious infections, pneumonia and upper respiratory tract infection (n=1) and influenza (n=1). There were no new cytokine release syndrome (CRS) AEs. In ZUMA-3, no new-onset CRS, neurological events, infections, or hypogammaglobulinemia of any grade have occurred since the Phase 2 primary analysis. One new Grade 5 AE has occurred since the primary analysis (graft-versus-host disease; deemed not treatment-related).

Tecartus is currently approved for the treatment of relapsed or refractory MCL, as the first and only CAR T-cell therapy to receive accelerated approval from the U.S. Food and Drug Administration (FDA) in this indication. Tecartus is also approved for relapsed or refractory B-cell ALL, as the first and only CAR T-cell therapy approved for adults (≥18 years old) with ALL. The Tecartus U.S. Prescribing Information has a Boxed Warning in its product label regarding the risks of CRS and neurologic toxicities, and Tecartus is approved with a risk evaluation and mitigation strategy (REMS) due to these risks; see below for Indication and Important Safety Information.

About MCL

MCL is a rare form of non-Hodgkin lymphoma (NHL) that arises from cells originating in the "mantle zone" of the lymph node and predominantly affects men over the age of 60. Approximately 33,000 people worldwide are diagnosed with MCL each year. MCL is highly aggressive following relapse, with many patients progressing following therapy.

About B-ALL

ALL is an aggressive type of blood cancer that can also involve the lymph nodes, spleen, liver, central nervous system and other organs. Globally, approximately 64,200 people are diagnosed with ALL each year. Of those, 60% of cases occur in those under age 20. Approximately 1,000 adults in the U.S. are treated annually for relapsed or refractory ALL. B-cell precursor ALL is the most common form, accounting for approximately 75% of cases, and treatment is typically associated with inferior outcomes compared with other types of ALL. Survival rates remain very poor in adult patients with relapsed or refractory ALL, with median OS at less than eight months.

About Tecartus

Please see full Prescribing Information, including BOXED WARNING and Medication Guide.

Tecartus is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of:

Adult patients with relapsed or refractory mantle cell lymphoma (MCL).
This indication is approved under accelerated approval based on overall response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).
U.S. IMPORTANT SAFETY INFORMATION

BOXED WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITIES

Cytokine Release Syndrome (CRS), including life-threatening reactions, occurred in patients receiving Tecartus. Do not administer Tecartus to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.
Neurologic toxicities, including life-threatening reactions, occurred in patients receiving Tecartus, including concurrently with CRS or after CRS resolution. Monitor for neurologic toxicities after treatment with Tecartus. Provide supportive care and/or corticosteroids as needed.
Tecartus is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Yescarta and Tecartus REMS Program.
Cytokine Release Syndrome (CRS), including life-threatening reactions, occurred following treatment with Tecartus. In ZUMA-2, CRS occurred in 91% (75/82) of patients receiving Tecartus, including ≥ Grade 3 CRS in 18% of patients. Among the patients who died after receiving Tecartus, one had a fatal CRS event. The median time to onset of CRS was three days (range: 1 to 13 days) and the median duration of CRS was ten days (range: 1 to 50 days). Among patients with CRS, the key manifestations (>10%) were similar in MCL and ALL and included fever (93%), hypotension (62%), tachycardia (59%), chills (32%), hypoxia (31%), headache (21%), fatigue (20%), and nausea (13%). Serious events associated with CRS included hypotension, fever, hypoxia, tachycardia, and dyspnea.

Ensure that a minimum of two doses of tocilizumab are available for each patient prior to infusion of Tecartus. Following infusion, monitor patients for signs and symptoms of CRS daily for at least seven days for patients with MCL and at least 14 days for patients with ALL at the certified healthcare facility, and for four weeks thereafter. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated.

Neurologic Events, including those that were fatal or life-threatening, occurred following treatment with Tecartus. Neurologic events occurred in 81% (66/82) of patients with MCL, including ≥ Grade 3 in 37% of patients. The median time to onset for neurologic events was six days (range: 1 to 32 days) with a median duration of 21 days (range: 2 to 454 days) in patients with MCL. Neurologic events occurred in 87% (68/78) of patients with ALL, including ≥ Grade 3 in 35% of patients. The median time to onset for neurologic events was seven days (range: 1 to 51 days) with a median duration of 15 days (range: 1 to 397 days) in patients with ALL. For patients with MCL, 54 (66%) patients experienced CRS before the onset of neurological events. Five (6%) patients did not experience CRS with neurologic events and eight patients (10%) developed neurological events after the resolution of CRS. Neurologic events resolved for 119 out of 134 (89%) patients treated with Tecartus. Nine patients (three patients with MCL and six patients with ALL) had ongoing neurologic events at the time of death. For patients with ALL, neurologic events occurred before, during, and after CRS in 4 (5%), 57 (73%), and 8 (10%) of patients; respectively. Three patients (4%) had neurologic events without CRS. The onset of neurologic events can be concurrent with CRS, following resolution of CRS or in the absence of CRS.

The most common neurologic events (>10%) were similar in MCL and ALL and included encephalopathy (57%), headache (37%), tremor (34%), confusional state (26%), aphasia (23%), delirium (17%), dizziness (15%), anxiety (14%), and agitation (12%). Serious events including encephalopathy, aphasia, confusional state, and seizures occurred after treatment with Tecartus.

Monitor patients daily for at least seven days for patients with MCL and at least 14 days for patients with ALL at the certified healthcare facility and for four weeks following infusion for signs and symptoms of neurologic toxicities and treat promptly.

REMS Program: Because of the risk of CRS and neurologic toxicities, Tecartus is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Yescarta and Tecartus REMS Program which requires that:

Healthcare facilities that dispense and administer Tecartus must be enrolled and comply with the REMS requirements. Certified healthcare facilities must have on-site, immediate access to tocilizumab, and ensure that a minimum of two doses of tocilizumab are available for each patient for infusion within two hours after Tecartus infusion, if needed for treatment of CRS.
Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense, or administer Tecartus are trained in the management of CRS and neurologic toxicities. Further information is available at www.YescartaTecartusREMS.com or 1-844-454-KITE (5483).
Hypersensitivity Reactions: Serious hypersensitivity reactions, including anaphylaxis, may occur due to dimethyl sulfoxide (DMSO) or residual gentamicin in Tecartus.

Severe Infections: Severe or life-threatening infections occurred in patients after Tecartus infusion. Infections (all grades) occurred in 56% (46/82) of patients with MCL and 44% (34/78) of patients with ALL. Grade 3 or higher infections, including bacterial, viral, and fungal infections, occurred in 30% of patients with ALL and MCL. Tecartus should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after Tecartus infusion and treat appropriately. Administer prophylactic antimicrobials according to local guidelines.

Febrile neutropenia was observed in 6% of patients with MCL and 35% of patients with ALL after Tecartus infusion and may be concurrent with CRS. The febrile neutropenia in 27 (35%) of patients with ALL includes events of "febrile neutropenia" (11 (14%)) plus the concurrent events of "fever" and "neutropenia" (16 (21%)). In the event of febrile neutropenia, evaluate for infection and manage with broad spectrum antibiotics, fluids, and other supportive care as medically indicated.

In immunosuppressed patients, life-threatening and fatal opportunistic infections have been reported. The possibility of rare infectious etiologies (e.g., fungal and viral infections such as HHV-6 and progressive multifocal leukoencephalopathy) should be considered in patients with neurologic events and appropriate diagnostic evaluations should be performed.

Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against B cells. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.

Prolonged Cytopenias: Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and Tecartus infusion. In patients with MCL, Grade 3 or higher cytopenias not resolved by Day 30 following Tecartus infusion occurred in 55% (45/82) of patients and included thrombocytopenia (38%), neutropenia (37%), and anemia (17%). In patients with ALL who were responders to Tecartus treatment, Grade 3 or higher cytopenias not resolved by Day 30 following Tecartus infusion occurred in 20% (7/35) of the patients and included neutropenia (12%) and thrombocytopenia (12%); Grade 3 or higher cytopenias not resolved by Day 60 following Tecartus infusion occurred in 11% (4/35) of the patients and included neutropenia (9%) and thrombocytopenia (6%). Monitor blood counts after Tecartus infusion.

Hypogammaglobulinemia: B cell aplasia and hypogammaglobulinemia can occur in patients receiving treatment with Tecartus. Hypogammaglobulinemia was reported in 16% (13/82) of patients with MCL and 9% (7/78) of patients with ALL. Monitor immunoglobulin levels after treatment with Tecartus and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement.

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

Secondary Malignancies may develop. Monitor life-long for secondary malignancies. In the event that one occurs, contact Kite at 1-844-454-KITE (5483) to obtain instructions on patient samples to collect for testing.

Effects on Ability to Drive and Use Machines: Due to the potential for neurologic events, including altered mental status or seizures, patients are at risk for altered or decreased consciousness or coordination in the 8 weeks following Tecartus infusion. Advise patients to refrain from driving and engaging in hazardous activities, such as operating heavy or potentially dangerous machinery, during this period.

Adverse Reactions: The most common non-laboratory adverse reactions (≥ 20%) were fever, cytokine release syndrome, hypotension, encephalopathy, tachycardia, nausea, chills, headache, fatigue, febrile neutropenia, diarrhea, musculoskeletal pain, hypoxia, rash, edema, tremor, infection with pathogen unspecified, constipation, decreased appetite, and vomiting. The most common serious adverse reactions (≥ 2%) were cytokine release syndrome, febrile neutropenia, hypotension, encephalopathy, fever, infection with pathogen unspecified, hypoxia, tachycardia, bacterial infections, respiratory failure, seizure, diarrhea, dyspnea, fungal infections, viral infections, coagulopathy, delirium, fatigue, hemophagocytic lymphohistiocytosis, musculoskeletal pain, edema, and paraparesis.

On June 4, 2022 Kite, a Gilead Company (Nasdaq: GILD), reported findings from two pre-planned, subgroup analyses of the landmark ZUMA-7 trial of Yescarta (axicabtagene ciloleucel), which led to the U.S. Food and Drug Administration’s (FDA) recent expanded approval of Yescarta as initial treatment in adults with large B-cell lymphoma (LBCL) that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy (Press release, Kite Pharma, JUN 4, 2022, View Source [SID1234615568]). These results include an analysis of clinical and patient-reported outcomes (PROs) in patients aged 65 or older, as well as an exploratory analysis of the association of pre-treatment tumor characteristics with clinical outcomes in patients with both low and high tumor burden and elevated and non-elevated lactate dehydrogenase (LDH). The data were presented today at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Abstracts #7548 and #7565).

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"Patients with large B-cell lymphoma aged 65 and above are at higher risk of not being eligible for or able to tolerate the standard of care, which can lead to poorer outcomes and health-related quality of life," said Jason Westin, MD, MS, FACP, ZUMA-7 Principal Investigator, Director, Lymphoma Clinical Research, and Associate Professor, Department of Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center. "These data demonstrate that older patients, who are frequently considered transplant-ineligible based on age, can safely receive second-line CAR T-cell therapy with curative intent."

In the ZUMA-7 sub-analysis of patients aged 65 and older, the primary endpoint of event-free survival (EFS) demonstrated that Yescarta (n=51) was superior to SOC (salvage chemoimmunotherapy followed by high-dose chemotherapy and stem cell transplant in those who respond; n=58; Hazard Ratio [HR], 0.276; descriptive P<0.0001), with over eight-fold greater median EFS (21.5 months vs 2.5 months) and over three-fold greater estimated 24-month EFS rate (47.8% vs 15.1%). Objective response rate (ORR) was higher with Yescarta vs. SOC (88% vs 52%; Odds Ratio: 8.81; descriptive P<0.0001). Complete response (CR) rates in the Yescarta group were over double that of the SOC group (75% vs 33%). Overall survival (OS), evaluated as a preplanned interim analysis, was prolonged in the Yescarta arm compared with the SOC arm (HR, 0.517). Fifty-seven percent of patients in the SOC arm received subsequent cellular immunotherapy (off protocol).

Yescarta also showed meaningful improvement in quality of life (QoL) over SOC with faster recovery to pre-treatment quality of life among patients 65 years of age or older. Among those evaluable for the PRO portion of the study, Yescarta (n=46) showed clinically meaningful differences in QoL at Day 100 compared to patients receiving SOC (n=42) for three prespecified PRO domains (European Organisation for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire [QLQ]-C30 Global Health Status/QOL, EORTC QLQ-C30 Physical Functioning, and EQ-5D-5L visual analog scale [VAS]). For all three domains, scores continued to favor Yescarta over SOC at Day 150 (descriptive P<0.05).

The safety profile of Yescarta was consistent with previous studies and real-world data in patients of all ages. Rates of cytokine release syndrome (CRS) and neurologic events (NE) for patients 65 and older were slightly higher than those observed in the overall patient population. Notably, compared with SOC patients, more Yescarta patients had high-risk features at baseline, including second-line age-adjusted International Prognostic Index (IPI) 2-3 (53% vs 31%), elevated LDH (61% vs 41%), and high grade B‑cell lymphoma (including double/triple-hit‑ lymphoma (33% vs 14%)).

"The consistent benefit of Yescarta over standard of care in the second-line setting in higher-risk patients, such as those aged 65+ and those with high tumor burden or LDH, can provide additional confidence to physicians that Yescarta should be considered the new standard of care as initial treatment for relapsed/refractory LBCL," said Frank Neumann, MD, PhD, SVP & Global Head of Clinical Development, Kite.

In a separate exploratory analysis of pre-treatment tumor characteristics including tumor burden and LDH, EFS was superior for Yescarta compared to SOC for patients with high and low pre-treatment tumor burden (HR, 0.29 and 0.49, respectively; descriptive P<0.001 for both) and elevated and non-elevated LDH (HR, 0.32 and 0.5, respectively; descriptive P<0.001 for both). EFS in Yescarta patients was not significantly different for patients with high or low pre-treatment tumor burden (HR, 0.92; descriptive P=0.68) or elevated and non-elevated LDH (HR, 1.11; descriptive P=0.61), but was worse in patients who received SOC with high pre-treatment tumor burden (HR, 1.51; descriptive P=0.02) or elevated LDH (HR, 1.56; descriptive P=0.01). Durable responses with Yescarta were greatest in tumors with prominent B-cell features, but were superior to SOC regardless of these features.

"High tumor burden and elevated LDH levels are typically associated with poorer outcomes, especially when patients have exhausted treatment options," said Frederick L. Locke, MD, ZUMA-7 Principal Investigator and Co-Leader of the Immuno-Oncology Program at Moffitt Cancer Center, Tampa, Florida. "These are factors that clinicians take into consideration when determining eligibility for standard of care in the second-line setting as well as CAR T-cell therapy in the third-line setting. In this analysis, response rates to axi-cel in the second-line setting were consistent regardless of level of tumor burden or LDH, which reaffirms that axi-cel should be considered the new standard of care in this earlier setting."

Yescarta was the first CAR T-cell therapy to be approved by the FDA for the treatment of adult patients with relapsed or refractory LBCL after two or more lines of systemic therapy. Yescarta was also approved by the FDA in April 2022 as the first CAR T-cell therapy for adult patients with LBCL that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy. The Yescarta U.S. Prescribing Information has a BOXED WARNING for the risks of CRS and neurologic toxicities, and Yescarta is approved with a Risk Evaluation and Mitigation Strategy (REMS) due to these risks; see below for Important Safety Information.

About LBCL

Globally, LBCL is the most common type of non-Hodgkin lymphoma (NHL). In the United States, more than 18,000 people are diagnosed with LBCL each year. About 30-40% of patients with LBCL will need second-line treatment, as their cancer will either relapse (return) or become refractory (not respond) to initial treatment.

About Yescarta

Please see full Prescribing Information, including BOXED WARNING and Medication Guide.

YESCARTA is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of:

Adult patients with large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy.
Adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

Limitations of Use: YESCARTA is not indicated for the treatment of patients with primary central nervous system lymphoma.
Adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
U.S. IMPORTANT SAFETY INFORMATION

BOXED WARNING: CYTOKINE RELEASE SYNDROME AND NEUROLOGIC TOXICITIES

Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving YESCARTA. Do not administer YESCARTA to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.
Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving YESCARTA, including concurrently with CRS or after CRS resolution. Monitor for neurologic toxicities after treatment with YESCARTA. Provide supportive care and/or corticosteroids as needed.
YESCARTA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the YESCARTA and TECARTUS REMS Program.
CYTOKINE RELEASE SYNDROME (CRS)

CRS, including fatal or life-threatening reactions, occurred. CRS occurred in 90% (379/422) of patients with non-Hodgkin lymphoma (NHL), including ≥ Grade 3 in 9%. CRS occurred in 93% (256/276) of patients with large B-cell lymphoma (LBCL), including ≥ Grade 3 in 9%. Among patients with LBCL who died after receiving YESCARTA, 4 had ongoing CRS events at the time of death. For patients with LBCL in ZUMA-1, the median time to onset of CRS was 2 days following infusion (range: 1-12 days) and the median duration was 7 days (range: 2-58 days). For patients with LBCL in ZUMA-7, the median time to onset of CRS was 3 days following infusion (range: 1-10 days) and the median duration was 7 days (range: 2-43 days). CRS occurred in 84% (123/146) of patients with indolent non-Hodgkin lymphoma (iNHL) in ZUMA-5, including ≥ Grade 3 in 8%. Among patients with iNHL who died after receiving YESCARTA, 1 patient had an ongoing CRS event at the time of death. The median time to onset of CRS was 4 days (range: 1-20 days) and median duration was 6 days (range: 1-27 days) for patients with iNHL.

Key manifestations of CRS (≥ 10%) in all patients combined included fever (85%), hypotension (40%), tachycardia (32%), chills (22%), hypoxia (20%), headache (15%), and fatigue (12%). Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), renal insufficiency, cardiac failure, respiratory failure, cardiac arrest, capillary leak syndrome, multi-organ failure, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome.

The impact of tocilizumab and/or corticosteroids on the incidence and severity of CRS was assessed in 2 subsequent cohorts of LBCL patients in ZUMA-1. Among patients who received tocilizumab and/or corticosteroids for ongoing Grade 1 events, CRS occurred in 93% (38/41), including 2% (1/41) with Grade 3 CRS; no patients experienced a Grade 4 or 5 event. The median time to onset of CRS was 2 days (range: 1-8 days) and the median duration of CRS was 7 days (range: 2-16 days). Prophylactic treatment with corticosteroids was administered to a cohort of 39 patients for 3 days beginning on the day of infusion of YESCARTA. Thirty-one of the 39 patients (79%) developed CRS and were managed with tocilizumab and/or therapeutic doses of corticosteroids with no patients developing ≥ Grade 3 CRS. The median time to onset of CRS was 5 days (range: 1-15 days) and the median duration of CRS was 4 days (range: 1-10 days). Although there is no known mechanistic explanation, consider the risk and benefits of prophylactic corticosteroids in the context of pre-existing comorbidities for the individual patient and the potential for the risk of Grade 4 and prolonged neurologic toxicities.

Ensure that 2 doses of tocilizumab are available prior to YESCARTA infusion. Monitor patients for signs and symptoms of CRS at least daily for 7 days at the certified healthcare facility, and for 4 weeks thereafter. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated.

NEUROLOGIC TOXICITIES

Neurologic toxicities (including immune effector cell-associated neurotoxicity syndrome) that were fatal or life-threatening occurred. Neurologic toxicities occurred in 78% (330/422) of all patients with NHL receiving YESCARTA, including ≥ Grade 3 in 25%. Neurologic toxicities occurred in 87% (94/108) of patients with LBCL in ZUMA-1, including ≥ Grade 3 in 31% and in 74% (124/168) of patients in ZUMA-7 including ≥ Grade 3 in 25%. The median time to onset was 4 days (range: 1-43 days) and the median duration was 17 days for patients with LBCL in ZUMA-1. The median time to onset for neurologic toxicity was 5 days (range: 1-133 days) and median duration was 15 days in patients with LBCL in ZUMA-7. Neurologic toxicities occurred in 77% (112/146) of patients with iNHL, including ≥ Grade 3 in 21%. The median time to onset was 6 days (range: 1-79 days) and the median duration was 16 days. Ninety-eight percent of all neurologic toxicities in patients with LBCL and 99% of all neurologic toxicities in patients with iNHL occurred within the first 8 weeks of YESCARTA infusion. Neurologic toxicities occurred within the first 7 days of infusion for 87% of affected patients with LBCL and 74% of affected patients with iNHL.

The most common neurologic toxicities (≥ 10%) in all patients combined included encephalopathy (50%), headache (43%), tremor (29%), dizziness (21%), aphasia (17%), delirium (15%), and insomnia (10%). Prolonged encephalopathy lasting up to 173 days was noted. Serious events, including aphasia, leukoencephalopathy, dysarthria, lethargy, and seizures occurred. Fatal and serious cases of cerebral edema and encephalopathy, including late-onset encephalopathy, have occurred.

The impact of tocilizumab and/or corticosteroids on the incidence and severity of neurologic toxicities was assessed in 2 subsequent cohorts of LBCL patients in ZUMA-1. Among patients who received corticosteroids at the onset of Grade 1 toxicities, neurologic toxicities occurred in 78% (32/41) and 20% (8/41) had Grade 3 neurologic toxicities; no patients experienced a Grade 4 or 5 event. The median time to onset of neurologic toxicities was 6 days (range: 1-93 days) with a median duration of 8 days (range: 1-144 days). Prophylactic treatment with corticosteroids was administered to a cohort of 39 patients for 3 days beginning on the day of infusion of YESCARTA. Of those patients, 85% (33/39) developed neurologic toxicities, 8% (3/39) developed Grade 3, and 5% (2/39) developed Grade 4 neurologic toxicities. The median time to onset of neurologic toxicities was 6 days (range: 1-274 days) with a median duration of 12 days (range: 1-107 days). Prophylactic corticosteroids for management of CRS and neurologic toxicities may result in higher grade of neurologic toxicities or prolongation of neurologic toxicities, delay the onset and decrease the duration of CRS.

Monitor patients for signs and symptoms of neurologic toxicities at least daily for 7 days at the certified healthcare facility, and for 4 weeks thereafter, and treat promptly.

REMS

Because of the risk of CRS and neurologic toxicities, YESCARTA is available only through a restricted program called the YESCARTA and TECARTUS REMS Program which requires that: Healthcare facilities that dispense and administer YESCARTA must be enrolled and comply with the REMS requirements and must have on-site, immediate access to a minimum of 2 doses of tocilizumab for each patient for infusion within 2 hours after YESCARTA infusion, if needed for treatment of CRS. Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense, or administer YESCARTA are trained about the management of CRS and neurologic toxicities. Further information is available at www.YescartaTecartusREMS.com or 1-844-454-KITE (5483).

HYPERSENSITIVITY REACTIONS

Allergic reactions, including serious hypersensitivity reactions or anaphylaxis, may occur with the infusion of YESCARTA.

SERIOUS INFECTIONS

Severe or life-threatening infections occurred. Infections (all grades) occurred in 45% of patients with NHL. ≥ Grade 3 infections occurred in 17% of patients, including ≥ Grade 3 infections with an unspecified pathogen in 12%, bacterial infections in 5%, viral infections in 3%, and fungal infections in 1%. YESCARTA should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after infusion and treat appropriately. Administer prophylactic antimicrobials according to local guidelines.

Febrile neutropenia was observed in 36% of all patients with NHL 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.

In immunosuppressed patients, including those who have received YESCARTA, life-threatening and fatal opportunistic infections including disseminated fungal infections (e.g., candida sepsis and aspergillus infections) and viral reactivation (e.g., human herpes virus-6 [HHV-6] encephalitis and JC virus progressive multifocal leukoencephalopathy [PML]) have been reported. The possibility of HHV-6 encephalitis and PML should be considered in immunosuppressed patients with neurologic events and appropriate diagnostic evaluations should be performed.

Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against B cells, including YESCARTA. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.

PROLONGED CYTOPENIAS

Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and YESCARTA infusion. ≥ Grade 3 cytopenias not resolved by Day 30 following YESCARTA infusion occurred in 39% of all patients with NHL and included neutropenia (33%), thrombocytopenia (13%), and anemia (8%). Monitor blood counts after infusion.

HYPOGAMMAGLOBULINEMIA B-cell aplasia and hypogammaglobulinemia can occur. Hypogammaglobulinemia was reported as an adverse reaction in 14% of all patients with NHL. Monitor immunoglobulin levels after treatment and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement. The safety of immunization with live viral vaccines during or following YESCARTA 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 YESCARTA treatment, and until immune recovery following treatment.

SECONDARY MALIGNANCIES

Secondary malignancies may develop. Monitor life-long for secondary malignancies. In the event that one occurs, contact Kite at 1-844-454-KITE (5483) to obtain instructions on patient samples to collect for testing.

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

Due to the potential for neurologic events, including altered mental status or seizures, patients are at risk for altered or decreased consciousness or coordination in the 8 weeks following YESCARTA 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.

ADVERSE REACTIONS

The most common non-laboratory adverse reactions (incidence ≥ 20%) in patients with LBCL in ZUMA-7 included fever, CRS, fatigue, hypotension, encephalopathy, tachycardia, diarrhea, headache, musculoskeletal pain, nausea, febrile neutropenia, chills, cough, infection with unspecified pathogen, dizziness, tremor, decreased appetite, edema, hypoxia, abdominal pain, aphasia, constipation, and vomiting.

The most common adverse reactions (incidence ≥ 20%) in patients with LBCL in ZUMA-1 included CRS, fever, hypotension, encephalopathy, tachycardia, fatigue, headache, decreased appetite, chills, diarrhea, febrile neutropenia, infections with pathogen unspecified, nausea, hypoxia, tremor, cough, vomiting, dizziness, constipation, and cardiac arrhythmias.

The most common non-laboratory adverse reactions (incidence ≥ 20%) in patients with iNHL in ZUMA-5 included fever, CRS, hypotension, encephalopathy, fatigue, headache, infections with pathogen unspecified, tachycardia, febrile neutropenia, musculoskeletal pain, nausea, tremor, chills, diarrhea, constipation, decreased appetite, cough, vomiting, hypoxia, arrhythmia, and dizziness.

On June 4, 2022 Gilead Sciences, Inc. (Nasdaq: GILD) reported positive results from the primary analysis of the Phase 3 TROPiCS-02 study of Trodelvy (sacituzumab govitecan-hziy) versus physicians’ choice of chemotherapy (TPC) in heavily pre-treated HR+/HER2- metastatic breast cancer patients who received prior endocrine therapy, CDK4/6 inhibitors and two to four lines of chemotherapy (Press release, Gilead Sciences, JUN 4, 2022, View Source [SID1234615567]). The study met its primary endpoint of progression-free survival (PFS) with a statistically significant and clinically meaningful 34% reduction in the risk of disease progression or death (median PFS 5.5 vs. 4 months; HR: 0.66; 95% CI: 0.53-0.83; P<0.0003). The first interim analysis of the key secondary endpoint of overall survival (OS) demonstrated a trend in improvement. These data are immature, and patients will be followed for subsequent OS analysis. These findings will be featured in both a press briefing and an oral session (Abstract #LBA1001) on Saturday, June 4, during the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting.

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This press release features multimedia. View the full release here: View Source

The study demonstrated that at the one-year mark, three times as many patients were progression-free when treated with Trodelvy compared to those who received TPC (21% versus 7%). Improvements in PFS with Trodelvy were also consistent across key patient subgroups, including patients who had previously received three or more chemotherapy regimens for metastatic disease (HR: 0.70; CI: 0.52-0.95), patients with visceral metastasis (HR: 0.66; CI: 0.53-0.83), and the elderly (≥65 years of age; HR: 0.59; CI: 0.38-0.93).

"For patients with HR+/HER2- metastatic breast cancer, resistance to endocrine therapy is inevitable in almost all cases. The standard of care is then limited to sequential single agent chemotherapy, with declining response rates, disease control and quality of life," said Dr. Hope Rugo, Professor of Medicine and Director, Breast Oncology and Clinical Trials Education at the University of California San Francisco Comprehensive Cancer Center, U.S. "In TROPiCS-02, we enrolled heavily pre-treated patients with metastatic breast cancer who had disease progression following multiple lines of chemotherapy. To observe a clinically meaningful reduction in the risk of disease progression or death in these patients with limited treatment options is remarkable. Sacituzumab govitecan-hziy will be an important potential future treatment option for these patients."

A prespecified quality of life (QoL) analysis, one of the secondary endpoints using the EORTC QLQ-C30 instrument, also favored Trodelvy over TPC demonstrating meaningful benefit. In the evaluable population, improvements in global health status and fatigue with Trodelvy (n=234) compared with those who received TPC (n=207) were also observed.

"With Trodelvy, our bold ambition is that it will help transform care for people living with cancer, including in pre-treated HR+/HER2- metastatic breast cancer, where more options are needed," said Bill Grossman, MD, PhD, Senior Vice President, Therapeutic Area Head, Gilead Oncology. "We look forward to continuing discussions with regulatory agencies to further understand how Trodelvy can impact this patient population with a high unmet need."

The safety profile for Trodelvy was consistent with prior studies, with no new safety concerns identified in this patient population. The most frequent Grade ≥3 treatment-related adverse reactions for Trodelvy compared to TPC were neutropenia (51% versus 38%), diarrhea (9% versus 1%), leukopenia (9% versus 5%), anemia (6% versus 3%), fatigue (6% versus 2%) and febrile neutropenia (5% versus 4%).

Trodelvy has not been approved by any regulatory agency for the treatment of HR+/HER2- metastatic breast cancer. Its safety and efficacy have not been established for this indication. Trodelvy has a Boxed Warning for severe or life-threatening neutropenia and severe diarrhea; please see below for additional Important Safety Information.

About HR+/HER2- Metastatic Breast Cancer

Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer is the most common type of breast cancer and accounts for approximately 70% of all new cases, or nearly 400,000 diagnoses worldwide each year. Almost one in three cases of early-stage breast cancer eventually become metastatic, and among patients with HR+/HER2- metastatic disease, the five-year relative survival rate is 30%. As patients with HR+/HER2- metastatic breast cancer become resistant to endocrine-based therapy, their primary treatment option is limited to single-agent chemotherapy. In this setting, it is common to receive multiple lines of chemotherapy regimens over the course of treatment, and the prognosis remains poor.

About the TROPiCS-02 Study

The TROPiCS-02 study is a global, multicenter, open-label, Phase 3 study, randomized 1:1 to evaluate Trodelvy versus physicians’ choice of chemotherapy (eribulin, capecitabine, gemcitabine, or vinorelbine) in 543 patients with HR+/HER2- metastatic breast cancer who were previously treated with endocrine therapy, CDK4/6 inhibitors and two to four lines of chemotherapy for metastatic disease. The primary endpoint is progression-free survival per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) as assessed by blinded independent central review (BICR) for participants treated with Trodelvy compared to those treated with chemotherapy. Secondary endpoints include overall survival, overall response rate, clinical benefit rate and duration of response, as well as assessment of safety and tolerability and quality of life measures. In the study, HER2 negativity was defined per American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) and the College of American Pathologists (CAP) criteria as immunohistochemistry (IHC) score of 0, IHC 1+ or IHC 2+ with a negative in-situ hybridization (ISH) test. More information about TROPiCS-02 is available at View Source

About Trodelvy

Trodelvy (sacituzumab govitecan-hziy) is a first-in-class Trop-2 directed antibody-drug conjugate. Trop-2 is a cell surface antigen highly expressed in multiple tumor types, including in more than 90% of breast and bladder cancers. Trodelvy is intentionally designed with a proprietary hydrolyzable linker attached to SN-38, a topoisomerase I inhibitor payload. This unique combination delivers potent activity to both Trop-2 expressing cells and the microenvironment.

Trodelvy is approved in more than 35 countries, with multiple additional regulatory reviews underway worldwide, for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) who have received two or more prior systemic therapies, at least one of them for metastatic disease. Trodelvy is also approved in the U.S. under the accelerated approval pathway for the treatment of adult patients with locally advanced or metastatic urothelial cancer (UC) who have previously received a platinum-containing chemotherapy and either programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor.

Trodelvy is also being developed for potential investigational use in other TNBC and metastatic UC populations, as well as a range of tumor types where Trop-2 is highly expressed, including hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer, metastatic non-small cell lung cancer (NSCLC), metastatic small cell lung cancer (SCLC), head and neck cancer, and endometrial cancer.

U.S. Indication for Trodelvy

In the United States, Trodelvy is indicated for the treatment of:

Adult patients with unresectable locally advanced or metastatic TNBC who have received two or more prior systemic therapies, at least one of them for metastatic disease.
Adult patients with locally advanced or metastatic UC who have previously received a platinum-containing chemotherapy and either programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
U.S. Important Safety Information for Trodelvy

BOXED WARNING: NEUTROPENIA AND DIARRHEA

Severe or life-threatening neutropenia may occur. Withhold Trodelvy for absolute neutrophil count below 1500/mm3 or neutropenic fever. Monitor blood cell counts periodically during treatment. Consider G-CSF for secondary prophylaxis. Initiate anti-infective treatment in patients with febrile neutropenia without delay.
Severe diarrhea may occur. Monitor patients with diarrhea and give fluid and electrolytes as needed. Administer atropine, if not contraindicated, for early diarrhea of any severity. At the onset of late diarrhea, evaluate for infectious causes and, if negative, promptly initiate loperamide. If severe diarrhea occurs, withhold Trodelvy until resolved to ≤Grade 1 and reduce subsequent doses.
CONTRAINDICATIONS

Severe hypersensitivity reaction to Trodelvy.
WARNINGS AND PRECAUTIONS

Neutropenia: Severe, life-threatening, or fatal neutropenia can occur and may require dose modification. Neutropenia occurred in 61% of patients treated with Trodelvy. Grade 3-4 neutropenia occurred in 47% of patients. Febrile neutropenia occurred in 7%. Withhold Trodelvy for absolute neutrophil count below 1500/mm3 on Day 1 of any cycle or neutrophil count below 1000/mm3 on Day 8 of any cycle. Withhold Trodelvy for neutropenic fever.

Diarrhea: Diarrhea occurred in 65% of all patients treated with Trodelvy. Grade 3-4 diarrhea occurred in 12% of patients. One patient had intestinal perforation following diarrhea. Neutropenic colitis occurred in 0.5% of patients. Withhold Trodelvy for Grade 3-4 diarrhea and resume when resolved to ≤Grade 1. At onset, evaluate for infectious causes and if negative, promptly initiate loperamide, 4 mg initially followed by 2 mg with every episode of diarrhea for a maximum of 16 mg daily. Discontinue loperamide 12 hours after diarrhea resolves. Additional supportive measures (e.g., fluid and electrolyte substitution) may also be employed as clinically indicated. Patients who exhibit an excessive cholinergic response to treatment can receive appropriate premedication (e.g., atropine) for subsequent treatments.

Hypersensitivity and Infusion-Related Reactions: Serious hypersensitivity reactions including life-threatening anaphylactic reactions have occurred with Trodelvy. Severe signs and symptoms included cardiac arrest, hypotension, wheezing, angioedema, swelling, pneumonitis, and skin reactions. Hypersensitivity reactions within 24 hours of dosing occurred in 37% of patients. Grade 3-4 hypersensitivity occurred in 2% of patients. The incidence of hypersensitivity reactions leading to permanent discontinuation of Trodelvy was 0.3%. The incidence of anaphylactic reactions was 0.3%. Pre-infusion medication is recommended. Observe patients closely for hypersensitivity and infusion-related reactions during each infusion and for at least 30 minutes after completion of each infusion. Medication to treat such reactions, as well as emergency equipment, should be available for immediate use. Permanently discontinue Trodelvy for Grade 4 infusion-related reactions.

Nausea and Vomiting: Nausea occurred in 66% of all patients treated with Trodelvy and Grade 3 nausea occurred in 4% of these patients. Vomiting occurred in 39% of patients and Grade 3-4 vomiting occurred in 3% of these patients. Premedicate with a two or three drug combination regimen (e.g., dexamethasone with either a 5-HT3 receptor antagonist or an NK1 receptor antagonist as well as other drugs as indicated) for prevention of chemotherapy-induced nausea and vomiting (CINV). Withhold Trodelvy doses for Grade 3 nausea or Grade 3-4 vomiting and resume with additional supportive measures when resolved to Grade ≤1. Additional antiemetics and other supportive measures may also be employed as clinically indicated. All patients should be given take-home medications with clear instructions for prevention and treatment of nausea and vomiting.

Increased Risk of Adverse Reactions in Patients with Reduced UGT1A1 Activity: Patients homozygous for the uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1)*28 allele are at increased risk for neutropenia, febrile neutropenia, and anemia and may be at increased risk for other adverse reactions with Trodelvy. The incidence of Grade 3-4 neutropenia was 67% in patients homozygous for the UGT1A1*28, 46% in patients heterozygous for the UGT1A1*28 allele and 46% in patients homozygous for the wild-type allele. The incidence of Grade 3-4 anemia was 25% in patients homozygous for the UGT1A1*28 allele, 10% in patients heterozygous for the UGT1A1*28 allele, and 11% in patients homozygous for the wild-type allele. Closely monitor patients with known reduced UGT1A1 activity for adverse reactions. Withhold or permanently discontinue Trodelvy based on clinical assessment of the onset, duration and severity of the observed adverse reactions in patients with evidence of acute early-onset or unusually severe adverse reactions, which may indicate reduced UGT1A1 function.

Embryo-Fetal Toxicity: Based on its mechanism of action, Trodelvy can cause teratogenicity and/or embryo-fetal lethality when administered to a pregnant woman. Trodelvy contains a genotoxic component, SN-38, and targets rapidly dividing cells. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Trodelvy and for 6 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Trodelvy and for 3 months after the last dose.

ADVERSE REACTIONS

In the ASCENT study (IMMU-132-05), the most common adverse reactions (incidence ≥25%) were fatigue, neutropenia, diarrhea, nausea, alopecia, anemia, constipation, vomiting, abdominal pain, and decreased appetite. The most frequent serious adverse reactions (SAR) (>1%) were neutropenia (7%), diarrhea (4%), and pneumonia (3%). SAR were reported in 27% of patients, and 5% discontinued therapy due to adverse reactions. The most common Grade 3-4 lab abnormalities (incidence ≥25%) in the ASCENT study were reduced neutrophils, leukocytes, and lymphocytes.

In the TROPHY study (IMMU-132-06), the most common adverse reactions (incidence ≥25%) were diarrhea, fatigue, neutropenia, nausea, any infection, alopecia, anemia, decreased appetite, constipation, vomiting, abdominal pain, and rash. The most frequent serious adverse reactions (SAR) (≥5%) were infection (18%), neutropenia (12%, including febrile neutropenia in 10%), acute kidney injury (6%), urinary tract infection (6%), and sepsis or bacteremia (5%). SAR were reported in 44% of patients, and 10% discontinued due to adverse reactions. The most common Grade 3-4 lab abnormalities (incidence ≥25%) in the TROPHY study were reduced neutrophils, leukocytes, and lymphocytes.

DRUG INTERACTIONS

UGT1A1 Inhibitors: Concomitant administration of Trodelvy with inhibitors of UGT1A1 may increase the incidence of adverse reactions due to potential increase in systemic exposure to SN-38. Avoid administering UGT1A1 inhibitors with Trodelvy.

UGT1A1 Inducers: Exposure to SN-38 may be substantially reduced in patients concomitantly receiving UGT1A1 enzyme inducers. Avoid administering UGT1A1 inducers with Trodelvy.