Date: 16-Apr-2021

US FDA Grants Accelerated Approval To Gilead’s Trodelvy To Treat Advanced Or Metastatic Urothelial Cancer

Gilead Sciences announced that the US Food and Drug Administration (FDA) has granted accelerated approval of Trodelvy (sacituzumab govitecan-hziy) for use in adult patients with locally advanced or metastatic urothelial cancer (UC) who have previously received a platinum-containing chemotherapy and either a programmed death receptor-1 (PD-1) or a programmed death-ligand 1 (PD-L1) inhibitor.

The accelerated approval was based on data from the international phase 2, single-arm TROPHY study. Of the 112 patients who were evaluable for efficacy, 27.7% of those treated with Trodelvy responded to treatment, with 5.4% experiencing a complete response and 22.3% experiencing a partial response. The median duration of response was 7.2 months (95% CI: 4.7-8.6).

The FDA’s accelerated approval mechanism enables drugs that treat serious diseases with unmet medical need to be approved based on a surrogate or intermediate clinical endpoint. Continued approval is contingent upon verification and description of clinical benefit in a confirmatory trial.

“Only a fraction of patients derives long-term benefit from previously approved cytotoxic therapy or immunotherapy, leaving a great unmet need for treatment options for patients with advanced urothelial cancer who have progressed on first- and second-line therapies,” said Scott T. Tagawa, MD, MS, FACP, Professor of Medicine and Urology at Weill Cornell Medicine, an oncologist at New York-Presbyterian/Weill Cornell Medical Center and principal investigator of the TROPHY study.i “The response rate and tolerability seen with sacituzumab govitecan-hziy may provide physicians an effective new treatment option for patients whose cancer continues to progress even after multiple therapies.”

UC is the most common type of bladder cancer and occurs when the urothelial cells that line the inside of the bladder and other parts of the urinary tract grow unusually or uncontrollably. An estimated 83,000 Americans will be diagnosed with bladder cancer in 2021, and almost 90% of those diagnoses will be UC. The relative five-year survival rate for patients with metastatic UC is 5.5%.

“Cases of urothelial cancer continue to rise in the US, yet prognosis remains the same for the vast majority of patients,” said Andrea Maddox-Smith, CEO of the Bladder Cancer Advocacy Network (BCAN). “Bladder cancer patients need as many treatment options as possible, and we are pleased that Trodelvy can be a potentially viable treatment for them.”

Trodelvy’s safety profile in the TROPHY study is consistent with previous observations in metastatic UC and other tumor types. Among all evaluable treated metastatic UC patients (n=113), the most common (=25%) adverse reactions were diarrhea (72%), anemia (71%), fatigue (68%), neutropenia (67%), nausea (66%), alopecia (49%), decreased appetite (41%), constipation (34%), vomiting (34%) and abdominal pain (31%). Adverse reactions leading to treatment discontinuation occurred in 10% of those receiving Trodelvy, with 4% discontinuing treatment due to neutropenia.

“Today’s accelerated approval is thanks to the patients and healthcare professionals involved in the TROPHY study, and we appreciate their partnership,” said Merdad Parsey, MD, PhD, chief medical officer, Gilead Sciences. “This achievement, coupled with last week’s full FDA approval in unresectable locally advanced or metastatic triple-negative breast cancer, underscores our commitment toward rapidly delivering Trodelvy to patients facing some of the most difficult-to-treat cancers.”

Trodelvy (sacituzumab govitecan-hziy) is a first-in-class antibody and topoisomerase inhibitor conjugate directed to the Trop-2 receptor, a protein frequently expressed in multiple types of epithelial tumors, including metastatic triple-negative breast cancer (TNBC) and metastatic UC, where high expression is associated with poor survival and relapse.

The phase 2 TROPHY-U01 (also known as IMMU-132-06) trial is an ongoing, international, multi-center, open-label, multi-cohort, single-arm study evaluating Trodelvy monotherapy or combination therapy in patients with metastatic UC after progression on a platinum-based regimen and anti-PD-1/PD-L1-based immunotherapy. In Cohorts 1 and 2, patients received Trodelvy 10 mg/kg administered intravenously on Days 1 and 8 of a 21-day cycle to be continued until disease progression or loss of clinical benefit. Trodelvy is approved under accelerated approval based on the objective response rate (ORR) and duration of response (DoR) established in Cohort 1.

Cohorts 2, 3, 4 and 5 of the study are ongoing. Cohort 2 is assessing the safety and efficacy of Trodelvy monotherapy in platinum-ineligible patients after progression on anti-PD-1/PD-L1-based immunotherapy. Cohort 3 is assessing the safety and efficacy of Trodelvy on Days 1 and 8 of a 21-day cycle followed by pembrolizumab at the standard approved dose (200 mg) only on Day 1 of a 21-day cycle in patients with metastatic UC who have progressed after prior platinum therapy. Cohorts 4 and 5 are assessing the safety and efficacy of Trodelvy combination therapy in patients with treatment naive metastatic UC, with those in Cohort 4 receiving cisplatin and those in Cohort 5 receiving cisplatin and avelumab, respectively, in addition to Trodelvy.

The primary endpoint is ORR based on RECIST 1.1 criteria evaluated by independent central review in all five cohorts. In Cohorts 1 and 2, secondary endpoints are DoR and progression-free survival (PFS) based on central review and overall survival (OS). Secondary endpoints in Cohorts 3, 4 and 5 include DoR, clinical benefit rate (CBR) and PFS based on central review by RECIST 1.1 criteria; DoR, CBR and PFS based on investigator review by RECIST 1.1 and iRECIST criteria, OS and safety and tolerability of Trodelvy in combination with pembrolizumab, cisplatin, or cisplatin and avelumab, depending on the Cohort.

Date: 25-May-2021

US FDA Grants Accelerated Approval To Janssens Rybrevant To Treat NSCLC With EGFR Exon 20 Insertion Mutations

The Janssen Pharmaceutical Companies of Johnson & Johnson announced the US Food and Drug Administration (FDA) has granted the accelerated approval of Rybrevant (amivantamab-vmjw) for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.

Rybrevant is the first fully-human, bispecific antibody approved for the treatment of patients with NSCLC that targets EGFR exon 20 insertion mutations, which are the third most prevalent activating EGFR mutation. Today’s approval follows the FDA’s decision to grant Breakthrough Therapy Designation (BTD) in March 2020 and to initiate a Priority Review of the Biologics License Application (BLA) in December 2020. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.1

“Today’s FDA approval is an important development for people living with non-small cell lung cancer with exon 20 insertion mutations who, until now, have had no approved treatment options to target their disease,” said Jill Feldman, co-founder of the EGFR Resisters, an advocacy organization patient group, and a lung cancer patient advocate. “We are excited by the promise this new treatment option brings to people with this particular type of lung cancer and their families.”

Lung cancer is the leading cause of cancer death among both men and women, accounting for almost 25 percent of all cancer deaths. Currently available targeted treatments, like EGFR tyrosine kinase inhibitors (TKI) are generally insensitive in treating NSCLC driven by EGFR exon 20 insertion mutations and are not FDA-approved for these patients. In addition, NSCLC driven by this mutation carries a worse prognosis and shorter survival rates compared with lung cancer driven by more common EGFR mutations, such as exon 19 deletions and L858R substitutions. Patients newly diagnosed with metastatic NSCLC with EGFR exon 20 insertion mutations have a real-world median overall survival (OS) of 16.2 months (95 per cent confidence interval [CI], 11.0 – 19.4), which is lower than patients with EGFR exon 19 deletions/L858R mutations, who have a real-world median OS of 25.5 months (95 per cent CI, 24.5 – 27.0).

“Lung cancer is a complex disease, and through the study and deeper understanding of genetic alterations like EGFR exon 20 insertion mutations, we are able to target the disease in new ways and improve treatment outcomes for patients,” said Joshua K. Sabari, M.D., New York University Langone’s Perlmutter Cancer Center and study investigator, who presented the latest clinical trial results at the International Association for the Study of Lung Cancer’s (IASLC WCLC) 2020 World Conference on Lung Cancer Singapore. “Amivantamab-vmjw is an innovative bispecific antibody that brings an important new therapeutic approach to physicians caring for patients with this serious and rare type of lung cancer.”

Rybrevant is a fully-human bispecific antibody directed against EGFR and MET receptors.1 Rybrevant binds extracellularly (outside of the cell) inhibiting tumor growth and leading to tumor cell death.1 Today’s accelerated FDA approval is based on positive results from the phase 1 CHRYSALIS study, a multicenter, open-label, clinical study evaluating Rybrevant as a monotherapy in patients enrolled in the prior platinum containing chemotherapy cohort. Initial results from the CHRYSALIS EGFR exon 20 insertion mutation population, which supported the BTD, were presented at the American Society of Clinical Oncology 2020 Virtual Scientific Program, and updated results were presented at the IASLC WCLC 2020.

“The approval of Rybrevant, along with the companion diagnostic test, addresses high unmet need in the treatment of people with genetically defined non-small cell lung cancer,” said Peter Lebowitz, M.D., Ph.D., global therapeutic area head, oncology, Janssen Research & Development, LLC. “At Janssen, we are committed to the development of innovative therapies like Rybrevant and believe that advancing medicines targeting specific pathways can bring the greatest benefits and improve outcomes for patients with tumor alterations such as EGFR and MET.”

The FDA simultaneously approved Guardant Health’s Guardant360 CDx liquid biopsy blood test as a companion diagnostic for use with Rybrevant.

Next-generation sequencing tests offer an alternative to polymerase chain reaction (PCR)-based tests which fail to identify 50 per cent or more of exon 20 insertion mutations.

“Today’s milestone reflects progress and determination in our mission to develop and deliver transformational therapies to improve the lives of people diagnosed with some of the most devastating and complex diseases of our time,” said Mathai Mammen, M.D., Ph.D., global head, Janssen Research & Development, Johnson & Johnson. “The approval of Rybrevant, the first lung cancer treatment for Johnson & Johnson, strengthens our commitment to harness science, expertise and scale to dramatically alter the trajectory of lung cancer, and reduce the impact of the world’s leading cause of cancer mortality.”

Rybrevant is being studied in a comprehensive clinical development program for people with untreated advanced EGFR-mutated NSCLC, including the Phase 3 MARIPOSA (NCT04487080) trial studying Rybrevant in combination with lazertinib, Another phase 3 trial, PAPILLON (NCT04538664), is studying Rybrevant in combination with carboplatin-pemetrexed for people with advanced or metastatic EGFR-mutated NSCLC with exon 20 insertion mutations. Rybrevant received US FDA BTD in March 2020 and Priority Review Designation following the BLA announcement in December 2020. Janssen has filed regulatory submissions for Rybrevant with health authorities in Europe and other markets.