FDA Actions: Fall 2022

FDA Approves First Bispecific Antibody, Teclistamab, for R/R Multiple Myeloma

The FDA on October 25, 2022, granted approval to Janssen Biotech’s teclistamab (Tecvayli) for treatment of relapsed or refractory multiple myeloma, marking a new class of therapy now available for patients whose disease had progressed on other types of therapy.

Teclistamab is a bispecific T-cell engager antibody that targets both B-cell maturation antigen (BCMA) expressed on the surface of myeloma cells and the CD3 receptor expressed on the surface of T cells, according to a release from Janssen.¹ It is injected subcutaneously, and its approval is for adults with multiple myeloma who have received at least 4 earlier lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

The accelerated approval was based on the results of MajesTEC-1, a single-arm, multicenter phase 1/2 study (NCT03145181 and NCT04557098) involving 110 patients who had previously received at least 3 lines of therapy (including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody) but who had not yet received BCMA-targeted therapy. The median number of prior lines of therapy was 5, and 78% of patients had received 4 or more prior lines of therapy.

Investigators found an overall response rate of 61.8% (95% CI, 52.1%-70.9%) among these patients receiving teclistamab in the trial, and 28.2% of patients achieved a complete response or better. The effects were seen quickly, with a median time to first response of 1.2 months. These results were first reported at the American Society of Hematology Annual Meeting & Exposition in December 2021.²

The FDA’s approval of teclistamab comes with a boxed warning for cytokine release syndrome (CRS) and neurologic toxicity, including immune effector cell–associated neurotoxicity syndrome (ICANS). As such, the drug will be available only through a Risk Evaluation and Mitigation Strategy program. In MajesTEC-1, CRS occurred in 72% of patients, neurologic toxicity in 57%, and ICANS in 6%. Clinicians are advised to follow a step-up dosing schedule when initiating treatment with teclistamab to lower the risk of CRS, which can be life-threatening or fatal.

Other common adverse reactions occurring in at least 20% of patients were fever, musculoskeletal pain, injection site reaction, and fatigue. The most frequent grade 3 to 4 laboratory abnormalities were decreases in lymphocytes, neutrophils, white blood cells, hemoglobin, and platelets.

“As a clinician and researcher, I see firsthand the human toll of this incurable disease. The approval of teclistamab, as the first bispecific antibody in relapsed or refractory multiple myeloma, is a meaningful step in helping many of these hard-to-treat patients,” Ajai Chari, MD, professor of medicine at the Icahn School of Medicine at Mount Sinai, New York, New York, and an investigator on MajesTEC-1, said in the company’s news release.

References
1. U.S. FDA approves TECVAYLI (teclistamab-cqyv), the first bispecific T-cell engager antibody for the treatment of patients with relapsed or refractory multiple myeloma. News release. Janssen. October 25, 2022. Accessed November 5, 2022. https://bit.ly/3Tbq8q6
2. Moreau P, Usmani SZ, Garfall A, et al. Updated results from majesTEC-1: phase 1/2 study of teclistamab, a B-cell maturation antigen × CD3 bispecific antibody, in relapsed/refractory multiple myeloma. Presented at: 63rd American Society of Hematology (ASH) Annual Meeting & Exposition; December 11-14, 2021; Atlanta, GA. Virtual.


Combination of Tremelimumab and Durvalumab Approved by FDA for Unresectable Liver Cancer

The FDA has approved a dual immunotherapy option of tremelimumab, sold as Imjudo, in combination with durvalumab, sold as Imfinzi, for the treatment of adult patients with unresectable hepatocellular carcinoma (HCC), the most common type of liver cancer. The drugs’ sponsor, AstraZeneca, announced the approval October 24, 2022.¹

This regimen includes a single 300-mg dose of the anticytotoxic T lymphocyte–associated antigen 4 antibody tremelimumab added to a 1500-mg dose of the anti–programmed cell death ligand-1 antibody durvalumab, followed by a 1500-mg dose of durvalumab every 4 weeks.

Approval is based on positive results from the phase 3 HIMALAYA trial (NCT03298451), presented in June 2022 at the American Society of Clinical Oncology annual meeting. Results showed that patients taking the tremelimumab/durvalumab regimen experienced a 22% reduction in risk of death compared with patients treated with sorafenib (HR, 0.78; 95% CI, 0.66-0.92; P = .0035).

Results appearing in NEJM Evidence showed that 31% of patients treated with the combination were still alive after 3 years, compared with 20% of patients treated with sorafenib at the point of follow-up.²

Both therapies are made by AstraZeneca, which announced the approval in a statement.

Liver cancer, the sixth most diagnosed cancer worldwide, is the fastest-rising cause of cancer death in the United States; an estimated 36,000 cases will be diagnosed in this country in 2022.

“Patients with unresectable liver cancer are in need of well-tolerated treatments that can meaningfully extend overall survival,” Ghassan Abou-Alfa, MD, MBA, attending physician at Memorial Sloan Kettering Cancer Center, New York, New York, and principal investigator in HIMALAYA, said in a statement. “In addition to this regimen demonstrating a favorable 3-year survival rate in the HIMALAYA trial, safety data showed no increase in severe liver toxicity or bleeding risk for the combination, important factors for patients with liver cancer who also have advanced liver disease.”

Andrea Wilson Woods, president and founder of Blue Faery: The Adrienne Wilson Liver Cancer Foundation, said that previously, patients living with liver cancer had few treatment options.

“With this approval, we are grateful and optimistic for new, innovative, therapeutic options. These new treatments can improve long-term survival for those living with unresectable hepatocellular carcinoma, the most common form of liver cancer. We appreciate the patients, their families, and the broader liver cancer community who continue to fight for new treatments and advocate for others.”

The safety profiles of the combination of Imjudo added to Imfinzi and for Imfinzi alone were consistent with the known profiles of each medicine, and no new safety signals were identified. The most common adverse events (AEs) among patients with unresectable HCC in the trial were rash, diarrhea, fatigue, pruritis, musculoskeletal pain, and abdominal pain; 41% of patients receiving the combination in HIMALAYA reported serious AEs. 

References
1. Imjudo (tremelimumab) in combination with Imfinzi approved in the US for patients with unresectable liver cancer. News release. AstraZeneca. October 24, 2022. Accessed November 5, 2022. https://www.astrazeneca.com/media-centre/press-releases/2022/imfinzi-and-imjudo-approved-in-advanced-liver-cancer.html
2. Abou-Alfa GK, Lau G, Kudo M, et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid. 2022;1(8). doi:10.1056/EVIDoa2100070


FDA Approves Cemiplimab/Chemotherapy Combo as First-line NSCLC Treatment

The PD-L1 inhibitor cemiplimab (Libtayo) was approved in combination with platinum-based chemotherapy for the first-line treatment of adult patients with advanced non–small cell lung cancer (NSCLC) with no EGFR, ALK, or ROS1 aberrations, its manufacturer reported on November 8.¹

The pivotal trial leading to the approval had been stopped early based on a recommendation by the independent data monitoring committee after the combination demonstrated a significant improvement in overall survival (OS), the primary end point.²

Patients must either have metastatic or locally advanced tumors that are not candidates for surgical resection or definitive chemoradiation, according to a statement from Regeneron Pharmaceuticals, and patients may be treated with this combination irrespective of PD-L1 expression or histology.¹

The approval is based on data from a global phase 3 trial, EMPOWER-Lung 3, which investigated cemiplimab in combination with a physician’s choice of platinum-doublet chemotherapy (cemiplimab combination), compared with platinum-doublet chemotherapy alone.

The trial enrolled 466 patients with locally advanced or metastatic NSCLC, with no ALK, EGFR, or ROS1 aberrations, irrespective of PD-L1 expression or tumor histology.

Among those enrolled, 43% had tumors with squamous histology, 67% had tumors with <50% PD-L1 expression, 15% had inoperable locally advanced disease not eligible for definitive chemoradiation, and 7% had pretreated and clinically stable brain metastases.

Patients were randomized 2:1 to receive either cemiplimab 350 mg (n = 312) or placebo (n = 154) intravenously every 3 weeks, plus histology-specific platinum-doublet chemotherapy.

Efficacy results comparing the combination therapy with chemotherapy
alone showed:

• Median OS of 22 vs 13 months, representing a 29% relative reduction in the risk of death (HR, 0.71; 95% CI, 0.53-0.93; P = .014). The 12-month probability of survival was 66% for the cemiplimab combination vs 56% for chemotherapy, per Kaplan-Meier estimates.
• Median progression-free survival (PFS) of 8 vs 5 months, representing a 44% reduction in the risk of disease progression (HR, 0.56; 95% CI, 0.44-0.70; P <.0001). The 12-month probability of PFS for the cemiplimab combination was 38% vs 16% for chemotherapy.
• Overall response rate of 43% vs 23%.

Cemiplimab previously demonstrated favorable efficacy as monotherapy compared with chemotherapy in the EMPOWER-Lung 1 trial, leading to its 2021 approval for advanced NSCLC with high PD-L1 expression (tumor proportion score ≥50%), and with no EGFR, anaplastic ALK, or ROS1 aberrations.

Safety was assessed in 312 patients in the cemiplimab combination group (median duration of exposure, 38 weeks) and 153 patients in the chemotherapy group (median duration of exposure, 21 weeks).
The most common adverse events (AEs), occurring in >15% of patients, were alopecia (37% intervention vs 43% placebo), musculoskeletal pain (30% vs 36%), nausea (25% vs 16%), fatigue (23% vs 18%), peripheral neuropathy (23% vs 19%), and decreased appetite (17% vs 12%).

Serious AEs occurred in 25% of patients, with treatment discontinuations due to AEs in 5% and fatal AEs in 6%.

The trial did not show any new safety signals. 

References
1. Libtayo (cemiplimab-rwlc) in combination with chemotherapy approved by the FDA as first-line treatment for advanced non-small cell lung cancer (NSCLC). News release. Regeneron; November 8, 2022. Accessed November 8, 2022. https://investor.regeneron.com/news-releases/news-release-details/libtayor-cemiplimab-rwlc-combination-chemotherapy-approved-fda/
2. Rosenberg J. Phase 3 trial backs first-line use of cemiplimab with chemotherapy in aNSCLC. The American Journal of Managed Care® webiste. September 21, 2022. Accessed November 16, 2022. https://www.ajmc.com/view/phase-3-trial-backs-first-line-use-of-cemiplimab-with-chemotherapy-in-ansclc


FDA Approves Mirvetuximab Soravtansine-gynx for Platinum-Resistant Ovarian Cancer

The FDA granted mirvetuximab soravtansine-gynx (Elahere; ImmunoGen) accelerated approval for adults with folate receptor α (FRα)–positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who have received 1 to 3 previous systemic treatment regimens.
The therapy is a FRα-directed antibody and microtubule inhibitor conjugate. It is the first antibody-drug conjugate approved for platinum-resistant disease.

“The approval of Elahere is significant for patients with FRα-positive platinum-resistant ovarian cancer, which is characterized by limited treatment options and poor outcomes,” said Ursula Matulonis, MD, in a statement.1 Matulonis is chief of the Division of Gynecologic Oncology at the Dana-Farber Cancer Institute, professor of medicine at Harvard Medical School, and co-principal investigator of SORAYA, the pivotal trial of mirvetuximab soravtansine-gynx. “Elahere’s impressive anti-tumor activity, durability of response, and overall tolerability observed in SORAYA demonstrate the benefit of this new therapeutic option, and I look forward to treating patients with Elahere.”

The FDA also approved the VENTANA FOLR1 (FOLR-2.1) RxDx Assay as a companion diagnostic to determine which patients are eligible for mirvetuximab soravtansine-gynx.

The therapy was approved based on results from SORAYA (also known as Study 0417), a single-arm trial of 106 patients, all of whom had received bevacizumab as one of their previous regimens. However, the approval is for patients regardless of prior bevacizumab use. Using FOLR-2.1, patients were confirmed to have FRα-positive tumors.

Patients received 6 mg/kg (adjusted for ideal body weight) intravenously once every 3 weeks. In the study, the objective response rate was 31.7% (95% CI, 22.9%-41.6%) and the median duration of response was 6.9 months (95% CI, 5.6-9.7). Five patients had a complete response.

The most common adverse events were vision impairment, fatigue, increased aspartate aminotransferase and alanine aminotransferase, nausea, keratopathy, abdominal pain, decreased lymphocytes, peripheral neuropathy, diarrhea, decreased albumin, constipation, increased alkaline phosphatase, dry eye, decreased magnesium, decreased leukocytes, decreased neutrophils, and decreased hemoglobin.

Since mirvetuximab soravtansine-gynx was granted accelerated approval, continued approval may be contingent on verification and description of benefit in a confirmatory trial. Data from the confirmatory trial MIRASOL are expected in early 2023.

“Platinum-resistant ovarian cancer is a notoriously challenging disease to treat,” said Anna Berkenblit, MD, MMS, senior vice president and chief medical officer of ImmunoGen. “Given that there have been no new therapies approved by the FDA for this indication since 2014, Elahere’s accelerated approval is a tremendous advance in the ovarian cancer treatment paradigm.” 

Reference
ImmunoGen announces FDA accelerated approval of Elahere (mirvetuximab soravtansine-gynx) for the treatment of platinum-resistant ovarian cancer. News release. ImmunoGen; November 14, 2022. Accessed November 16, 2022. https://investor.immunogen.com/news-releases/news-release-details/immunogen-announces-fda-accelerated-approval-elaheretm