FDA NEWS: February 28, 2022 to March 31, 2022

TOP - May 2022 Vol 15, No 3 - FDA Updates

This section provides a brief overview of new cancer drugs and new indications approved by the FDA between February 28 and March 31, 2022.

NEW DRUGS

Pluvicto FDA Approved for PSMA-Positive Metastatic Prostate Cancer

On March 23, 2022, the FDA accelerated the approval of lutetium Lu 177 vipivotide tetraxetan, formerly known as 177Lu PSMA-617 (Pluvicto; Novartis/Advanced Accelerator Applications) for the treatment of adults with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) after receiving an androgen receptor (AR) inhibitor and taxane-based chemotherapy. The FDA granted this application a priority review and a breakthrough therapy designation.

Lu 177 vipivotide tetraxetan is the first FDA-approved targeted radioligand therapy for patients with mCRPC that combines a targeting compound (ligand) with a therapeutic radioisotope (a radioactive particle).

“The approval of Pluvicto is an important clinical advancement for people with progressing mCRPC, as it can significantly improve survival rates for those who have limited treatment options,” said Oliver Sartor, MD, Medical Director, Tulane Cancer Center, LA. “Pluvicto is a step forward in the evolution of precision medicine for prostate cancer.”

On the same day, the FDA approved gallium Ga 68 gozetotide (Locametz), a radioactive diagnostic agent for (positron-emission tomography) of PSMA-positive lesions, including the selection of patients with metastatic prostate cancer for whom lutetium Lu 177 vipivotide tetraxetan PSMA-directed therapy is indicated. This is the first radioactive diagnostic agent approved by the FDA for selecting patients for a radioligand therapeutic agent.

Patients with previously treated mCRPC should be selected for treatment with lutetium Lu 177 vipivotide tetraxetan using gallium Ga 68 gozetotide or another FDA-approved PSMA-11 imaging agent, based on PSMA expression in tumors. PSMA-positive mCRPC was defined as having ≥1 tumor lesions with gallium Ga 68 gozetotide uptake of more than normal liver. Patients were excluded from the study if any lesion exceeding certain size criteria in the short axis had uptake of less than or equal to uptake in normal liver.

The approval of lutetium Lu 177 vipivotide tetraxetan was based on results of the VISION study, a randomized (2:1), multicenter, open-label clinical trial of 831 patients with progressive, PSMA-positive mCRPC. The patients were randomized to lutetium Lu 177 vipivotide tetraxetan plus best standard of care (N = 551) or to best standard of care alone (N = 280). All patients received a gonadotropin-releasing hormone analog or had previous bilateral orchiectomy. Patients had to have received ≥1 AR inhibitors and 1 or 2 previous taxane-based chemotherapy regimens. Patients received lutetium Lu 177 vipivotide tetraxetan 7.4 GBq (200 mCi) every 6 weeks for up to 6 doses plus best standard of care or best standard of care alone.

The primary end points were overall survival (OS) and radiographic progression-free survival (PFS). The OS was significantly better with lutetium Lu 177 vipivotide tetraxetan plus best standard of care (hazard ratio, 0.62; 95% confidence interval [CI], 0.52-0.74; P <.001) compared with best standard of care alone. The median OS was 15.3 months (95% CI, 14.2-16.9) and 11.3 months (95% CI, 9.8-13.5), respectively. The interpretation of the magnitude of the radiographic PFS effect was limited because of a high degree of censoring from early dropout in the control arm.

The most common (≥20%) adverse reactions that had greater incidence in patients in the active group were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation. The most common laboratory abnormalities that worsened from baseline in ≥30% of patients receiving lutetium Lu 177 vipivotide tetraxetan were decreased levels of lymphocytes, hemoglobin, leukocytes, platelets, calcium, and sodium.

Treatment with lutetium Lu 177 vipivotide tetraxetan may be associated with radiation exposure risk, myelosuppression, and renal adverse events. The safety follow-up duration in the VISION study was not sufficient to capture late adverse events associated with radiation.

The recommended dose of lutetium Lu 177 vipivotide tetraxetan is 7.4 GBq (200 mCi) intravenously, every 6 weeks, for up to 6 doses, or until disease progression or unacceptable adverse events.

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Opdualag, a Novel Immunotherapy Combination, FDA Approved for Advanced Melanoma

On March 18, 2022, the FDA approved the combination of 2 types of immune checkpoint inhibitors, the PD-1 inhibitor nivolumab (Opdivo; Bristol Myers Squibb) plus the novel LAG-3 inhibitor relatlimab-rmbw (Opdualag; Bristol Myers Squibb), for patients aged ≥12 years with unresectable or metastatic melanoma. Opdualag is a new fixed-dose combination of the 2 monoclonal antibodies, relatlimab-rmbw and nivolumab.

The FDA approved this new combination therapy based on results of the RELATIVITY-047 clinical trial, a randomized (1:1) double-blind study of 714 patients with newly diagnosed metastatic or unresectable stage III or IV melanoma. The study excluded patients with active autoimmune disease requiring systemic therapy with moderate- or high-dose corticosteroids or immunosuppressive medications, uveal melanoma, or active or untreated brain or leptomeningeal metastases.

Patients were randomized to the combination of intravenous (IV) nivolumab 480 mg plus IV relatlimab 160 mg or to IV nivolumab 480 mg, alone, either infused every 4 weeks until disease progression or until unacceptable toxicity. The key efficacy outcome was progression-free survival (PFS) using RECIST version 1.1.

The results showed a significant PFS improvement favoring relatlimab plus nivolumab versus nivolumab alone (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.62-0.92; P = .0055). The median PFS was 10.1 months (95% CI, 6.4-15.7) with relatlimab plus nivolumab versus 4.6 months (95% CI, 3.4-5.6) with nivolumab alone. The overall survival (OS) was not significantly different between the 2 arms (HR, 0.80; 95% CI, 0.64-1.01), and the median OS was not reached (NR) in the relatlimab plus nivolumab arm (95% CI, 34.2-NR) and was 34.1 months (95% CI, 25.2-NR) in the nivolumab-alone arm.

“As the data from the RELATIVITY-047 trial mature, if the survival benefit of relatlimab–nivolumab is shown to be similar to or better than that of nivolumab–ipilimumab, this finding would reinforce the relatlimab–nivolumab regimen as the new standard of care for previously untreated patients with advanced melanoma,” Dr Frampton and Dr Sivakumar wrote in an editorial in the New England Journal of Medicine (Framptom AE, et al. N Engl J Med. 2022;386:91-92).

The most common (≥20%) adverse reactions seen with this monoclonal antibodies combination were musculoskeletal pain, fatigue, rash, pruritus, and diarrhea. The most common (≥20%) laboratory abnormalities were decreased hemoglobin levels, decreased lymphocytes, increased aspartate aminotransferase, increased alanine aminotransferase, and decreased sodium.

The recommended dose of relatlimab plus nivolumab for patients aged ≥12 years weighing ≥40 kg is IV nivolumab 480 mg and IV relatlimab 160 mg every 4 weeks until disease progression or unacceptable toxicity occurs. The recommended dose for patients aged ≤12 years weighing <40 kg has not been established.

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Carvykti Second BCMA-Directed CAR T-Cell Therapy FDA Approved for Multiple Myeloma

On February 28, 2022, the FDA approved ciltacabtagene autoleucel (Carvykti; Janssen Biotech) for the treatment of adults with relapsed or refractory multiple myeloma after ≥4 lines of therapy, including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 monoclonal antibody. Ciltacabtagene autoleucel is a B-cell maturation antigen (BCMA)-directed genetically modified autologous chimeric antigen receptor (CAR) T-cell therapy. It is the second BCMA-directed CAR T-cell therapy approved by the FDA for this patient population.

The FDA granted this application a priority review, a breakthrough therapy designation, and an orphan drug designation.

This approval was based on results of the CARTITUDE-1 clinical trial, an open-label, phase 1/2 multicenter study of 97 patients with relapsed or refractory multiple myeloma who received ≥3 previous lines of therapy, including a PI, an IMiD, and an anti-CD38 monoclonal antibody, whose disease progressed during or after the last chemotherapy regimen; 82% of the patients had received ≥4 lines of antimyeloma therapy.

“The responses in the CARTITUDE-1 study showed durability over time and resulted in the majority of heavily pretreated patients achieving deep responses after 18-month follow-up,” said Sundar Jagannath, MD, Director, Center of Excellence for Multiple Myeloma and Professor of Medicine, Hematology and Medical Oncology, The Tisch Cancer Institute, Icahn School of Medicine, Mount Sinai, and principal study investigator. “The approval of cilta-cel provides physicians an immunotherapy treatment option that offers patients an opportunity to be free from anti-myeloma therapies for a period of time.”

The overall response rate (ORR) and the duration of response (DOR) with ciltacabtagene autoleucel were evaluated using the International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma. The ORR was 97.9% (95% confidence interval [CI], 92.7-99.7). Among the 95 patients who had a response to the CAR T-cell therapy, the median DOR was 21.8 months (95% CI, 21.8-not evaluable), with a median duration of follow-up of 18 months.

The drug’s prescribing information includes a boxed warning for cytokine-release syndrome (CRS), hemophagocytic lymphohistiocytosis or macrophage activation syndrome, immune effector cell–associated neurotoxicity syndrome, Parkinson disease, Guillain-Barré syndrome, and prolonged and/or recurrent cytopenia, all of which are life-threatening.

The most common (≥20%) adverse reactions with ciltacabtagene autoleucel were pyrexia, CRS, hypogammaglobulinemia, musculoskeletal pain, fatigue, infections, diarrhea, nausea, encephalopathy, headache, coagulopathy, constipation, and vomiting.

Ciltacabtagene autoleucel is approved with a Risk Evaluation and Mitigation Strategy program requiring that healthcare professionals who administer this medication must be certified to recognize and manage CRS and neurologic adverse events. The FDA is requiring the manufacturer to conduct a postmarketing study to evaluate the long-term safety of the drug in patients who received ciltacabtagene autoleucel.

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NEW INDICATIONS

Keytruda Monotherapy FDA Approved for Endometrial Carcinoma with a Biomarker

On March 21, 2022, the FDA approved a new indication for the PD-1 inhibitor pembrolizumab (Keytruda; Merck) as monotherapy for advanced endometrial carcinoma that is microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR), as determined by an FDA-approved test, in patients whose disease progressed after systemic therapy in any setting and who are not candidates for curative surgery or radiation therapy.

The FDA previously approved the combination of pembrolizumab plus lenvatinib (Lenvima) for the treatment of this patient population.

On the same day, the FDA also approved the VENTANA MMR RxDx Panel (Ventana Medical Systems) as a companion diagnostic device for the selection of patients with solid tumors and dMMR who are eligible for pembrolizumab therapy. The FDA previously approved the FoundationOne CDx (F1CDx, by Foundation Medicine) as a companion diagnostic device for the selection of patients with solid tumors and MSI-H who are eligible for pembrolizumab therapy.

The approval of this new indication was based on the KEYNOTE-158 clinical trial, a multicenter, nonrandomized, open-label, multicohort study of 90 patients with unresectable or metastatic MSI-H or dMMR endometrial carcinoma in cohorts D and K of the study. MSI-H or dMMR tumor status was determined using polymerase chain reaction and immunohistochemistry, respectively. Patients received pembrolizumab 200 mg intravenously every 3 weeks until unacceptable toxicity or until disease progression. Patients without disease progression could continue to receive pembrolizumab for up to 24 months.

The major efficacy outcomes were objective response rate (ORR) and duration of response (DOR) using RECIST version 1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The ORR was 46%, and the median DOR was not reached; 68% of the patients had a response lasting ≥12 months, and 44% had a response lasting ≥24 months.

The most common (≥20%) adverse reactions in the study were fatigue, musculoskeletal pain, rash, diarrhea, pyrexia, cough, decreased appetite, pruritus, dyspnea, constipation, pain, abdominal pain, nausea, and hypothyroidism. The immune-mediated side effects associated with pembrolizumab include pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, and skin reactions.

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Lynparza Receives FDA Approval for Adjuvant Treatment of High-Risk Early Breast Cancer with BRCA mutation

On March 11, 2022, the FDA accelerated the approval of the oral PARP inhibitor olaparib (Lynparza; AstraZeneca) for the adjuvant treatment of adults with HER2-negative, high-risk early breast cancer and deleterious or suspected deleterious germline BRCA mutation after neoadjuvant or adjuvant chemotherapy. Patients must be selected for olaparib therapy for this indication based on an FDA-approved test.

This approval was based on the OlympiA study, a randomized (1:1), double-blind, placebo-controlled, international clinical trial of 1836 patients with HER2-negative, high-risk early breast cancer and germline BRCA mutation who completed definitive local treatment and neoadjuvant or adjuvant chemotherapy. Patients were randomized to 1 year of olaparib 300 mg orally twice daily or to placebo. Patients had to have completed ≥6 cycles of neoadjuvant or adjuvant chemotherapy containing anthracyclines, taxanes, or both. Patients with hormone receptor–positive breast cancer were allowed to continue concurrent treatment with endocrine therapy.

The primary efficacy end point was invasive disease-free survival (IDFS), defined as the time from randomization to the date of first recurrence (ie, invasive locoregional or distant recurrence), contralateral invasive breast cancer, new cancer, or death from any cause.

At a prespecified interim analysis at a median follow-up of 2.5 years, the 3-year IDFS rate was 85.9% in the olaparib arm versus 77.1% in the placebo arm, amounting to an 8.8% difference (95% confidence interval [CI], 4.5-13.0) and a hazard ratio (HR) of 0.58 for invasive disease or death (99.5% CI, 0.41-0.82; P <.0001). A total of 56 deaths were reported in the olaparib arm and 86 in the placebo arm, but the difference was not statistically significant (HR, 0.68; 99% CI, 0.44-1.05; P = .02).

The most common (≥10%) adverse reactions in this study were nausea, fatigue (including asthenia), anemia, vomiting, headache, diarrhea, leukopenia, neutropenia, decreased appetite, dysgeusia, dizziness, and stomatitis.

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Opdivo plus Platinum-Based Chemotherapy FDA Approved as First Neoadjuvant Treatment in Early-Stage NSCLC

On March 4, 2022, the FDA accelerated the approval of the PD-1 inhibitor nivolumab (Opdivo; Bristol Myers Squibb) in combination with platinum-doublet chemotherapy for the neoadjuvant treatment of adults with resectable non–small-cell lung cancer (NSCLC). This represents the first FDA approval for neoadjuvant therapy for early-stage NSCLC.

The efficacy was evaluated in the CheckMate-816 study, a randomized, open-label clinical trial of patients with resectable, stage IB (≥4 cm), stage II, or stage IIIA NSCLC. Patients were enrolled regardless of the tumor PD-1 or PD-L1 status. A total of 358 patients were randomized to nivolumab plus platinum-doublet chemotherapy or to platinum-chemotherapy alone, administered every 3 weeks for up to 3 cycles in each arm.

The main efficacy outcomes were event-free survival (EFS) and pathologic complete response (pCR) by blinded independent central review. The median EFS was 31.6 months (95% confidence interval [CI], 30.2-not reached) in the nivolumab plus chemotherapy arm and 20.8 months (95% CI, 14.0-26.7) in the chemotherapy-alone arm. The hazard ratio was 0.63 (97.38% CI, 0.43-0.91; P = .0052). The pCR rate was 24% (95% CI, 18.0-31.0) with nivolumab plus chemotherapy versus 2.2% (95% CI, 0.6-5.6) with chemotherapy alone.

The most common (≥20%) adverse reactions in this study were nausea, constipation, fatigue, decreased appetite, and rash. The addition of nivolumab to chemotherapy did not result in more frequent delays or cancellations of surgery. The median lengths of hospital days after definitive surgery, and the rates of adverse reactions identified as surgical complications were similar in both groups.

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Last modified: July 21, 2022