FDA NEWS: January 25, 2022, and March 21, 2022

TON - April 2022 Vol 15, No 2


Opdualag, Novel Combination of 2 Distinct Checkpoint Inhibitors, FDA Approved for Advanced Melanoma

On March 18, 2022, the FDA approved the combination of 2 distinct immune checkpoint inhibitors, the new LAG-3 antibody relatlimab-rmbw (Opdualag; Bristol Myers Squibb) plus the PD-1 inhibitor nivolumab (Opdivo; 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 and nivolumab.

The FDA approved this new combination therapy based on results of the RELATIVITY-047 clinical trial, a randomized, 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 in a 1:1 ratio 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 using RECIST version 1.1.

The results showed a significant improvement in progression-free survival favoring relatlimab plus nivolumab versus nivolumab alone (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.62-0.92; P = .0055). The median progression-free survival 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.

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

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FDA Approves Vonjo for Treatment of Patients with Myelofibrosis and Thrombocytopenia

On February 28, 2022, the FDA accelerated the approval of pacritinib (Vonjo; CTI BioPharma), a kinase inhibitor, for the treatment of adult patients with intermediate- or high-risk primary or secondary (postpolycythemia vera or postessential thrombocythemia) myelofibrosis with a platelet count below 50 × 109/L. The FDA granted pacritinib priority review, fast track designation, and orphan drug designation for this indication.

“Today’s approval of Vonjo establishes a new standard of care for myelofibrosis patients suffering from cytopenic myelofibrosis,” said John Mascarenhas, MD, Associate Professor, Medicine, Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York City. “Myelofibrosis with severe thrombocytopenia, defined as blood platelet counts below 50 × 109/L, has been shown to result in poor survival outcomes coupled with debilitating symptoms. Limited treatment options have rendered this disease as an area of urgent unmet medical need. I am pleased to see that a new, efficacious, and safe treatment option is now available for these patients.”

The FDA based its approval on efficacy results from the phase 3 PERSIST-2 clinical trial that included 63 patients with intermediate- or high-risk primary or secondary myelofibrosis and low platelet counts who received pacritinib 200 mg twice daily or standard therapy. Efficacy was determined based on the proportion of patients who had ≥35% spleen volume reduction from baseline to week 24. Nine (29%) patients in the pacritinib arm had a ≥35% reduction in spleen volume compared with 1 (3%) patient in the standard therapy arm.

The most common (≥20%) adverse reactions are diarrhea, thrombocytopenia, nausea, anemia, and peripheral edema. The most common (≥3%) serious adverse reactions are anemia, thrombocytopenia, pneumonia, cardiac failure, disease progression, pyrexia, and squamous-cell carcinoma of the skin. Patients must not use pacritinib if they are also taking certain other medications, such as strong CYP3A4 inhibitors or inducers.

As part of the accelerated approval, the manufacturer of pacritinib is required to describe a clinical benefit in a confirmatory trial. To fulfill this postapproval requirement, it plans to complete the PACIFICA trial, with expected results in mid-2025.

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Kimmtrak, a Bispecific CD3 T-Cell Engager, First FDA-Approved Drug for Unresectable or Metastatic Uveal Melanoma

On January 25, 2022, the FDA accelerated the approval of tebentafusp-tebn (Kimmtrak; Immunocore), a bispecific gp100 peptide-HLA–directed CD3 T-cell engager, for the treatment of adult patients with HLA-A*02:01 unresectable or metastatic uveal (intraocular) melanoma. The FDA granted tebentafusp breakthrough therapy and orphan drug designations for this indication.

The efficacy was evaluated in the IMCgp100-202 clinical trial, a randomized, open-label, multicenter study of 378 patients with metastatic uveal melanoma. All patients had to have the HLA-A*02:01 genotype, as detected by a central assay. Patients who had previously received systemic therapy or localized liver-directed therapy were excluded, but patients who had undergone surgical resection of oligometastatic disease were allowed to participate. Patients with cardiac disease or symptomatic, untreated brain metastases were also excluded from the study.

The patients were randomized in a 2:1 ratio to tebentafusp (N = 252) or to the investigator’s choice (N = 126) of either pembrolizumab (Keytruda), ipilimumab (Yervoy), or dacarbazine. Tebentafusp was administered weekly by intravenous infusion at 20 mcg on day 1; 30 mcg on day 8; 68 mcg on day 15; and every subsequent week, until disease progression or unacceptable adverse events.

The main end point in the trial was overall survival. An additional efficacy outcome was investigator-assessed progression-free survival per RECIST version 1.1.

The median overall survival was 21.7 months (95% confidence interval [CI], 18.6-28.6) in patients who received tebentafusp versus 16 months (95% CI, 9.7-18.4) in the investigator’s choice arm (hazard ratio, 0.51; 95% CI, 0.37- 0.71; P <.0001). The progression-free survival was 3.3 months (95% CI, 3-5) with tebentafusp and 2.9 months (95% CI, 2.8-3) with the investigator’s choice (hazard ratio, 0.73; 95% CI, 0.58-0.94; P = .0139).

The most common (≥30%) adverse reactions were cytokine-release syndrome, rash, pyrexia, pruritus, fatigue, nausea, chills, abdominal pain, edema, hypotension, dry skin, headache, and vomiting. The most common (≥50%) laboratory abnormalities were decreased lymphocyte count, increased creatinine, increased glucose, increased aspartate aminotransferase, increased alanine aminotransferase, decreased hemoglobin, and decreased phosphate levels.

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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 previous systemic therapy in any setting and who are not candidates for curative surgery or radiation.

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, by Roche Tissue Diagnostics) as a companion diagnostic device for the selection of patients with solid tumor 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.

This approval 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% (95% confidence interval, 35-56), 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

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, double-blind, placebo-controlled, international clinical trial of 1836 patients with gBRCAm HER2-negative high-risk early breast cancer and germline BRCA mutation who completed definitive local treatment and neoadjuvant or adjuvant chemotherapy. Patients were randomized in a 1:1 ratio 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 loco-regional or distant recurrence), contralateral invasive breast cancer, new cancer, or death from any cause.

The IDFS rate was 12% in the olaparib arm and 20% in the placebo arm (hazard ratio [HR], 0.58; 95% confidence interval [CI], 0.46-0.74; P <.0001). The IDFS rate at 3 years was 86% (95% CI, 82.8-88.4) with olaparib and 77% (95% CI, 73.7-80.1) with placebo. The overall survival (OS) was an additional efficacy end point. A total of 75 deaths (8%) were reported in the olaparib arm and 109 (12%) in the placebo arm (HR, 0.68; 95% CI, 0.50-0.91; P = .0091). A significant improvement in IDFS and OS was seen in the olaparib arm versus the placebo arm.

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 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). The median EFS was 31.6 months in the nivolumab plus chemotherapy arm and 20.8 months in the chemotherapy-alone arm. The hazard ratio was 0.63 (97.38% confidence interval, 0.43-0.91; P = .0052). The pCR rate was 24% with nivolumab plus chemotherapy versus 2.2% with chemotherapy alone.

The most common (≥20%) adverse reactions were nausea, constipation, fatigue, decreased appetite, and rash.

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