On November 14, 2022, the FDA granted accelerated approval to mirvetuximab soravtansine-gynx (Elahere; ImmunoGen) for adult patients with folate receptor alpha (FRα)-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who have received 1 to 3 previous systemic treatment regimens. Mirvetuximab soravtansine-gynx is an FRα-directed antibody and microtubule inhibitor conjugate. Patients are selected for therapy based on an FDA-approved test.
On the same day, the FDA also approved the VENTANA FOLR1 RxDx Assay (Ventana Medical Systems) as a companion diagnostic device to select patients for the above indication.
Efficacy was evaluated in SORAYA, a single-arm trial of 106 patients with FRα-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer. Patients were permitted to receive up to 3 previous lines of systemic therapy, regardless of bevacizumab (Avastin; Genentech) use. The trial enrolled patients whose tumors were positive for FRα expression as determined by VENTANA FOLRI RxDx. Patients were excluded if they had corneal disorders, ocular conditions requiring ongoing treatment, grade >1 peripheral neuropathy, or noninfectious interstitial lung disease.
Patients received mirvetuximab soravtansine-gynx 6 mg/kg (based on adjusted ideal body weight) as an intravenous infusion every 3 weeks until disease progression or unacceptable toxicity. Tumor response assessments occurred every 6 weeks for the first 36 weeks and every 12 weeks thereafter.
The main efficacy outcome measures were investigator-assessed overall response rate (ORR) and duration of response (DOR) evaluated according to RECIST version 1.1. In the efficacy-evaluable population of patients who had platinum-resistant, measurable disease, and received at least 1 dose (104 patients), the confirmed ORR was 31.7% (95% confidence interval [CI], 22.9-41.6) and median DOR was 6.9 months (95% CI, 5.6-9.7).
The most common (≥20%) adverse reactions, including laboratory abnormalities, were vision impairment, fatigue, increased aspartate aminotransferase, nausea, increased alanine aminotransferase, 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. The prescribing information includes a boxed warning for ocular toxicity.
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On October 25, 2022, the FDA granted accelerated approval to teclistamab-cqyv (Tecvayli; Janssen Biotech), the first bispecific B-cell maturation antigen (BCMA)-directed CD3 T-cell engager, for adult patients with relapsed or refractory multiple myeloma who received at least 4 previous lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. The FDA granted this application a priority review, a breakthrough designation, and an orphan drug designation.
Teclistamab-cqyv was evaluated in MajesTEC-1, a single-arm, multicohort, open-label, multicenter study. The efficacy population consisted of 110 patients who had received at least 3 previous therapies, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody, and had not received previous BCMA-targeted therapy.
The main efficacy outcome measure was overall response rate (ORR) as determined by the Independent Review Committee assessment using International Myeloma Working Group 2016 criteria. The ORR was 61.8% (95% confidence interval [CI], 52.1-70.9). With a median follow-up of 7.4 months among responders, the estimated duration of response rate was 90.6% (95% CI, 80.3%-95.7%) at 6 months and 66.5% (95% CI, 38.8%-83.9%) at 9 months.
The most common (≥20%) adverse reactions occurring in the 165 patients in the safety population were pyrexia, CRS, musculoskeletal pain, injection-site reaction, fatigue, upper respiratory tract infection, nausea, headache, pneumonia, and diarrhea. The most common (≥20%) grade 3 or 4 laboratory abnormalities were decreased lymphocytes, decreased neutrophils, decreased white blood cells, decreased hemoglobin, and decreased platelets.
The prescribing information for teclistamab-cqyv has a boxed warning for life-threatening or fatal cytokine release syndrome (CRS) and neurologic toxicity, including immune effector cell–associated neurotoxicity syndrome (ICANS). Among patients who received teclistamab-cqyv at the recommended dose, CRS occurred in 72% of patients, neurologic toxicity in 57%, and ICANS in 6%. Grade 3 CRS occurred in 0.6% of patients and grade 3 or 4 neurologic toxicity occurred in 2.4%.
Because of the risks for CRS and neurologic toxicity, including ICANS, teclistamab-cqyv is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), called the Tecvayli REMS.
On October 21, 2022, the FDA approved tremelimumab (Imjudo; AstraZeneca Pharmaceuticals) in combination with durvalumab (Imfinzi; AstraZeneca Pharmaceuticals) for adult patients with unresectable hepatocellular carcinoma (HCC). The FDA granted this application an orphan drug designation.
Efficacy was evaluated in HIMALAYA, a randomized, open-label, multicenter study in patients with confirmed unresectable HCC who had not received previous systemic treatment for HCC. Patients were randomized to 1 of 3 arms: tremelimumab 300 mg as a 1-time single intravenous (IV) infusion plus durvalumab 1500 mg IV on the same day, followed by durvalumab 1500 mg IV every 4 weeks; durvalumab 1500 mg IV every 4 weeks; or sorafenib (Nexavar; Bayer) 400 mg orally twice daily until disease progression or unacceptable toxicity. This approval was based on a comparison of the 782 patients randomized to tremelimumab plus durvalumab to sorafenib.
The major efficacy outcome was overall survival (OS). Tremelimumab plus durvalumab demonstrated a statistically significant and clinically meaningful improvement in OS compared with sorafenib (stratified hazard ratio [HR] of 0.78 [95% confidence interval {CI}, 0.66-0.92]; 2-sided P value = .0035); the median OS was 16.4 months (95% CI, 14.2-19.6) versus 13.8 months (95% CI, 12.3-16.1). Additional efficacy outcomes included investigator-assessed progression-free survival (PFS) and overall response rate (ORR) according to RECIST v1.1. The median PFS was 3.8 months (95% CI, 3.7-5.3) and 4.1 months (95% CI, 3.7-5.5) for the tremelimumab plus durvalumab and sorafenib arms, respectively (stratified HR, 0.90; 95% CI, 0.77-1.05). The ORR was 20.1% (95% CI, 16.3-24.4) in the tremelimumab plus durvalumab arm and 5.1% (95% CI, 3.2-7.8) for those treated with sorafenib.
The most common (≥20%) adverse reactions were rash, diarrhea, fatigue, pruritus, musculoskeletal pain, and abdominal pain.
On November 10, 2022, the FDA approved tremelimumab (Imjudo; AstraZeneca Pharmaceuticals) in combination with durvalumab (Imfinzi; AstraZeneca Pharmaceuticals) and platinum-based chemotherapy for adult patients with metastatic non–small-cell lung cancer (NSCLC) with no sensitizing EGFR mutation or ALK genomic tumor aberrations.
Efficacy was evaluated in POSEIDON, a randomized, multicenter, active-controlled, open-label study in patients with metastatic NSCLC who had not received previous systemic treatment. Patients were randomized to 1 of 3 treatment arms: (1) tremelimumab, durvalumab, and platinum-based chemotherapy for 4 cycles, followed by durvalumab and maintenance chemotherapy every 4 weeks; patients were treated with a fifth tremelimumab dose at week 16; (2) durvalumab plus platinum-based chemotherapy for 4 cycles followed by durvalumab and maintenance chemotherapy; or (3) platinum-based chemotherapy for 6 cycles followed by maintenance chemotherapy.
Treatment was continued until disease progression or unacceptable toxicity. The FDA approval was based on a comparison of treatment arm 1 and 3 (675 patients).
The major efficacy outcome measures were progression-free survival (PFS) assessed using blinded independent central review according to RECIST v1.1 and overall survival (OS). Tremelimumab plus durvalumab and platinum-based chemotherapy demonstrated a statistically significant and clinically meaningful improvement in OS compared with platinum-based chemotherapy alone (hazard ratio [HR] 0.77 [95% confidence interval {CI}, 0.65-0.92]; 2-sided P value = .00304); the median OS was 14 months (95% CI, 11.7-16.1) and 11.7 months (95% CI, 10.5-13.1) in treatment arms 1 and 3, respectively. Median PFS was 6.2 months (95% CI, 5.0-6.5) and 4.8 months (95% CI, 4.6-5.8) in the treatment arms, respectively (HR, 0.72 [95% CI, 0.60-0.86]; 2-sided P value = .00031).
The overall response rate was 39% (95% CI, 34-44) and 24% (95% CI, 20-29) in treatment arms 1 and 3, respectively. The median duration of response was 9.5 months (95% CI, 7.2-not reached) and 5.1 months (95% CI, 4.4-6.0) in the 2 treatment arms.
The most common (≥20%) adverse reactions were nausea, fatigue, decreased appetite, musculoskeletal pain, rash, and diarrhea. Grade 3 or 4 laboratory abnormalities (≥10%) were neutropenia, anemia, leukopenia, lymphocytopenia, increased lipase, hyponatremia, and thrombocytopenia.
On November 10, 2022, the FDA approved brentuximab vedotin (Adcetris; Seagen) in combination with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide for pediatric patients aged ≥2 years with previously untreated, high-risk classical Hodgkin lymphoma. This is the first pediatric approval for brentuximab vedotin. The FDA granted this application a priority review. Brentuximab vedotin also has an orphan drug designation for the treatment of Hodgkin lymphoma.
Efficacy was evaluated in a randomized, open-label, actively controlled trial. High risk was identified as Ann Arbor Stage IIB with bulk disease, Stage IIIB, Stage IVA, or Stage IVB. Of the 600 total patients randomized, 300 were randomized to brentuximab vedotin plus doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide (AVEPC), and 300 patients were randomized to doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC). Patients in each treatment arm received up to 5 cycles of the following:
The main efficacy outcome measure was event-free survival (EFS), defined as the time from randomization to the earliest of disease progression or relapse, second malignancy, or death due to any cause. Median EFS was not reached in either arm. There were 23 (8%) events in the brentuximab vedotin plus AVEPC arm and 52 (17%) events in the ABVE-PC arm with a corresponding hazard ratio of 0.41 (95% confidence interval, 0.25-0.67; P = .0002).
The most common (≥5%) grade ≥3 adverse reactions in pediatric patients treated with brentuximab vedotin in combination with AVEPC were neutropenia, anemia, thrombocytopenia, febrile neutropenia, stomatitis, and infection.
On November 8, 2022, the FDA approved cemiplimab-rwlc (Libtayo; Regeneron Pharmaceuticals) in combination with platinum-based chemotherapy for adult patients with advanced non–small-cell lung cancer (NSCLC) and no EGFR, ALK, or ROS1 aberrations.
Efficacy was evaluated in Study 16113, a randomized, multicenter, multinational, double-blind, active-controlled trial in 466 patients with advanced NSCLC who had not received previous systemic treatment. Patients were randomized (2:1) to either cemiplimab-rwlc plus platinum-based chemotherapy every 3 weeks for 4 cycles, followed by cemiplimab-rwlc and maintenance chemotherapy or placebo plus platinum-based chemotherapy every 3 weeks for 4 cycles, followed by placebo and maintenance chemotherapy.
The main efficacy outcome measure was overall survival (OS). Additional efficacy outcome measures were progression-free survival (PFS) and overall response rate (ORR) as assessed by blinded independent central review (BICR).
Cemiplimab-rwlc plus platinum-based chemotherapy demonstrated a statistically significant and clinically meaningful improvement in OS compared with placebo plus chemotherapy (hazard ratio [HR] of 0.71 [95% confidence interval {CI}, 0.53-0.93], 2-sided P value = .0140). The median OS was 21.9 months (95% CI, 15.5-not evaluable) in the cemiplimab-rwlc plus chemotherapy arm and 13.0 months (95% CI, 11.9-16.1) in the placebo plus chemotherapy arm. Median PFS per BICR was 8.2 months (95% CI, 6.4-9.3) in the cemiplimab-rwlc plus chemotherapy arm and 5.0 months (95% CI, 4.3-6.2) in the placebo plus chemotherapy arm (HR, 0.56; 95% CI, 0.440.70; P <.0001). Confirmed ORR per BICR was 43% (95% CI, 38-49) and 23% (95% CI, 16-30) in the respective treatments.
The most common (≥15%) adverse reactions were alopecia, musculoskeletal pain, nausea, fatigue, peripheral neuropathy, and decreased appetite.
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