Accelerated Approval to Capmatinib for Metastatic Non-Small Cell Lung Cancer
The FDA granted accelerated approval to capmatinib for adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have a mutation that leads to mesenchymal-epithelial transition (MET) exon 14 skipping as detected by an FDA-approved test.
The FDA also approved the FoundationOne CDx assay as a companion diagnostic for capmatinib. Efficacy was demonstrated in the GEOMETRY mono-1 trial (NCT02414139), a multi-center, non-randomized, open-label, multi-cohort study enrolling 97 patients with metastatic NSCLC with confirmed MET exon 14 skipping. Patients received capmatinib 400 mg orally twice daily until disease progression or unacceptable toxicity.
The main efficacy outcome measures were overall response rate (ORR) determined by a blinded independent review committee using RECIST 1.1 and response duration. Among the 28 treatment-naive patients, the ORR was 68 percent (95% CI: 48, 84) with a response duration of 12.6 months (95% CI: 5.5, 25.3). Among the 69 previously treated patients, the ORR was 41 percent (95% CI: 29, 53) with a response duration of 9.7 months (95% CI: 5.5, 13.0).
The most common adverse reactions (>= 20% of patients) were peripheral edema, nausea, fatigue, vomiting, dyspnea, and decreased appetite. Capmatinib can also cause interstitial lung disease, hepatotoxicity, photosensitivity, and embryo-fetal toxicity. Based on a clear positive signal for phototoxicity in early laboratory studies in cells, patients may be more sensitive to sunlight and should be advised to take precautions to cover their skin, use sunscreen, and not tan while taking capmatinib.
The recommended capmatinib dose is 400 mg orally twice daily with or without food.
Selpercatinib for Lung & Thyroid Cancers With RET Gene Mutations or Fusions
The FDA granted accelerated approval to selpercatinib for the following indications:
* adult patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC);
* adult and pediatric patients >=12 years of age with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) who require systemic therapy; and
* adult and pediatric patients >=12 years of age with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (RAI) (if radioactive iodine is appropriate).
Efficacy was investigated in a multi-center, open-label, multi-cohort clinical trial (LIBRETTO-001) in patients whose tumors had RET alterations. Identification of RET gene alterations was prospectively determined in local laboratories using either next-generation sequencing, polymerase chain reaction, or fluorescence in situ hybridization. The main efficacy outcome measures were overall response rate (ORR) and response duration determined by a blinded independent review committee using RECIST 1.1.
Efficacy for RET fusion-positive NSCLC was evaluated in 105 adult patients previously treated with platinum chemotherapy. The ORR was 64 percent (95% CI: 54%, 73%); 81 percent of responding patients had responses lasting 6 months or longer. Efficacy was also evaluated in 39 patients who never received systemic treatment. The ORR for these patients was 85 percent (95% CI: 70%, 94%); 58 percent of responding patients had responses lasting 6 months or longer.
Efficacy for advanced or metastatic RET-mutant MTC was investigated in adults and pediatric patients (>=12 years of age). The trial enrolled patients previously treated with cabozantinib, vandetanib or both, as well as patients who had not received these drugs. The ORR for the 55 previously treated patients was 69 percent (95% CI: 55%, 81%); 76 percent of responding patients had responses lasting 6 months or longer. Efficacy was also evaluated in 88 patients not previously treated with an approved therapy for MTC. The ORR for these patients was 73 percent (95% CI: 62%, 82%); 61 percent of responding patients had responses lasting 6 months or longer.
Efficacy for RET fusion-positive thyroid cancer was evaluated in adults and pediatric patients (>=12 years of age). The trial enrolled 19 patients who were RAI-refractory (if appropriate) and had received another prior systemic treatment, and eight patients who were RAI-refractory and had not received any additional therapy. The ORR for the 19 previously treated patients was 79 percent (95% CI: 54%, 94%); 87 percent of responding patients had responses lasting 6 months or longer. Efficacy was also evaluated in eight patients who received RAI and no other subsequent therapy. All eight patients responded (95% CI: 63%, 100%) and 75 percent had responses lasting 6 months or longer.
The most common adverse reactions, including laboratory abnormalities, (>= 25%) were increased aspartate aminotransferase, increased alanine aminotransferase, increased glucose, decreased leukocytes, decreased albumin, decreased calcium, dry mouth, diarrhea, increased creatinine, increased alkaline phosphatase, hypertension, fatigue, edema, decreased platelets, increased total cholesterol, rash, decreased sodium, and constipation.
The recommended selpercatinib dose is weight-based-120 mg for patients less than 50 kg and 160 mg for those 50 kg or greater. Selpercatinib is taken orally twice daily with or without food, or with food when co-administered with a proton pump inhibitor.
Olaparib + Bevacizumab for Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
The FDA expanded the indication of olaparib to include its combination with bevacizumab for first-line maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency positive status defined by either a deleterious or suspected deleterious BRCA mutation and/or genomic instability. The FDA also approved the Myriad myChoice CDx as a companion diagnostic for olaparib.
Efficacy of this new indication was investigated in PAOLA-1 (NCT03737643), a randomized, double-blind, placebo-controlled, multi-center trial comparing olaparib with bevacizumab versus placebo plus bevacizumab in patients with advanced high-grade epithelial ovarian cancer, fallopian tube, or primary peritoneal cancer following first-line platinum-based chemotherapy and bevacizumab.
Randomization was stratified by first-line treatment outcome and tumor BRCA mutation (tBRCAm) status, determined by prospective local testing. All available clinical samples were retrospectively tested with Myriad myChoice CDX test.
Patients were randomized (2:1) to receive olaparib tablets 300 mg orally twice daily in combination with bevacizumab (n=537) 15 mg/kg every 3 weeks or placebo plus bevacizumab (n=269). Patients continued bevacizumab in the maintenance setting and started olaparib after a minimum of 3 weeks and up to a maximum of 9 weeks following their last chemotherapy dose. Olaparib was continued for up to 2 years or until disease progression or unacceptable toxicity.
The major efficacy outcome measure was investigator-assessed progression-free survival (PFS) evaluated according to RECIST 1.1. An additional efficacy endpoint was overall survival (OS). Estimated median PFS in the subgroup of 387 patients with HRD-positive tumors was 37.2 months in the olaparib with bevacizumab arm and 17.7 months in the placebo plus bevacizumab arm (HR 0.33; 95% CI: 0.25-0.45). Results from a blinded independent review of PFS were consistent with the investigator-assessed PFS analysis. OS data were not mature.
The most common adverse reactions in the olaparib with bevacizumab treatment (>=10% of patients) were nausea, fatigue (including asthenia), anemia, lymphopenia, vomiting, diarrhea, neutropenia, leukopenia, urinary tract infection, and headache.
The recommended olaparib dose is 300 mg taken orally twice daily, with or without food. When used with olaparib, the recommended bevacizumab dose is 15 mg/kg intravenously every 3 weeks.
Accelerated Approval of Pomalidomide for Kaposi Sarcoma
The FDA expanded the indication of pomalidomide to include treating adult patients with AIDS-related Kaposi sarcoma after failure of highly active antiretroviral therapy and Kaposi sarcoma in adult patients who are HIV-negative.
Efficacy was investigated in Study 12-C-0047, an open-label, single-arm clinical trial conducted by the National Cancer Institute. Twenty-eight patients (18 HIV-positive, 10 HIV-negative) received 5 mg of pomalidomide orally once daily on days 1 through 21 of each 28-day cycle until disease progression or unacceptable toxicity. All HIV-positive patients continued highly active antiretroviral therapy.
The main efficacy outcome measure was overall response rate (ORR), which included complete response, clinical complete response, and partial response. Response was assessed by the investigator according to the AIDS Clinical Trial Group Oncology Committee response criteria for Kaposi sarcoma. Among the 18 HIV-positive patients, the ORR was 67 percent (95% CI: 41, 87) with a median response duration of 12.5 months (95% CI: 6.5, 24.9). Among the 10 HIV-negative patients, the ORR was 80 percent (95% CI: 44, 98) with a median response duration of 10.5 months (95% CI: 3.9, 24.2).
The most common adverse reactions including laboratory abnormalities (>= 30%) of patients who received pomalidomide were decreased absolute neutrophil count or white blood cells, elevated creatinine or glucose, rash, constipation, fatigue, decreased hemoglobin, platelets, phosphate, albumin, or calcium, increased ALT, nausea, and diarrhea.
The recommended pomalidomide dose for Kaposi sarcoma is 5 mg once daily taken orally with or without food on days 1 through 21 of each 28-day cycle until disease progression or unacceptable toxicity. Continue highly active antiretroviral therapy as HIV treatment in patients with AIDS-related Kaposi sarcoma.
Nivolumab + Ipilimumab for First-Line Metastatic Non-Small Cell Lung Cancer
The FDA approved the combination of nivolumab plus ipilimumab as first-line treatment for patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 (>=1%), as determined by an FDA-approved test, with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations.
The FDA also approved the PD-L1 IHC 28-8 pharmDx as a companion diagnostic device for selecting patients with NSCLC for treatmen with nivolumab plus ipilimumab.
Efficacy was investigated in CheckMate-227 (NCT02477826), a randomized, open-label, multi-part trial in patients with metastatic or recurrent NSCLC and no prior anticancer therapy. In Part 1a of the trial, 793 patients with PD-L1 tumor expression >=1 percent were randomized to receive either the combination of nivolumab plus with ipilimumab (n=396) or platinum-doublet chemotherapy (n=397).
The trial demonstrated a statistically significant improvement in overall survival (OS) for patients with PD-L1 tumor expression >=1 percent receiving nivolumab plus ipilimumab compared to those treated with platinum-doublet chemotherapy. Median OS was 17.1 months (95% CI: 15, 20.1) versus 14.9 (95% CI: 12.7, 16.7) (HR 0.79; 95% CI: 0.67, 0.94; p=0.0066).
Median progression-free survival (PFS) per blinded independent central review (BICR) was 5.1 months (95% CI: 4.1, 6.3) in the nivolumab plus ipilimumab arm and 5.6 months (95% CI: 4.6, 5.8) in the platinum-doublet chemotherapy arm (HR 0.82; 95% CI: 0.69, 0.97). Confirmed overall response rate (ORR) per BICR was 36 percent (95% CI: 31, 41) and 30 percent (95% CI: 26, 35), respectively. Median response duration was 23.2 months in the nivolumab plus ipilimumab arm and 6.2 months in the platinum-doublet chemotherapy arm.
The most common adverse reactions in >=20 percent of patients receiving the combination of nivolumab plus ipilimumab in CheckMate-227 were fatigue, rash, decreased appetite, musculoskeletal pain, diarrhea/colitis, dyspnea, cough, pruritis, nausea, and hepatitis.
The recommended doses for metastatic NSCLC are nivolumab 3 mg/kg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression.
Rucaparib for BRCA-Mutated Metastatic Castration-Resistant Prostate Cancer
The FDA granted accelerated approval to rucaparib for patients with deleterious BRCA mutation (germline and/or somatic)-associated metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor-directed therapy and a taxane-based chemotherapy.
Efficacy was investigated in TRITON2 (NCT02952534), an ongoing, multi-center, single-arm clinical trial in 115 patients with BRCA-mutated (germline and/or somatic) mCRPC who had been treated with androgen receptor-directed therapy and taxane-based chemotherapy. Patients received rucaparib 600 mg orally twice daily and concomitant GnRH analog or had prior bilateral orchiectomy.
Objective response rate (ORR) and duration of response (DOR) were assessed in 62 patients with measurable disease. The confirmed ORR was 44 percent (95% CI: 31, 57). Median DOR was not evaluable (NE; 95% CI: 6.4, NE). The range for the DOR was 1.7-24+ months. Fifteen of the 27 (56%) patients with confirmed objective responses had a DOR of >=6 months.
The most common adverse reactions (>=20%) among all 115 patients with BRCA-mutated mCRPC were fatigue, nausea, anemia, increased ALT/AST, decreased appetite, rash, constipation, thrombocytopenia, vomiting, and diarrhea.
The recommended rucaparib dose is 600 mg orally twice daily with or without food. Patients receiving rucaparib for mCRPC should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy.