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Ripretinib for Advanced Gastrointestinal Stromal Tumors

The FDA approved ripretinib for adult patients with advanced gastrointestinal stromal tumor (GIST) who have received prior treatment with three or more kinase inhibitors, including imatinib.

  
FDA; oncology resear... - Click to enlarge in new windowFDA; oncology research. FDA; oncology research

Efficacy was evaluated in INVICTUS (NCT03353753), an international, multi-center, randomized (2:1), double-blind, placebo-controlled trial in 129 patients with GIST who were previously treated with imatinib, sunitinib, and regorafenib. Patients received ripretinib 150 mg or placebo orally once daily until disease progression or unacceptable toxicity. Crossover was permitted at disease progression for patients randomized to receive placebo.

 

The major efficacy outcome measure was progression-free survival (PFS) based on assessment by blinded independent central review (BICR) using modified RECIST 1.1 in which lymph nodes and bone lesions were not target lesions and a progressively growing new tumor nodule within a pre-existing tumor mass must meet specific criteria to be considered unequivocal evidence of progression. Additional efficacy outcome measures included overall response rate (ORR) by BICR and overall survival (OS).

 

The trial demonstrated a statistically significant improvement in PFS for patients in the ripretinib arm compared with those in the placebo arm (HR 0.15; 95% CI: 0.09, 0.25; p<0.0001). The median PFS was 6.3 months (95% CI: 4.6, 6.9) for ripretinib compared with 1.0 month (95% CI: 0.9, 1.7) for placebo. The ORR was 9 percent (95% CI: 4.2, 18) in the ripretinib arm compared with 0 percent (95% CI: 0, 8) in the placebo arm, though this difference was not statistically significant. The median OS in the ripretinib arm was 15.1 months (95% CI: 12.3, 15.1) compared with 6.6 months (95% CI: 4.1, 11.6) in the placebo arm with a HR of 0.36 (95% CI: 0.21, 0.62), though OS was not evaluated for statistical significance as a result of the sequential testing procedure for the secondary endpoints (i.e., PFS, then ORR, then OS).

 

The most common adverse reactions (>=20%) with ripretinib were alopecia, fatigue, nausea, abdominal pain, constipation, myalgia, diarrhea, decreased appetite, palmar-plantar erythrodysesthesia, and vomiting. Other important risks of ripretinib include new primary cutaneous malignancies, hypertension, and cardiac dysfunction.

 

The recommended ripretinib dose is 150 mg orally once daily with or without food.

 

Atezolizumab for First-Line Treatment of Metastatic NSCLC With High PD-L1 Expression

The FDA approved atezolizumab for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression (PD-L1 stained >= 50% of tumor cells [TC >= 50%] or PD-L1 stained tumor-infiltrating immune cells [IC] covering >= 10 percent of the tumor area [IC >= 10%]), with no EGFR or ALK genomic tumor aberrations.

 

The FDA also approved the VENTANA PD-L1 (SP142) assay as a companion diagnostic device for selecting patients with NSCLC for treatment with atezolizumab.

 

Efficacy was evaluated in IMpower110 (NCT02409342), a multi-center, international, randomized, open-label trial in patients with stage IV NSCLC whose tumors express PD-L1 (TC >= 1% or IC >= 1%) and who had received no prior chemotherapy for metastatic disease. Patients were randomized (1:1) to receive atezolizumab 1,200 mg every 3 weeks until disease progression or unacceptable toxicity or platinum-based chemotherapy. The main efficacy outcome measure was overall survival (OS).

 

The trial demonstrated a statistically significant improvement in OS for patients with high PD-L1 tumor expression receiving atezolizumab compared to those treated with platinum-based chemotherapy. Median OS was 20.2 months (95% CI: 16.5, NE) for patients in the atezolizumab arm compared with 13.1 months (95% CI: 7.4, 16.5) in the chemotherapy arm (HR 0.59; 95% CI: 0.40, 0.89; p=0.0106). There was no statistically significant difference in OS for the other two PD-L1 subgroups (TC >=5% or IC >=5%; and TC >=1% or IC >=1%) at the interim or final analyses.

 

Median progression-free survival per investigator was 8.1 months (95% CI: 6.8, 11.0) in the atezolizumab arm and 5.0 months (95% CI: 4.2, 5.7) in the platinum-based chemotherapy arm (HR 0.63; 95%CI: 0.45, 0.88). Confirmed overall response rate per investigator was 38 percent (95% CI: 29, 48) and 29 percent (95% CI: 20, 39), respectively.

 

The most common adverse reaction (>= 20%) with atezolizumab as a single-agent in IMpower110 was fatigue/asthenia.

 

The recommended atezolizumab dose for treatment of NSCLC is 840 mg every 2 weeks, 1,200 mg every 3 weeks, or 1,680 mg every 4 weeks, administered intravenously over 60 minutes.

 

Olaparib for HRR Gene-Mutated Metastatic Castration-Resistant Prostate Cancer

The FDA approved olaparib for adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC), who have progressed following prior treatment with enzalutamide or abiraterone.

 

The FDA also approved FoundationOne CDx for selection of patients with mCRPC carrying HRR gene alterations and the BRACAnalysis CDx test for selection of patients with mCRPC carrying germline BRCA1/2 alterations as companion diagnostic devices for treatment with olaparib.

 

Efficacy was investigated in PROfound (NCT02987543), an open-label, multi-center trial randomizing (2:1) 256 patients to olaparib 300 mg twice daily and 131 patients to investigator's choice of enzalutamide or abiraterone acetate. All patients received a GnRH analog or had prior bilateral orchiectomy. Patients were divided into two cohorts based on their HRR gene mutation status. Patients with mutations in either BRCA1, BRCA2, or ATM were randomized in Cohort A (N=245); patients with mutations among 12 other genes involved in the HRR pathway were randomized in Cohort B (N=142); those with co-mutations (Cohort A gene and a Cohort B gene) were assigned to Cohort A.

 

The major efficacy outcome of the trial was radiological progression-free survival (rPFS) (Cohort A). Additional efficacy outcomes included confirmed objective response rate (ORR) (Cohort A) in patients with measurable disease, rPFS (combined Cohorts A+B), and overall survival (OS) (Cohort A).

 

A statistically significant improvement was demonstrated for olaparib compared to investigator's choice in Cohort A for rPFS with a median of 7.4 months versus 3.6 months (HR 0.34; 95% CI: 0.25, 0.47; p<0.0001), for OS with a median of 19.1 months versus 14.7 months (HR 0.69; 95% CI: 0.50, 0.97, p=0.0175), and for ORR 33 percent versus 2 percent (p<0.0001). A statistically significant improvement for olaparib compared to investigator's choice was also demonstrated for rPFS in Cohort A+B, with a median of 5.8 months versus 3.5 months (HR 0.49; 95% CI: 0.38, 0.63; p<0.0001).

 

The most common adverse reactions in PROfound for olaparib (>=10% of patients) were anemia, nausea, fatigue (including asthenia), decreased appetite, diarrhea, vomiting, thrombocytopenia, cough, and dyspnea. Venous thromboembolic events, including pulmonary embolism, occurred in 7 percent of patients randomized to the olaparib arm compared to 3.1 percent of those receiving enzalutamide or abiraterone.

 

The recommended olaparib dose is 300 mg taken orally twice daily, with or without food.

 

Brigatinib for ALK-Positive Metastatic NSCLC

The FDA approved brigatinib for adult patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) as detected by an FDA-approved test. The Vysis ALK Break Apart FISH Probe Kit was also approved as a companion diagnostic for brigatinib.

 

Efficacy was investigated in ALTA-1L (NCT02737501), a randomized (1:1), open-label, multi-center trial in adult patients with advanced ALK-positive NSCLC who had not previously received an ALK-targeted therapy. The trial required patients to have an ALK rearrangement based on a local standard-of-care testing. The trial randomized 275 patients to receive brigatinib 180 mg orally once daily with a 7-day lead-in at 90 mg once daily (n=137) or crizotinib 250 mg orally twice daily (n=138). A subset of the clinical samples was retrospectively tested with the Vysis ALK Break Apart FISH Probe Kit. Of the enrolled patients, 239 had positive results using the Vysis diagnostic test (central results were negative for 20 patients and unavailable for 16 patients).

 

The major efficacy outcome measure was progression-free survival (PFS) evaluated by a blinded independent review committee according to RECIST 1.1. An additional efficacy outcome measure as evaluated by the BIRC was confirmed overall response rate (ORR).

 

Estimated median PFS for patients treated with brigatinib was 24 months (95% CI: 18.5, NE) compared with 11 months (95% CI: 9.2, 12.9) for those treated with crizotinib (HR 0.49; 95% CI: 0.35, 0.68; p<.0001). Confirmed ORR was 74 percent (95% CI: 66, 81) and 62 percent (95% CI: 53, 70), respectively.

 

The most common adverse reactions (>=25%) with brigatinib were diarrhea, fatigue, nausea, rash, cough, myalgia, headache, hypertension, vomiting, and dyspnea.

 

The recommended brigatinib dose is 90 mg orally once daily for the first 7 days, then increase to 180 mg orally once daily. Brigatinib may be taken with or without food.

 

Nivolumab + Ipilimumab & Chemo for First-Line Treatment of Metastatic NSCLC

The FDA approved the combination of nivolumab plus ipilimumab and 2 cycles of platinum-doublet chemotherapy as first-line treatment for patients with metastatic or recurrent non-small cell lung cancer (NSCLC), with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations.

 

Efficacy was investigated in CHECKMATE-9LA (NCT03215706), a randomized, open-label trial in patients with metastatic or recurrent NSCLC. Patients were randomized to receive either the combination of nivolumab plus ipilimumab and 2 cycles of platinum-doublet chemotherapy (n=361) or platinum-doublet chemotherapy for 4 cycles (n=358).

 

The trial demonstrated a statistically significant benefit in overall survival (OS) for patients treated with nivolumab plus ipilimumab plus chemotherapy compared to those who received chemotherapy. Median OS was 14.1 months (95% CI: 13.2, 16.2) versus 10.7 months (95% CI: 9.5, 12.5), HR 0.69; 96.71% CI: 0.55, 0.87).

 

Median progression-free survival (PFS) per blinded independent central review (BICR) was 6.8 months (95% CI: 5.6, 7.7) in the nivolumab plus ipilimumab and chemotherapy arm and 5 months (95% CI: 4.3, 5.6) in the chemotherapy arm (HR 0.70; 95% CI: 0.57, 0.86). Confirmed overall response rate per BICR was 38 percent (95% CI: 33, 43) and 25 percent (95% CI: 21, 30), respectively. Median response duration was 10 months in the nivolumab plus ipilimumab and chemotherapy arm, and 5.1 months in the chemotherapy arm.

 

The most common adverse reactions in >=20 percent of patients receiving nivolumab in combination with ipilimumab and platinum-doublet chemotherapy were fatigue, musculoskeletal pain, nausea, diarrhea, rash, decreased appetite, constipation, and pruritus.

 

The recommended nivolumab dose for this indication is 360 mg every 3 weeks with ipilimumab 1 mg/kg every 6 weeks and 2 cycles of platinum-doublet chemotherapy. The nivolumab and ipilimumab are continued until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression.

 

Atezolizumab + Bevacizumab for Unresectable Hepatocellular Carcinoma

The FDA approved atezolizumab in combination with bevacizumab for patients with unresectable or metastatic hepatocellular carcinoma who have not received prior systemic therapy.

 

Efficacy was investigated in IMbrave150 (NCT03434379), a multi-center, international, open-label, randomized trial in patients with locally advanced unresectable or metastatic hepatocellular carcinoma who had not received prior systemic therapy. A total of 501 patients were randomized (2:1) to receive either atezolizumab 1,200 mg as an IV infusion followed by bevacizumab 15 mg/kg IV on the same day, every 3 weeks, or sorafenib orally twice daily.

 

The main efficacy outcome measures were overall survival (OS) and independent review facility (IRF)-assessed progression-free survival (PFS) per RECIST 1.1. Additional efficacy outcome measures were IRF-assessed overall response rate (ORR) per RECIST 1.1 and mRECIST.

 

Median OS was not reached in the patients who received atezolizumab plus bevacizumab and was 13.2 months (95% CI: 10.4, NE) in the patients who received sorafenib (HR 0.58; 95% CI: 0.42, 0.79; p=0.0006). Estimated median PFS was 6.8 months (95% CI: 5.8, 8.3) versus 4.3 months (95% CI: 4.0, 5.6), respectively (HR 0.59; 95% CI: 0.47, 0.76; p<0.0001). The ORR per RECIST 1.1 was 28 percent (95% CI: 23, 33) in the atezolizumab plus bevacizumab group compared with 12 percent (95% CI: 7,17) in the sorafenib group (p<0.0001). The ORR per mRECIST was 33 percent (95% CI: 28, 39) versus 13 percent (95% CI: 8, 19), respectively (p<0.0001).

 

The most common adverse reactions (reported in >=20% of patients) with atezolizumab plus bevacizumab in patients with HCC were hypertension, fatigue, and proteinuria.

 

The recommended atezolizumab dose is 1,200 mg, followed by 15 mg/kg bevacizumab on the same day every 3 weeks. If bevacizumab is discontinued, atezolizumab should be given either as 840 mg every 2 weeks, 1,200 mg every 3 weeks, or 1,680 mg every 4 weeks.

 

Ramucirumab + Erlotinib for First-Line Metastatic NSCLC

The FDA approved ramucirumab in combination with erlotinib for first-line treatment of metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) mutations.

 

Efficacy was evaluated in RELAY (NCT02411448), a multinational, randomized, double-blind, placebo-controlled, multi-center study in patients with previously untreated metastatic NSCLC whose tumors have EGFR exon 19 deletion or exon 21 (L858R) substitution mutations. A total of 449 patients were randomized (1:1) to receive either ramucirumab 10 mg/kg or placebo every 2 weeks as an IV infusion, in combination with erlotinib 150 mg orally once daily, until disease progression or unacceptable toxicity.

 

The major efficacy outcome measure was progression-free survival (PFS) as assessed by the investigator (RECIST 1.1). Additional efficacy outcome measures included overall survival (OS), overall response rate (ORR), and duration of response (DoR). Median PFS was 19.4 months in the ramucirumab plus erlotinib arm compared with 12.4 months in the placebo plus erlotinib arm (HR 0.59; 95% CI: 0.46, 0.76; p<0.0001).

 

ORR was 76 percent in the ramucirumab plus erlotinib arm and 75 percent in the placebo plus erlotinib arm, with median DoR of 18.0 months and 11.1 months, respectively. At the time of the final analysis of PFS, OS data were not mature as only 26 percent of the deaths required for the final analysis had occurred (HR 0.83; 95% CI: 0.53, 1.30).

 

The most common adverse reactions observed in patients treated with ramucirumab with erlotinib at a rate of >=20 percent and >=2 percent higher than placebo with erlotinib were infections, hypertension, stomatitis, proteinuria, alopecia, epistaxis, and peripheral edema. The most common laboratory abnormalities at a rate of >=20 percent and >=2 percent higher difference in incidence between arms were increased alanine aminotransferase, increased aspartate aminotransferase, anemia, thrombocytopenia, neutropenia, increased alkaline phosphatase, and hypokalemia.

 

The recommended dose of ramucirumab for metastatic NSCLC in combination with erlotinib is 10 mg/kg every 2 weeks.