Jason M. Broderick

The FDA has approved cabozantinib (Cabometyx, Exelixis) as a treatment for patients with hepatocellular carcinoma (HCC) who previously received sorafenib (Nexavar, Bayer), according to Exelixis, the company developing the therapy.

The approval was based on findings from the phase III CELESTIAL trial, in which overall survival (OS) was improved by 2.2 months with cabozantinib versus placebo. Median OS with cabozantinib was 10.2 versus 8.0 months for placebo, representing a 24% reduction in the risk of death (HR, 0.76; 95% CI, 0.63-0.92; P = .0049).

Results from the CELESTIAL trial were first presented at the 2018 Gastrointestinal Cancers Symposium. The study was stopped in October 2017, following a positive interim analysis that showed a significant improvement in OS for cabozantinib. The stoppage was preplanned if the P value for OS reached ≤.021.

“Patients with this form of advanced liver cancer have few treatment options, particularly once their disease progresses following treatment with sorafenib,” CELESTIAL trial lead investigator Ghassan K. Abou-Alfa, MD, Memorial Sloan Kettering Cancer Center, said in a statement.

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The FDA has approved cabozantinib (Cabometyx, Exelixis) as a treatment for patients with hepatocellular carcinoma (HCC) who previously received sorafenib (Nexavar, Bayer).

Cabozantinib Granted FDA Approval for Advanced HCC

The FDA has granted an accelerated approval to larotrectinib (Vitrakvi, Loxo Oncology) for the treatment of adult and pediatric patients with solid tumors that have an NTRKgene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment.

The approval is based on findings from patients with TRK-positive tumors enrolled across 3 clinical trials. In results published in the 

 in February 2018, larotrectinib induced an objective response rate (ORR) of 75% (95% CI, 61-85) by independent review and 80% (95% CI, 67-90) by investigator assessment in 55 evaluable patients. Per the independent assessment, there were 7 (13%) complete responses, 34 (62%) partial responses, and 7 (13%) patients with stable disease (SD).

At 1 year, 71% of responses were ongoing. More than half (55%) of patients remained progression-free at 1 year. The median duration of response had not been reached after a median follow-up of 8.3 months. The same was true for median progression-free survival after a median follow-up of 9.9 months.

FDA Grants Onc Drug Accelerated Approval for Key Genetic Driver of Cancer

The FDA has granted an accelerated approval to larotrectinib for the treatment of adult and pediatric patients with solid tumors that have an 

 gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment.

The approval is based on findings from patients with TRK-positive tumors enrolled across 3 clinical trials.  In results published in the 

in February 2018, larotrectinib induced an objective response rate of 75% (95% CI, 61-85) by independent review and 80% (95% CI, 67-90) by investigator assessment in 55 evaluable patients. Per the independent assessment, there were 7 (13%) complete responses, 34 (62%) partial responses, and 7 (13%) patients with stable disease.

The FDA reviewed data from 55 adult and pediatric patients with TRK

 fusion—positive cancers enrolled across a phase I adult trial, the phase II NAVIGATE trial, and the phase I/II SCOUT pediatric trial. The data cutoff for the 

The FDA has granted an accelerated approval to larotrectinib for the treatment of adult and pediatric patients with solid tumors that have an NTRK gene fusion.

FDA Grants Accelerated Approval to Larotrectinib for NTRK+ Cancers

The FDA has granted lorlatinib (Lorbrena) an accelerated approval for the treatment of patients with 

-positive metastatic non—small cell lung cancer (NSCLC) who have progressed on 1 or more ALK tyrosine kinase inhibitors (TKIs).

Specifically, lorlatinib is approved for patients who have progressed on crizotinib (Xalkori) and at least 1 other ALK inhibitor for metastatic disease; alectinib (Alecensa) as the first ALK inhibitor therapy for metastatic disease; or ceritinib (Zykadia) as the first ALK inhibitor therapy for metastatic disease.

The approval is based on a nonrandomized, dose-ranging, multicohort, multicenter phase II study (B7461001) that included a subgroup of 215 patients with 

-positive metastatic NSCLC previously treated with ≥1 ALK kinase inhibitors. The overall response rate with lorlatinib in these 215 patients was 48% (95% CI, 42-55), including a complete response rate of 4% and a partial response rate of 44%.  The median duration of response was 12.5 months (95% CI, 8.4-23.7). 

The FDA-recommended dose of lorlatinib is 100 mg orally once daily.

“The last decade has witnessed dramatic improvements in the treatment of metastatic 

-positive non—small cell lung cancer due to earlier generation ALK biomarker-driven therapies. Yet almost all patients still relapse due to drug resistance, with a large proportion of patients developing new or worsening brain metastases,” Alice T. Shaw, MD, PhD, Professor of Medicine at Harvard Medical School, and Director of the Center for Thoracic Cancers at Massachusetts General Hospital, said in a press release. 

“In a clinical study which included patients with or without brain metastases, Lorbrena demonstrated clinical activity in patients with metastatic 

-positive non—small cell lung cancer who had failed other ALK biomarker-driven therapies," added Shaw. 

In the 215-patient efficacy population, 29 patients had prior crizotinib and no prior chemotherapy, 35 patients had prior crizotinib and 1 to 2 lines of prior chemotherapy, 28 patients had a prior ALK inhibitor (not crizotinib) with or without prior chemotherapy, 75 patients had 2 prior prior ALK inhibitors with or without prior chemotherapy, and 48 patients had 3 prior ALK inhibitors with or without prior chemotherapy.

The median age was 53 years (range, 29-85), 59% were female% 51% were white, and 34% were Asian. Ninety-six percent of patients had a baseline ECOG performance status of 0 or 1 and 95% had adenocarcinoma.

Sixty-nine percent of the 215 patients had a history of brain metastases, and 60% (n = 89) of these patients had measurable disease. Among this subgroup with measurable disease the intracranial response rate was 60% (95% CI, 49%-70%), comprising a 21% CR rate and a 38% PR rate. The median duration of response was 19.5 months (95% CI, 12.4 — not reached).

The safety population the FDA evaluated from Study B7461001 included 295 patients with 

-positive metastatic NSCLC who were treated with 100 mg of lorlatinib orally once daily. The median duration of treatment exposure was 12.5 months (range 1 day to 35 months), with 52% receiving the drug for at least 12 months.

The most common (≥20%) adverse reactions were edema, peripheral neuropathy, cognitive effects, dyspnea, fatigue, weight gain, arthralgia, mood effects, and diarrhea; the most common (≥20%) laboratory abnormalities were hypercholesterolemia, hypertriglyceridemia, anemia, hyperglycemia, increased AST, hypoalbuminemia, increased ALT, increased lipase, and increased alkaline phosphatase.

Thirty-two percent of patient had serious AEs. The most common serious AEs were pneumonia (3.4%), dyspnea (2.7%), pyrexia (2%), mental status changes (1.4%), and respiratory failure (1.4%). AEs resulting in death occurred in 2.7% of patients and included pneumonia (0.7%), myocardial infarction (0.7%), acute pulmonary edema (0.3%), embolism (0.3%), peripheral artery occlusion (0.3%), and respiratory distress (0.3%).

AE-related discontinuations occurred in 8% of patients, 48% of patients needed dose interruptions, and 24% needed at least 1 dose reduction.

The accelerated approval of lorlatinib in this setting is contingent on the results of a confirmatory trial.

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Lorlatinib approved for patients with ALK-positive metastatic NSCLC who have progressed on crizotinib (Xalkori) and at least 1 other ALK inhibitor for metastatic disease.

Lorbrena Gets FDA Accelerated Approval for ALK-Positive Non-Small Cell Lung Cancer

(Lorbrena) an accelerated approval for the treatment of patients with ALK-positive metastatic non—small cell lung cancer (NSCLC) who have progressed on 1 or more ALK tyrosine kinase inhibitors (TKIs).

The approval is based on a nonrandomized, dose-ranging, multicohort, multicenter phase II study (B7461001) that included a subgroup of 215 patients with ALK-positive metastatic NSCLC previously treated with ≥1 ALK kinase inhibitors. The overall response rate with lorlatinib in these 215 patients was 48% (95% CI, 42-55), including a complete response rate of 4% and a partial response rate of 44%.  The median duration of response was 12.5 months (95% CI, 8.4-23.7). 

The FDA has granted lorlatinib (Lorbrena) an accelerated approval for the treatment of patients with ALK-positive metastatic non–small cell lung cancer (NSCLC) who have progressed on 1 or more ALK tyrosine kinase inhibitors.

FDA Grants Accelerated Approval to Lorlatinib for ALK+ NSCLC

Officials with the FDA have approved duvelisib (Copiktra) for the treatment of patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) or relapsed/refractory follicular lymphoma.

The CLL/SLL indication is a standard approval and the follicular lymphoma indication is an accelerated approval contingent on the results of a confirmatory trial. Both indications are for the treatment of patients who have received at least 2 prior therapies.

The approval is based on data from the phase III DUO trial and the phase II DYNAMO study.

For more on this study, visit our sister website, 

Officials with the FDA have approved duvelisib (Copiktra) for the treatment of patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) or relapsed/refractory follicular lymphoma. 