Medical Intelligence

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Highlighting Key Developments in Clinical and Strategic Thinking
From Web-Based Sources.
Updated January 2018.

FDA Approves Cabozantinib (Cabometyx) Tablets forPreviously
Untreated Advanced RCC – Approval expands indication 
Acting earlier than expected, the FDA has approved cabozantinib tablets for the expanded indication of patients with advanced renal cell carcinoma (RCC). The FDA’s priority review and approval was based on results from the randomized phase 2 CABOSUN trial in patients with previously untreated RCC, which demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) versus sunitinib, a current standard of care. Previously, approval was not expected until February.

The label expansion follows the initial FDA approval of cabozantinib in April 2016 for the treatment of patients with advanced RCC who have previously received anti-angiogenic therapy.

“The CABOSUN trial enrolled treatment-naïve patients with advanced kidney cancer, including those who are known to fare poorly, such as patients with intermediate- or poor-prognostic factors and those with bone metastases or multiple sites of metastatic disease,” said Toni Choueiri, MD, a principal investigator on the CABOSUN trial and  Director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston.

“Physicians are already experienced in using CABOMETYX in the second-line advanced RCC setting, and it is a much-needed advance to also now have CABOMETYX as an option for their patients with previously untreated advanced RCC,” he added

The expanded approval of the agent is based on results of the phase 2 CABOSUN trial, which met its primary endpoint of improving PFS.

According to the independent radiology review committee analysis of the data, cabozantinib demonstrated a clinically meaningful andstatistically significant 52% reduction in the rate of disease progression or death (HR 0.48, 95% CI 0.31-0.74, P=0.0008).

Median PFS for cabozantinib was 8.6 months vs 5.3 months for sunitinib, corresponding to a 3.3 month (62%) improvement. All causality grade 3 or 4 adverse reactions occurred in 68% of patients receiving cabozantinib and 65% of patients receiving sunitinib. The most frequent all causality Grade 3-4 adverse reactions (≥5 percent) in patients treated with canozantinib were hypertension, diarrhea, hyponatremia, hypophosphatemia, palmarplantar erythrodysesthesia (PPE), fatigue, increased ALT, decreased appetite, stomatitis, pain, hypotension, and syncope. Twenty-one percent of patients in the cabozantinib arm compared to 22% of patients receiving sunitinib discontinued treatment due to adverse events.


FDA Approves Adjuvant Sunitinib for High-Risk RCC
The FDA has approved sunitinib (Sutent) for use as an adjuvant therapy in patients with renal cell carcinoma (RCC) who have received nephrectomy and are high risk for recurrence. Approval for sunitinib is based on findings from the phase III S-TRAC trial, which were presented at the 2016 ESMO Congress and published in the New England Journal of Medicine. In the study, adjuvant sunitinib prolonged disease-free survival (DFS) by 1.2 years compared with placebo following nephrectomy for patients with high-risk clear cell RCC.

After a median follow-up duration of 5.4 years, the median DFS was 6.8 years in the sunitinib arm compared with 5.6 years with placebo (HR, 0.76; 95% CI, 0.59-0.98; P = .03). In higher risk patients, the median DFS was 6.2 versus 4.0 years for sunitinib and placebo, respectively (HR, 0.74; 95% CI, 0.55-0.99; P = .04). Grade 3/4 adverse events (AEs) were experienced by 63.4% of patients in the sunitinib group compared with 21.7% in the placebo arm. The FDA approved sunitinib for this indication despite a 6-6 vote on the potential approval from its Oncologic Drugs Advisory Committee in September.

“This is the first adjuvant treatment approved for patients with renal cell carcinoma, which is significant because patients with this disease who have a nephrectomy are often at high risk of the cancer returning,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a statement. “There is now an approved therapy for patients who previously did not have options to potentially reduce cancer recurrence.”

The study randomized 615 patients with clear cell RCC to receive sunitinib (n = 309) or placebo (n = 306). Patient characteristics were well balanced between the arms. The median age of patients in the sunitinib arm was 57 years, and most were males (71.8%). Most patients had an ECOG performance score of 0 (73.8%). Overall, 90.6% of those in the sunitinib arm had a stage 3 tumor, with no nodal involvement and no metastasis. Of these patients, 37.2% were considered low-risk (any Fuhrman grade and ECOG score of 0 or Fuhrman grade 1 and ECOG score of ≥1) and 53.4% were high-risk (Fuhrman grade ≥2 and ECOG score of ≥1). Sunitinib was administered at 50 mg daily for 4 weeks followed by 2 weeks without treatment. One dose reduction was allowed in the study, to 37.5 mg per day. Overall, more than half of patients (54.2%) were able to maintain treatment with the starting dose of 50 mg per day. The median daily dose was 45.9 mg.

After 3 years, 64.9% of those in the sunitinib group were alive and remained disease-free compared with 59.5% in the placebo arm. At 5 years, the DFS rate was 59.3% with sunitinib versus 51.3% for placebo. Median overall survival findings were not yet mature at the time of the analysis; however, the hazard ratio between the two arms for survival was 1.01 (95% CI, 0.72-1.44; P = .94).

The investigator assessed median DFS in the sunitinib arm was 6.5 years compared with 4.5 years with placebo (HR, 0.81; 95% CI, 0.64-1.02; P = .08). In higher risk patients, the median DFS by investigator assessment was 5.9 versus 3.9 years for sunitinib and placebo, respectively (HR, 0.76; 95% CI, 0.58-1.01; P = .06).

Tivozanib Approved in Europe for Kidney Cancer
The European Commission (EC) has approved tivozanib (Fotivda) for the treatment of patients with advanced renal cell carcinoma (RCC). The drug is specifically approved for the frontline treatment of adult patients with advanced RCC and for adults with advanced RCC who are VEGFR- and mTOR-inhibitor mTOR-inhibitor naïve following disease progression after 1 prior treatment with cytokine therapy.

The approval, which follows a positive recommendation from the European Medicines Agency’s Committee for Medicinal Products for Human Use, is based on the phase III TiVO-1 trial, in which tivozanib reduced the risk of disease progression or death by over 20% vs sorafenib (Nexavar) in patients with advanced RCC who received up to 1 prior line of therapy (excluding targeted agents). Patients assigned to tivozanib were more likely remain on full treatment dose (86% vs 57%; P = .001). Only 14% of patients in the experimental arm required dose reduction due to adverse events (AEs) compared with 43% in the sorafenib arm. Patients in the tivozanib group were also less likely to experience AEs usually associated with other VEGFR-TKIs including diarrhea (23% vs 33%) and hand-foot syndrome (14% vs 54%).

Researchers at Institut Gustave Roussy are currently evaluating tivozanib in combination with nivolumab (Opdivo) for patients with advanced RCC in the phase I/II dose escalation/expansion TiNivo trial. Additionally, results are anticipated in 2018 for the pivotal TIVO-3 trial, a randomized, controlled, multicenter, open-label study comparing tivo-zanib to sorafenib in patients with refractory advanced RCC.

TIVO-3 Study Futility Analysis Completed—No Changes to Protocol
AVEO Oncology has announced the completion of a pre-planned futility analysis of the Phase 3 TIVO-3 trial, the company’s randomized, controlled, multi-center, open-label study to compare Fotivda® (tivozanib) to sorafenib in subjects with refractory advanced renal cell carcinoma (RCC). Based on results of the futility analysis, which was reviewed by an independent statistician, the study will continue as planned without modification. This analysis did not allow for early stopping due to efficacy to assure adequate follow-up for the key secondary endpoint of overall survival. The pre-planned futility analysis was triggered by the reporting of 128 progression events in early August. Additional events were recorded as part of the data management process leading into the futility analysis, resulting in a revised data cut-off date for the analysis of May 29. The Company continues to expect the TIVO-3 to read out in the first quarter of 2018.

The TIVO-3 trial, together with the previously completed TIVO-1 trial of tivozanib in the first line treatment of RCC, is designed to support regulatory approval of tivozanib in the US as a first and third line treatment for RCC.  The TIVO-3 trial was designed to enroll patients with recurrent RCC who have failed at least two prior regimens, including VEGFR-TKI therapy (other than sorafenib). Eligible patients may also have received checkpoint inhibitor therapy in earlier lines of treatment. Patients are randomized 1:1 to receive either tivozanib or sorafenib, with no crossover between arms. The primary endpoint of the study is progression free survival. Secondary endpoints include overall survival, overall response rate, and safety and tolerability.

The TiNivo trial is a Phase 1/2 study of tivozanib in combination with Bristol-Myers Squibb’s OPDIVO® (nivolumab), an immune checkpoint, or PD-1, inhibitor, for the treatment of RCC. The TiNivo trial is being led by the Institut Gustave Roussy in Paris under the direction of Bernard Escudier, MD, Chairman of the Genitourinary Oncology Committee. The trial advanced into the Phase 2 expansion portion following successful completion of the Phase 1 dose escalation portion. The combination was well tolerated to the full dose and schedule of single agent tivozanib, with no dose limiting toxicities. The expansion portion of the trial is expected to enroll an additional 20 subjects. Phase 1 results from the ongoing study have been submitted for presentation at a scientific meeting taking place in the fourth quarter.

Phase III IMmotion151 Study Shows Tecentriq (Atezolizumab) and
Avastin (Bevacizumab) Reduced Risk of Disease Worsening or
Death for Initial Treatment of Advanced RCC

TECENTRIQ and Avastin showed improvement in investigator-assessed progression-free survival (PFS) compared with sunitinib for patients whose disease expressed PD-L1. Data will be discussed with health authorities globally, including the FDA and European Medicines Agency.

Genentech has announced that the Phase III IMmotion151 study met its co-primary endpoint of investigator-assessed progression-free survival (PFS) and demonstrated that the combination of TECENTRIQ® (atezolizumab) and Avastin® (bevacizumab) provided a statistically significant and clinically meaningful reduction in the risk of disease worsening or death (PFS). The results were in patients whose disease expressed the PD-L1 (programmed death-ligand 1; PD-L1 expression ≥1 percent) protein compared with sunitinib for first-line treatment of metastatic renal cell carcinoma (mRCC).  KCJ