Top recent developments in cancer research.
Top recent developments in cancer research.
Nivolumab/Ipilimumab Combination Effective Across Doses
The combination of nivolumab and ipilimumab demonstrated activity as a first-line therapy for patients with advanced non—small cell lung cancer. Four different regimens of the PD-1 inhibitor nivolumab and the anti-CTLA-4 antibody ipilimumab led to response rates of 13% to 39% in 148 patients with no prior exposure to systemic therapy.
The combination induced responses that were both deep and durable, with a low rate of treatment-emergent grade 3/4 adverse events leading to discontinuation. The median progression-free survival ranged between 4.9 and 10.6 months. Median overall survival was not yet reached in all four arms. In the groups that received nivolumab at 3 mg/kg every 2 weeks and ipilimumab at 1 mg/kg every 12 weeks the ORR was 39% and the median PFS was 8 months. At the same dose of nivolumab and with ipilimumab at 1 mg/kg every 6 weeks the ORR was 31% and the PFS was 8.3 months.
The best PFS (median 10.6 months) was seen in those treated with nivolumab at 1 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks; however, the ORR in this group was the lowest at 13%. In terms of expense, ipilimumab is the more expensive drug at $157 per mg whereas nivolumab costs $29 per mg. This could place the price at between $125,000 and $200,000, based on the schedule, dose, and patient's weight. This is less than the anticipated $300,000 cost for the combination in melanoma; however, given the costs associated with this combination, it will be interesting to see whether that plays into the dose selection.
Osimertinib Shows Promise, FDA Approval Pending
The third-generation TKI osimertinib showed a 71% objective response rate in patients with EGFR T790M-mutant non—small cell lung cancer following resistance to frontline anti-EGFR therapy, according to results of the phase II AURA2 trial. The ORR was comprised of 2 complete responses and 139 partial responses.
The stable disease rate at ≥6 weeks was 21%, for a disease control rate of 92%. After a median follow-up of 6.7 months, the median progression-free survival was 8.6 months. The median duration of response was 7.8 months (27% maturity). These findings were slightly less than previous studies; however, the data were not as mature and this study only included those in the second-line or later setting, unlike the AURA trial that contained previously untreated patients.
In previously treated patients in the phase II AURA trial, the ORR was 61% with osimertinib (n = 201). The median PFS and duration of response were not yet mature. In the frontline cohort, early data demonstrated promising efficacy in 60 patients with EGFR-mutant advanced NSCLC treated with osimertinib. In this setting, the 12-month PFS rate was 72%. The ORR was 75%, and the longest observed response was ongoing at 18 months.
Findings from AURA and AURA2 were the basis for a new drug application for osimertinib, which was submitted earlier this year to the FDA and granted a priority review designation, according to the drug’s developer AstraZeneca. Under the priority review timeline, the FDA will make a decision on the medication in the first quarter of 2016.
Atezolizumab Effective With Chemo in NSCLC
Patients with newly diagnosed metastatic non-small cell lung cancer (NSCLC) had double the expected response when the PD-L1 inhibitor atezolizumab was added to chemotherapy. Overall, almost two thirds of 41 evaluable patients had objective responses with atezolizumab plus different platinum-based chemotherapy doublets.
The highest response rate occurred with the combination of atezolizumab, carboplatin, and pemetrexed, as 13 of 17 patients (76.5%) had partial responses. Four patients treated with the anti—PD-L1 inhibitor, carboplatin, and nab-paclitaxel had complete responses.
Overall, the "expected" frontline ORR with chemotherapy alone is around 30%. Response data showed that four of eight (50%) patients in the carboplatin-paclitaxel cohort achieved objective responses, as did nine of 16 (56%) patients who received carboplatin and nab-paclitaxel in addition to atezolizumab. Overall, 26 of the 41 (63.4%) evaluable patients met criteria for objective response, led by a 77% response rate in the pemetrexed arm.
A preliminary analysis of individual types of adverse events suggested that atezolizumab did not add substantially to the adverse events usually observed with cytotoxic chemotherapy. On Twitter, those following #WCLC2015 voiced a desire to avoid chemotherapy, given its side effects. This could weigh in favor of immunotherapy combinations.
Alectinib Receives Priority Review Designation for NSCLC
Alectinib has received an FDA priority review designation for patients with ALK-positive locally advanced or metastatic non—small cell lung cancer who have progressed or are intolerant to crizotinib. The priority review is based on two phase II trials (NP28673 and NP28761) which demonstrated that alectinib had robust activity in patients with ALK-positive NSCLC following progression on crizotinib, including individuals with CNS metastases.
In NP28673, crizotinib-pretreated patients received alectinib at 600 mg orally twice daily until progression. One hundred twenty-two patients were evaluable for response. The median age of patients was 51.6 years and 60% had baseline CNS metastases. Most patients (80%) had received prior chemotherapy. The overall response rate in the full population by independent review was 50%, which consisted of all partial responses. ORR by investigator assessment was 47.8%.
The median duration of response by independent review was 11.2 months. The median progression-free survival with alectinib was 8.9 months. The FDA’s action date for an approval decision is March 4, 2016.
FDA Approval Sought for Frontline Ibrutinib
Abbvie announced that it submitted a supplemental new drug application for ibrutinib as a therapy for treatment-naive patients with chronic lymphocytic leukemia who are over the age of 65. The application was based on findings from the phase III RESONATE-2 trial, which demonstrated superior outcomes with ibrutinib compared with chlorambucil in untreated patients with CLL.
Although exact data were not yet released, AbbVie announced that ibrutinib had improved progression-free survival, overall survival, and overall response rates compared with chlorambucil in the study. Data have been submitted for publication and presentation at an upcoming medical conference. In a prior phase Ib/II trial, single-agent ibrutinib demonstrated an ORR of 84%, with a 10% stable disease rate. At 30 months, the estimated PFS rate was 96% and the estimated OS rate was 97%.
This led to the phase III RESONATE-2 study, which was designated under a special protocol assessment with the FDA. In this program, the FDA ensures that the study is designed to fulfill the requirements needed for approval. Under the Prescription Drug User Fee Act, the FDA is scheduled to review the application within 60 days, at which point the agency will assign a review deadline.
Ixazomib Receives Priority Review Designation for Myeloma
The FDA recently granted a priority review designation to the oral proteasome inhibitor ixazomib in combination with lenalidomide and dexamethasone as a treatment for patients with relapsed and/or refractory multiple myeloma. The application for ixazomib was based on findings from the 722-patient phase III TOURMALINE-MM1 trial, which demonstrated an extension in progression-free survival with the oral triplet therapy compared with lenalidomide and dexamethasone alone.
With these findings, ixazomib became the first oral proteasome inhibitor to demonstrate efficacy in a phase III trial. The FDA will make a decision on the application for ixazomib within 6 months, placing a decision deadline on March 10, 2016. An application for ixazomib was also granted an accelerated assessment from the European Medicines Agency in August 2015. Under this program, the European regulatory agency is scheduled to make a decision in early 2016. This application now makes the third to receive a priority review for patients with multiple myeloma within just a few days.