Daniel Morgensztern, MD
Nab-paclitaxel (Abraxane) monotherapy has efficacy in patients with pretreated advanced nonsquamous non–small cell lung cancer (NSCLC) that is not improved by the addition of CC-486, according to findings presented at the 2017 ESMO Congress.
However, in a protocol amended nonrandomized cohort containing similar patients, as well as patients with squamous histology, treated with nab-paclitaxel plus durvalumab (Imfinzi) showed significantly improved response over both other regimens.
Treatment with nab-paclitaxel and CC-486 provided an overall response rate (ORR) of 13.6% compared to 13.8% with nab-paclitaxel monotherapy in patients with previously treated advanced NSCLC, yielding a response rate ratio of 0.99 (95% CI, 0.45-2.15).
No patients receiving the combination in either arm achieved complete response (CR); however partial response was achieved by 11 (13.6%) versus 11 (13.8%) patients, and stable disease (SD) was seen in 41 (50.6%) versus 43 (53.8%) patients on nab-paclitaxel plus CC-466 versus nab-paclitaxel, respectively, making the overall disease control rate (DCR) 64.2% versus 67.5%.
In patients receiving nab-paclitaxel plus durvalumab, the ORR was nearly doubled at 26.6%. One patient in this arm had a CR, PR was achieved by 20 (25.3%), and SD by 35 (44.3%) patients, providing a DCR of 70.9%.
Daniel Morgensztern MD, a medical oncologist at Washington University in St. Louis, discussed the multi-arm, phase II ABOUND.2L+ trial (NCT02250326), which assessed the safety and activity of nab-paclitaxel monotherapy and combination treatment with an immune checkpoint inhibitor or epigenetic therapy in patients with advanced nonsquamous NSCLC who had received ≤1 prior chemotherapy regimens.
“CC-486 is an epigenetic modifying agent that may increase the efficacy of chemotherapy and nab-paclitaxel is already approved for use in combination with carboplatin in the first-line treatment of NSCLC,” said Morgensztern.
CC-486 is an oral formulation of azacitidine, which is a cytidine nucleoside analogue that is incorporated into newly synthesized DNA and RNA. Once incorporated, CC-486 may deplete DNA methyltransferase 1 (DNMT1), induce DNA damage, and promote DNA hypomethylation.
In the nab-paclitaxel/CC-486, monotherapy, and nab-paclitaxel/durvalumab arms, the median age of the patients was 65 years (range, 44-81), 63 (range, 37-82) and 63 (range, 29-84) years, and 61.7%, 62.5%, and 68.4% patients were men, respectively. In the respective arms, 88.9%, 95.0%, and 88.6% were current or former smokers. No patients in the CC-486 or monotherapy arms had received prior immunotherapy, but 9 (11.4%) patients in the nab-paclitaxel/durvalumab arm had.
“At the preplanned futility analysis after 60 progression-free survival (PFS) events in the randomized cohort, the futility criteria were met, with a trending PFS benefit in favor of nab-paclitaxel alone, HR 1.27. We were advised to discontinue CC-486. We then proceeded to enroll patients for the durvalumab arm,” he explained.
Eighty-one patients were randomized to nab-paclitaxel at 100 mg/m2 on days 8 and 15 plus CC-486 at 200 mg daily on days 1 to 14 and 80 patients to nab-paclitaxel monotherapy at 100 mg/m2 on days 1 and 8, both administered every 3 weeks.
A protocol amendment added a nonrandomized treatment arm of 79 patients who received nab-paclitaxel monotherapy at 100 mg/m2 on days 1 and 8 plus durvalumab at 1125 mg on day 15, every 3 weeks. The durvalumab arm began enrolling after the other arms had completed enrollment and allowed the inclusion of patients with squamous histology or prior immunotherapy treatment. All patients on the 3 arms were treated until progression, intolerable toxicity, physician decision to discontinue, or withdrawal of consent.
Data were not evaluable for 8.6%, 8.7%, and 15.2% of patients in the respective CC-466, monotherapy, and durvalumab arms.
In the randomized cohort, median PFS was 3.2 months in patients on nab-paclitaxel plus CC-486 compared to 4.2 months with nab-paclitaxel monotherapy (HR, 1.3; 95% CI, 0.9-2.0). Median overall survival (OS) was 8.4 months versus 12.7 months, respectively (HR, 1.4; 95% CI, 0.88-2.31).
In the nonrandomized patients receiving durvalumab, median PFS was 4.4 months (95% CI, 3.0-5.7) in immunotherapy-naïve patients compared to 6.9 months (95% CI 1.4-NE) in patients who received prior immunotherapy.
Grade 3/4 adverse events reported by patients on nab-paclitaxel/CC-486 versus monotherapy, respectively, included dyspnea (6.3% vs 7.6%), peripheral sensory neuropathy (2.5% vs 7.6%), neutropenia (16.5% vs 10.1%), febrile neutropenia (2.5% vs 0), and anemia (1.3% vs 7.6%). In the durvalumab arm 5.1%, 3.8%, 6.4% and 3.8% of patients reported dyspnea, peripheral sensory neuropathy, neutropenia, and anemia, respectively.
Two deaths occurred with nab-paclitaxel/CC-486, 1 with monotherapy, and 13 with nab-paclitaxel/durvalumab.