Nab-Paclitaxel Demonstrates Efficacy Alone and With Durvalumab in NSCLC

Daniel Morgensztern, MD

According to findings presented at the 2017 ESMO Congress, nab-paclitaxel (Abraxane) monotherapy demonstrated efficacy in patients with pretreated advanced nonsquamous non—small cell lung cancer (NSCLC) that is not improved by the addition of CC-486. However, treatment with nab-paclitaxel plus durvalumab (Imfinzi) induced significantly improved response over both other regimens in a protocol amended nonrandomized cohort containing similar patients, as well as patients with squamous histology.

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.

“Single-agent nab-paclitaxel has promising preliminary efficacy and may be developed as a potential therapeutic option in patients with previously treated advanced nonsquamous NSCLC; however, addition of CC-486 did not appear to benefit these patients clinically,” said Morgensztern.

“The combination of nab-paclitaxel and durvalumab was feasible in patients with both squamous and nonsquamous NSCLC and showed improved PFS,” Morgensztern continued. “Updated data for the ongoing durvalumab combination arm of the study, including overall survival, will be presented in the future.”

Reference:

Morgensztern D, Ong T, Cobo Dols M, et al. ABOUND.2L+: nab-paclitaxel (nab-P) +/- CC-486 or durvalumab in previously treated patients with advanced non-small cell lung cancer (NSCLC). Presented at: 2017 ESMO Congress; September 8-12; Madrid, Spain. Abstract LBA48.