Durvalumab Encouraging for Select Heavily Pretreated Patients With NSCLC

Durvalumab (Imfinzi) showed a modest but encouraging clinical benefit in patients with <em>EGFR</em>-mutant or <em>ALK</em>-positive non&ndash;small cell lung cancer with high tumor PD-L1 expression of &ge;25% in the third-line setting or beyond.

Marina C. Garassino, MD

Durvalumab (Imfinzi) showed a modest but encouraging clinical benefit in patients withEGFR-mutant orALK-positive non—small cell lung cancer (NSCLC) with high tumor PD-L1 expression of ≥25% in the third-line setting or beyond, according to findings from the phase II ATLANTIC trial presented during the 2017 European Lung Cancer Conference.1

The objective response rate (ORR) with the PD-L1 inhibitor was 12.2% (95% CI, 5.7%-21.8%) in this heavily pretreated population, making up Cohort 1 of 3 of the ATLANTIC trial. A similar response rate was noted from Cohort 2 in results previously reported at the 2016 World Lung Cancer Conference.2

“The response rate in this cohort (PD-L1 high) was 12.2% and it was comparable to the results in theEGFRwild-type andALKwild-type population, in which the response rate was 16.4%,” Marina C. Garassino, MD, noted when presenting the results of the first cohort.

The open-label, single-arm, phase II trial enrolled patients with stage IIIb or IV NSCLC who were all heavily pretreated, having received ≥2 prior systemic therapies, including 1 platinum-based chemotherapy regimen and 1 tyrosine kinase inhibitor according to the patient’s rearrangement. Garassino, a medical consultant in the Division of Medical Oncology at the Fondazione IRCCS—Instituto Nazionale dei Tumori, commented that the trial was originally intended for all-comers, but had been restricted to patients with PD-L1 expression ≥25% following results of the phase I trial.

In cohort 1, 111 patients were divided between those with high tumoral PD-L1 expression (≥25%) and those with low to no PD-L1 expression (<25%), as assessed by immunohistochemistry with the VENTANA PD-L1 (SP263) Assay.

The median age of the participants was 61 and 41 patients (36.9%) were male. A majority of the patients had an ECOG score of 1 (58.6%) and did not have a smoking history (58.6%). Ninety-seven patients (87.4%) had anEGFRmutation and 15 patients (13.5%) had anALKtranslocation, including 1 patient that had both. Seventy-seven patients (69.4%) had ≥25% PD-L1 expression.

Additionally, 25 patients (22.5%) had central nervous system metastases that were asymptomatic and/or previously treated. The median number of treatments was 3.0 (range, 2-11) and 46 patients (41.4%) had ≥4 prior regimens.

All patients received 10 mg/kg of durvalumab every 2 weeks for up to 12 months. The primary endpoint of the trial was ORR. Key secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety profile.

Among patients with eitherEGFR-mutant and/orALK-positive disease and PD-L1—high expression (n = 74), 9 patients (12.2%) achieved a response and 23 patients (31.1%) achieved stable disease (SD) for ≥8 weeks (TABLE). The median DOR was 7.4 months (95% CI, 5.4-9.2).

No responses were noted in theALK-positive population (n = 10) with PD-L1—high expression, yet 2 patients achieved SD.

For patients withEGFR-mutant/ALK-positive disease with low/no PD-L1 expression (n = 28), the ORR was 3.6% (95% CI, 0.1%-18.3%) with 1 patient achieving a response. SD of ≥8 weeks was achieved in 5 patients (17.9%). Across all subgroups, all responses were partial responses.

PFS was 1.9 months for patients with both high (n = 77) and low/no (n = 30) PD-L1 expression, “but it seems that there is a different pattern of progression for patients with PD-L1 ≥25 and <25%,” Garassino said when presenting the Kaplain-Meier PFS curves. Patients withEGFR-mutant NSCLC (n = 66) had a PFS of 2.0 months (95% CI, 1.8-3.7) compared with 1.8 months (95% CI, 0.5-1.9) in patients withALK-positive disease (n = 12).

The median OS for patients with high PD-L1 expression was 13.3 months compared with 9.9 months for patients with low/no PD-L1 expression. The 1-year OS rate for those with high expression was 54.8% (95% CI, 41.5%-66.3%) compared with 40.0% (95% CI, 22.1%-57.4%) among patients with low/no expression.

“Higher PD-L1 expression, using 25% as a cutoff, appeared to be associated with a higher response rate, although the small number of patients with PD-L1 low or negative tumors complicates such a comparison,” she commented.

Among patients with anEGFRmutation, the median OS was not reached and the median OS for patients with anALKtranslocation was 6.3 months. At 1 year, the OS rates were 57.4% (95% CI, 42.8%-69.6%) and 35.7% (95% CI, 9.8%-63.3%) for patients withEGFR-mutant andALK&shy;-positive NSCLC, respectively.

“Overall survival data are encouraging in PD-L1—high and -low/negative patients but are limited by the short duration of follow-up,” Garassino said. The median follow-up for patients with high expression was 6.5 months, and the median follow-up was 8.2 months for those with low/no expression.

Treatment-related adverse events (AEs) were experienced by 53 patients (47.7%); there were 6 grade ≥3 AEs and 5 (4.5%) serious AEs with 1 leading to discontinuation. Fourteen patients had immune-mediated AEs (12.6%), including hypothyroidism (9.9%), hyperthyroidism (2.7%), pneumonitis (1.8%), dermatitis, and diarrhea (0.9% each).

Grade ≥3 treatment-related AEs occurred in 8.3% and 17.6% of cohort 2 and cohort 3 patients, respectively. “The safety profile of durvalumab in this selective cohort did not differ from theEGFRandALKwild-type cohort and the majority of AEs were low-grade and immune-mediated AEs were easily manageable,” she stated.

References:

  1. Garassino MC, Cho B-C, Gray JE, et al. Durvalumab in &ge;3rd-lineEGFRmutant/ALK+, locally advanced or metastatic NSCLC: results from the phase 2 ATLANTIC study. Presented at: 2017 European Lung Cancer Conference; May 5-8, 2017; Geneva, Switzerland. Abstract 82O.
  2. Garassino MC, Vansteenkiste JF, Kim J, et al. Durvalumab in &ge;3rd-line locally advanced or metastatic, EGFR/ALK wild-type NSCLC: results from the phase 2 ATLANTIC study. Presented at: 2016 World Lung Cancer Conference; December 4-7, 2016; Vienna, Austria. Abstract PL04a.03.