Immune Checkpoint Inhibitors in Advanced Non-Small Cell Lung Cancer: A New Paradigm Post-IASLC WCLC 2016

By Melody Watson

The first plenary session on the last day of IASLC WCLC 2016 covered one of the most exciting areas in NSCLC research today: immunotherapy. The first speaker, Julie R. Brahmer, MD, from the Sidney Kimmel Comprehensive Cancer Center at John Hopkins, Baltimore, US, presented key patient-related outcomes from KEYNOTE-024, a pivotal clinical trial comparing the PD-1 inhibitor pembrolizumab to “standard” platinum-doublet chemotherapy in untreated patients with stage IV NSCLC and PD-L1 tumor proportion score (TPS) ≥ 50%.

In addition to previously documented improvements in response rate, progression-free, and overall survival, pembrolizumab resulted in a significantly greater improvement in quality of life and patient-reported outcomes (PROs) compared with chemotherapy (+6.9 vs -0.9; p=0.002). Also pembrolizumab yielded significantly longer median time to deterioration in EORTC QLQ-LC13 composite endpoint of cough, chest pain, and dyspnea (HR: 0.66; 95% CI: 0.44–0.97; p=0.029). Pembrolizumab was also associated with better scores across almost all EORTC QLQ-C30 functioning scales, aside from cognitive functioning, compared with chemotherapy, as well as almost all EORTC QLQ-C30 symptom scales.

The next speaker, Shirish M. Gadgeel, MD, from the Karmanos Cancer Institute/ Wayne State University, Detroit, US, presented the results of subgroup analyses of the OAK trial, a phase III clinical trial of atezolizumab, a PD-L1 blocking monoclonal antibody, versus docetaxel in patients with advanced, platinumexposed NSCLC. Participants in this trial were not restricted on the basis of PD-L1 status, and could have received 1–2 prior lines of chemotherapy. In the primary analysis of OAK trial, atezolizumab resulted in a significantly longer median overall survival (primary endpoint), compared with docetaxel. This overall survival benefit was reported for the PD-L1 subgroups TC3 or IC3, TC2/3 or IC2/3, TC1/2/3 or IC1/2/3, as well as TC0 and IC0 (HRs of 0.41, 0.67, 0.74, and 0.75, respectively). In addition, an overall survival benefit from atezolizumab was shown in patients with non-squamous NSCLC (median 15.6 vs 11.2 months; HR: 0.73; 95% CI: 0.60–0.89; p=0.0015) as well as in patients with squamous disease (median 8.9 vs 7.7 months; HR: 0.73; 95% CI: 0.54–0.98; p=0.0383), regardless of PD-L1 status. The overall survival benefit from atezolizumab was similar in patients with CNS metastases (HR: 0.54), to that observed in patients with no CNS metastases (HR: 0.75) as well as the ITT population (HR: 0.73). Additionally, an overall survival advantage of atezoli-zumab was observed, irrespective of tobacco use and age.

The third speaker, Marina Chiara Garassino, MD, from the Fondazione IRCCS Instituto Nazionale dei Tumori, Milan, Italy, presented results from the phase II international ATLANTIC study, a non-comparative trial of durvalumab, a PD-L1 inhibitor, in heavily pretreated patients (≥3 lines) with locally advanced or metastatic EGFR/ALK wild-type NSCLC. The primary endpoint was objective response rate, assessed by independent central review. Durvalumab was active and was associated with durable response rates, particularly in patients with higher PD-L1 expression. Overall, 7.5% of patients with PD-L1 low/negative status and 16.4% of patients with PD-L1 ≥25% experienced an objective response, as did 30.9% of patients with PD-L1 ≥90%. Dr. Garassino pointed out that these patients were heavily pretreated.

The overall survival rate at 1 year was 34.5% for patients with low/negative PD-L1 expression, 48% for patients with PD-L1 ≥25%, and 51% for patients with PD-L1 ≥90%. Durvalumab appeared to be well tolerated; most adverse events were low grade, and immunological adverse events were manageable.

The final presentation of the session dealt with PD-L1 diagnostics. Julien Adam, MD, from the Institut Gustave Roussy, Villejuif, France, spoke on a multicenter harmonization study for PD-L1 IHC testing in NSCLC. Harmonization of assays and development of laboratory- developed tests (LDTs) are urgently needed in France (and the rest of the world) for several reasons: the Dako and/ or Ventana platforms are not available in all pathology laboratories, assays are still expensive, and PD-L1 testing reimbursement/ funding is insufficient to date.

The 22C3 (Dako), 28-8 (Dako), and SP263 (Ventana) assays performed in several centers were highly concordant and, among the 27 LDTs developed in 7 centers on Dako, Ventana, and Leica platforms, 51.8% demonstrated similar concordance compared to reference assays for tumor staining.

Low concordance was observed for immune cells staining when using a 4-category scale with 1%, 5%, and 10% thresholds. Clone SP263 achieved the highest concordance rate across all platforms.

However, Dr. Adam indicated that caution is required for validation and further use of LDT. Looking forward, selected LDTs will be validated in larger cohorts and by external quality assessment programs in France. Results from these studies will provide a basis for national recommendations on PD-L1 testing in France.