OPAL - For when osimertinib is not enough…

Osimertinib has been nothing short of a game-changer for a segment of lung cancer sufferers. For the approximately 30% of patients with non-squamous non-small cell lung cancer (NSCLC) who carry an EGFR mutation, osimertinib has stretched out the average expected survival from months to years. To date, osimertinib has only been studied as a single agent. Until now…

The OPAL study, published in the European Journal of Cancer earlier this month, is a phase 2 trial examining the safety and efficacy of osimertinib and platinum-based chemotherapy (OPP) in patients with previously untreated EGFR-mutated advanced NSCLC.

Patients were randomised to receive osimertinib 80 mg once daily - with either cisplatin or carboplatin - plus pemetrexed for four cycles and maintenance therapy of osimertinib 80 mg daily with pemetrexed every 3 weeks. The primary endpoints were safety and objective response rate (ORR), and the secondary endpoints were complete response rate (CRR), disease control rate (DCR), and progression-free survival (PFS).

In all, 67 patients (34 in arm A and 33 in arm B) were enrolled. The median age was 67 years, 64.2% were female, 31.3% smoked, 31.3% had an ECOG PS of 1, 98.5% had adenocarcinoma histology, 32.8% had central nervous system metastasis, and 52.2% had an L858R mutation.

As of an updated data cutoff for PFS and OS on August 31 2022, the median follow-up time was 33.4 months. Across the whole population, the ORR was 90.9%, with 60/66 evaluable patients achieving CR or PR. The CRR and DCR were 3.0% and 97.0% respectively. This resulted in some quite spectacular waterfall plots:

(C) European Journal of Cancer

The median PFS was 31.0 months, and the 12- and 24-month PFS rates were 90.4% and 71.8%. The median OS was not reached, and the 12- and 24-month survival rates were 96.9% and 92.3%. Analysis of the two cohorts revealed a median PFS of 29.5 months and 12- and 24-month PFS rates of 86.9% and 60.1% in arm A. In arm B, the median PFS was not reached, and the 12- and 24-month PFS rates were 93.7% and 83.6% respectively.

For comparison (which we should never do…) 12- and 24-month survival rates in the pivotal FLAURA trial of osimertinib alone were 89% and 74% respectively.

Grade 3/4 treatment-emergent adverse events were observed in 60 patients (89.6%). Patients in arm B were more frequently found to have haematological toxicity, including neutropenia, anemia, and thrombocytopenia. Prolonged QTc ≥ grade 3 occurred in 4 (11.8%) and 4 (12.1%) patients in arms A and B. Hypokalemia ≥ grade 3 occurred in 3 (8.8%) and 3 (9.1%) patients in arms A and B. Grade 2 pneumonitis was reported in two patients (5.9%) in arm A, whereas grade 1 pneumonitis was reported in one patient (3.0%) in arm B. No treatment-related deaths were reported.

The bottom line: every oncologist who is familiar with osimertinib will have horror stories of patients with advanced EGFR-mutant NSCLC who progress rapidly through osimertinib and are left with significantly inferior treatments and very short survival. OPAL suggests that the benefit of adding platinum-based chemotherapy to osimertinib in this space may improve response rates and ultimately survival. Obviously, a full phase 3 RCT is required to compare outcomes of OPP vs osimertinib alone, but it poses a very interesting question and proves that the book on EGFR-mutant NSCLC is not closed just yet.

Source: Phase 2 Study of Osimertinib in Combination with Platinum and Pemetrexed in Patients with Previously Untreated EGFR-Mutated Advanced Non-Squamous Non-Small Cell Lung Cancer: The OPAL Study. Saito, Ryota et al. European Journal of Cancer, Volume 0, Issue 0. Available from: https://www.ejcancer.com/article/S0959-8049(23)00115-6/fulltext#gr1