Perspectives from AACR 2018: Immunotherapy advances in the context of 1st line treatment of lung cancer

Speaker: Marina Garassino

Reporting from AACR 2018 in Chicago, Marina Garassino says that we now have multiple possibilities in first-line immunotherapy for metastatic non-small cells lung cancer (NSCLC). The results from two important phase III studies (KEYNOTE 189 and Check-Mate 227) were presented at the meeting and simultaneously published in the NEJM. Abstracts:

  • Keynote-189 phase III study
  • Results from the Check-Mate 227 phase III study

The KEYNOTE 189 study compared the platinum/pemetrexed doublet chemotherapy with addition of pembrolizumab or placebo in patients with non-squamous histology. Patient's enrolment was stopped at first interim analysis because the results were very positive both in terms of progression-free survival (PFS) and overall survival (OS) with reduction of relative risk of death of about 50% in the pembrolizumab arm. The benefit has been demonstrated in all subgroups (different PD-L1 Tumour Proportion Score groups), making this result potentially a practice changing.

Regarding safety, the triplet arm with pembrolizumab did not show a much increased rate of side effects, apart from renal toxicity which is rare. We don't know what is the immunity contribution in the nephritis and what is the effect of the cisplatin-based chemotherapy, but clinicians should be aware of that possible complication.

The Check-Mate 227 study explored if a combination of an anti-CTLA-4 inhibitor, ipilimumab with PD-1 inhibitor nivolumab could enhance the outcome in patients with advanced NSCLC. After the study design was amended, the two co-primary endpoints are PFS and OS based on Tumour Mutational Burden (TMB) status.

The results suggest that PD-L1 and TMB high are two independent predictive factors. In the TMB high patients, there is a benefit in PFS for the immunotherapy combination (HR 0.58). It is now needed to wait and see if these results will result in better OS, which wasn't the case in the Check-Mate 026 study.

Regarding clinical practice the challenge will be to introduce the TMB assessment which is currently not possible in all clinics.

From 3 potentially practice changing trials in the field, two are combining chemotherapy with immunotherapy, the KEYNOTE 189 and IMpower 150 study of combo consisting carboplatin/paclitaxel, bevacizumab, atezolizumab for which primary endpoint results were presented. The third trial is the Check-Mate 227 based on TMB and the PFS results.

Regarding KEYNOTE 189, the results are clear in terms of PFS and OS in “all comer” patients. We may have to decide if to treat with monotherapy or triplet in patients with PD-L1 over 50%.

Regarding TMB, the oncology community will have to implement the test in clinical practice, but there is a possibility to treat patients with combo if TMB high. We can wait for the OS results to learn what the benefit is with the combinations of nivolumab plus ipilimumab and the combination of carboplatin/paclitaxel, bevacizumab, and atezolizumab.

Abstracts:

  • Keynote-189 phase III study: A randomized, double-blind, study of pembrolizumab or placebo plus pemetrexed and platinum as first-line therapy for metastatic NSCLC. (CT075) L. Ghandi
    www.nejm.org/doi/full/10.1056/NEJMoa1801005
  • Results from the Check-Mate 227 phase III study: Nivolumab + ipilimumab vs platinum-doublet chemotherapy as first-line treatment for advanced non-small cell ling cancer. (CT077) M.D. Hellman
    www.nejm.org/doi/full/10.1056/NEJMoa1801946