New Challenges With Sequencing Targeted Treatments in NSCLC

Julie Renee Brahmer, MD, MSc, director of the thoracic oncology program and professor of oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, discusses upcoming and recent trials that may change the sequencing of targeted therapies in patients with locally advanced non–small cell lung cancer (NSCLC).

According to Brahmer, determining the sequence of treatment is a major challenge for oncologists that remains unanswered after significant studies of immunotherapies, PD-1/PD-L1 inhibitors, and tyrosine kinase inhibitors (TKIs) have shown efficacy in NSCLC.

The ongoing phase 3 EA5163/S1709 INSIGNA study (NCT03793179) of first-line immunotherapy alone or with chemotherapy may address how pembrolizumab (Keytruda) can be used in sequence with pemetrexed (Alimta) and carboplatin in patients with PD-L1–positive advanced non-squamous NSCLC, according to Brahmer.

Brahmer says that the FDA approval of sotorasib (Lumakras) for KRAS G12C‑mutated locally advanced or metastatic NSCLC based on the CodeBreaK 100 trial (NCT03600883) gives more options for precision medicine, since it was approved for patients who received 1 prior systemic therapy. However, it raises questions on when patients in subgroups should receive targeted treatment and what other treatments they should receive.

TRANSCRIPTION:

0:08 | One of the biggest challenges is trying to figure out how to sequence this type of treatment. Do you start with a combination? Do you start with single agent? And do you add on to chemotherapy if you don't get a response, or you have progression? And so [with] the INSIGNA study from ECOG and SWOG, we hope we'll be able to answer that question in the non-squamous cell histology group. That is a study that's ongoing for patients with PD-L1–positive disease.

I also do think that trying to use precision medicine, particularly in some of these driver mutation groups...we now have a TKI approved for use in the second line treatment setting for KRAS G12C-[mutated] disease. And the question is, what should we be giving first? Should we be giving the G12C inhibitor in that group? Or should they receive immunotherapy up front? So trying to use precision medicine in combination with treatment we hope will guide us in the future. And so, in a lot of these subgroups, we're waiting to see what is the best treatment to start with.