Deeper Understanding Emerging of KRAS Biology in NSCLC

Ferdinandos Skoulidis, MD, PhD

Approximately 25% to 30% of patients with non—small cell lung cancer (NSCLC) have activating mutations in KRAS, creating a challenging unmet treatment need, explained Ferdinandos Skoulidis, MD, PhD.

However, prior studies have shown that, by picking apart the KRAS subtype, there are smaller subsets harboring mutations that could be associated with response to immunotherapy agents. These subgroups include KL (STK11/LKB1 mutations), KP (TP53), and KC (CDKN2A/B). In an analysis further exploring these subtypes, it was found that tumors in the KP subgroup are more likely to respond to checkpoint inhibition.¹

Additionally, according to data from the CheckMate-057 trial, immunotherapy might offer a valid treatment option for these patients. This study randomized 582 patients after failure with platinum-based doublet chemotherapy to nivolumab (Opdivo) or docetaxel. In a subgroup analysis of CheckMate-057, patients with KRAS mutation were more like to benefit from nivolumab in terms of an improvement in overall survival (OS).²

“Immunotherapy has emerged as a major treatment option in both metastatic and even earlier stage squamous carcinoma and adenocarcinoma,” said Skoulidis.

OncLive: Please provide an overview of your presentation.

In an interview with OncLive^® at the 2017 State of the Science Summit^TM on Advanced NSCLC, Skoulidis, an assistant professor, Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discussed potential treatment options for KRAS-mutated lung cancer and highlighted developments in biomarker research in other areas in the field.Skoulidis: I discussed the role of biomarkers in the management of NSCLC. This is a very topical theme because lung adenocarcinoma is emerging as the pinnacle of precision cancer medicine among the solid tumors, with the recognition that NSCLC does not constitute a single disease. NSCLC consists of many different molecularly definitive entities, each of which needs to be treated in a unique way.

What are the best treatment options for patients with KRAS-mutant lung cancer?

I discussed the 5 biomarkers that are currently linked to FDA-approved therapies in NSCLC. Those mutations include EGFR, ALK, and ROS1 rearrangements, BRAF V600E, and the expression of PD-L1.KRAS represents the “elephant in the room” in the field of targeted cancer therapy. Approximately 25% to 30% of patients with lung adenocarcinoma will be found to have an activating mutation in KRAS. We have known about KRAS for a long time. There are no FDA-approved targeted therapies for patients with KRAS-mutant lung adenocarcinoma, so this represents a major unmet clinical need.

Over the last couple of years, immunotherapy has emerged as a major treatment option in both patients with metastatic and even earlier-stage squamous carcinomas and adenocarcinomas. There is some evidence from the CheckMate-057 trial that immunotherapy might represent a very valid treatment option for patients with KRAS-mutant lung cancer.

However, what has become clear to us is that KRAS-mutant lung adenocarcinoma is clinically heterogeneous, meaning one patient does not respond in the same way as another due to molecular diversity. We have previously shown that one of the major determinants of the heterogeneity of KRAS-mutant lung adenocarcinoma is common mutations or mutations in genes that happen together with KRAS.

We have identified mutations in 3 key tumor suppressor genes that we believe define 3 major subgroups of KRAS-mutant lung adenocarcinoma. Those are mutations in TP53 in the KP subgroup, STK11 in the KL subgroup, and the p16 gene (CDKN2a/INK4a) in the KC subgroup.

We have previously shown that there are many differences between these subgroups. Potentially, the most clinically relevant difference is in the response of the subgroups to immunotherapy. Through a large collaboration between The University of Texas MD Anderson Cancer Center, Memorial Sloan Kettering Cancer Center, Dana-Farber Cancer Institute, and Massachusetts General Hospital, we collected 174 patients with KRAS-mutant lung adenocarcinoma and assessed their response to immunotherapy based on common mutations.

What became immediately apparent was that there were very big differences in how these tumors responded to immunotherapy depending on their common mutations. Tumors that had common mutations in the KL subgroup exhibited primary resistance to immunotherapy. The likelihood of responding was only 7.4%. On the other hand, tumors in the KP subgroup had a 35.7% likelihood of responding to immunotherapy. This is more than 5-fold compared with the KL subgroup. This suggests that we should be looking at what happens with mutations together with KRAS.

In addition to differences of objective response rates (ORR) there were statistically significant differences in progression-free survival and OS. The median OS of the KP subgroup that responded to immunotherapy was more than double that of the median OS of the KL subgroup. This suggests that it adds an extra parameter to what we believe should be a composite predictive biomarker panel to determine benefit from immunotherapy. PD-L1 expression plays a role and will continue to have one.

What is the promise of combinations with immunotherapy in the field of lung cancer overall?

There are emerging data about tumor mutational burden as a predictive biomarker for response to immunotherapy. We believe that those 2 parameters should be coupled with mutations or genetic alterations. There are 3 individual genes that we are particularly interested in, which are KRAS, p53, and STK11. By adopting an integrative approach to biomarker development, we can achieve greater predictive power.The KEYNOTE-021 data suggested that the combination of pembrolizumab with platinum-doublet chemotherapy of carboplatin/pemetrexed was associated with a 55% ORR. This is almost double that of chemotherapy alone, which is in the region of 25% to 30%.

What else is important to note about genomic testing?

What was particularly interesting was that the benefit of combining chemotherapy to immunotherapy seemed to extend to PD-L1—negative tumors. These are tumors where we would not use immunotherapy as first-line treatment. Those are the more challenging tumors. By combining chemotherapy with immunotherapy, we are achieving an additive effect. We do not know whether it is synergistic, but at least there is an additive effect. This is a treatment option for patients whom monotherapy with a PD-1 inhibitor is not currently indicated. We would advocate for broad genomic profiling in every patient with lung adenocarcinoma that walks through the clinic. Some of these genetic alterations are already linked to FDA-approved therapies, and those should continue to be tested.

However, there is a broad panel of emerging biomarkers. For example, with MET exon 14 skipping mutation, the HER2 mutation, or RET rearrangements, there are no FDA-approved drugs in lung cancer. Yet, there are drugs [that target these mutations] that have been approved in other disease settings. Even if we cannot offer something as standard of care, we can at least direct patients into appropriate clinical trials.

Overall, broad genomic profiling in addition to determining PD-L1 expression status should be the standard of care for patients with stage IV disease that walk through the clinic.

References

1. Skoulidis F, Byers LA, Diao L, et al. Co-occurring genomic alterations define major subsets of KRAS -mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities. Cancer Discov. 2015;5(8): 860—877. doi: 10.1158/2159-8290.CD-14-1236.
2. Borghaei H, Paz-Ares, L, Horn L. Nivolumab versus docetaxel in advanced nonsquamous non—small-cell lung cancer. N Engl J Med. 2015;373:1627-1639. doi:10.1056/NEJMoa1507643.