What's Next for Immunotherapy and Targeted Therapy in Lung Cancer?

While immunotherapy is moving into multiple realms of oncology, it still has a strong influence in the treatment of lung cancer.

The PD-1 inhibitors Opdivo (nivolumab) and Keytruda (pembrolizumab), along with the PD-L1 inhibitor Tecentriq (atezolizumab), have all received FDA approvals as single-agents for the treatment of patients with non­—small cell lung cancer (NSCLC). Researchers are now focused on expanding this success through combination regimens, either combining immunotherapy agents or a checkpoint inhibitor with chemotherapy.

For example, the FDA has granted a priority review to a supplemental biologics license application (sBLA) for Keytruda in combination with pemetrexed plus carboplatin as a treatment for patients with metastatic or advanced NSCLC without EGFR or ALK mutations and regardless of PD-L1 expression. The sBLA was based on part 2 of cohort G in the KEYNOTE-021 trial, in which the Keytruda triplet elicited an objective response rate of 55 percent compared with 29 percent with the chemotherapy agents alone.

“This is unlikely to be just a chance finding. There is specific scientific rationale to support the combination of chemotherapy with immunotherapy, and there is a large body of literature suggesting that these combinations may be beneficial. The final judgment will be made by the FDA, but this data is quite impressive,” said Vassiliki A. Papadimitrakopoulou, M.D., professor, Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center.

What are the most important current developments in lung cancer?

In an interview with CURE, Papadimitrakopoulou discussed recent developments with immunotherapy in NSCLC and the continued significance of EGFR and ALK inhibitors in the field. The landscape is dominated by the recent approvals of checkpoint inhibitors for all non­—small cell lung cancer patients including adenocarcinoma and squamous histologies, both in frontline and second line or above. I think this is a pretty dramatic evolution in the landscape compared to a couple of years ago.

What regimens in immunotherapy look the most promising?

We also have significant developments in the field of targeted therapies for patients whose tumors carry EGFR mutations or ALK gene-fusion, with approvals of multiple new agents and several in the pipeline that are projected to be approved soon.The combination of chemotherapy and anti­—PD-1 appears to be active in all-comers with no prerequisite for high expression of PD-L1, making this indication a quite interesting proposition for patients that may not be candidates for standard-of-care Keytruda.

There is very interesting data that has emerged over the past year with combinations of immunotherapy agents, anti—PD-1 and anti–CTLA-4, as well as combinations of standard chemotherapy withe anti-PD-1 agents.

As it pertains to combinations of anti­—PD-1 and anti­–CTLA-4, the frontline study that included a small number of patients with combination of Opdivo and Yervoy (ipilimumab) suggested a high response rate and quite long duration of response, however this data is limited, and we need to see confirmatory trials in larger groups of patients and randomized clinical trial data. The data that we have so far is not definitive, it is not phase 3 data. So, highly encouraging, but still too early to definitively be established in this space.

What has been the impact of the approval of Keytruda in the first- and second-line settings?

We also have data from the combination of anti­—PD-L1 and anti-CTLA-4 with the combination of durvalumab and tremelimumab, which also suggests high response rates and long duration of response. However, this data was also in a setting where there was no randomization. This data was the preliminary evidence for a clinical trial that has completed accrual, which combines these two gents against the standard of care. We are eagerly awaiting these results.We have already defined a subset of patients that seem to benefit from single-agent anti­­—PD-1, which are patients who have a high expression of PD-L1—more than 50 percent of the cells. It is unclear whether this is the optimal way to determine benefit from this therapy, but this is a very active field of investigation. However, the approval of Keytruda in this setting cements that this is certainly a group of patients that should be considered for upfront immunotherapy.

Is there anything else in the lung cancer space that is particularly exciting?

The landscape has dramatically changed. If you think back to 2014 or 2015, there was no evidence that any addition to the standard chemotherapy regimens beyond Avastin (bevacizumab) would make significant impact in this disease. For our patients, it is an opportunity to receive active therapy that is much less toxic, and that may benefit them for a long period of time. This is a significant change for us and a clinically meaningful change for the patients.There are multiple options for first-line therapy for patients with EGFR-mutated tumors, and the first-generation EGFR TKIs are all being used in the community and the academic setting with Tarceva (erlotinib), Gilotrif (afatinib) and Iressa (gefitinib) being used by different percentages in the community.

Second-line therapy for patients who develop resistance to first-generation EGFR TKIs is now dominated by the approval of Tagrisso (osimertinib) with a confirmatory trial establishing these as the standard of care for patients whose tumors have developed T790M mutations. There is a lot of activity happening in terms of investigating additional resistance mechanisms.

For ALK gene-fusion, we now have three agents that have been approved. Originally Xalkori (crizotinib) was approved in 2011, followed by Zykadia (ceritinib) and Alecensa (alectinib), and there are two more agents being studied in this setting. There are also emerging options for frontline therapy. We just saw recent data with Alecensa from the Japanese trial, J-ALEX, that suggests that this is an acceptable and very active choice for patients that have this disease. However, the standard of care for this disease remains Xalkori. Zykadia has also demonstrated superiority compared to chemotherapy in this frontline setting indication. Both of these agents, Zykadia and Alecensa, are used in the second-line setting, and selection of patients who receive these agents depends on the clinical characteristics of the disease. CNS involvement is a significant feature of the disease and needs to be taken into account when we choose frontline therapy.