Santos Spotlights Success With Checkpoint Inhibition in Frontline Metastatic NSCLC

Immunotherapy has yielded impressive survival benefits when used as a frontline treatment for patients with non–small cell lung cancer (NSCLC); however, with its increasing up-front use, the issue of resistance to checkpoint inhibition has become more pronounced, according to Edgardo Santos, MD, FACP.

“Immunotherapy is generally very effective, very well tolerated, and most importantly, it improves overall survival [OS],” Santos said. “For patients who fail immunotherapy up front, it is very difficult for them to switch to a regular cytotoxic drug. As such, we are focusing right now on trying to overcome resistance to immunotherapy.”

In an interview with OncLive® during an Institutional Perspectives in Cancer webinar on Lung Cancer, Santos, a founding member of the Florida Precision Oncology Care, medical director of research services, and associate professor at Florida Atlantic University, discussed advances made with immunotherapy regimens in the first-line treatment of patients with metastatic NSCLC and areas of active investigation.

OncLive®: The phase 3 KEYNOTE-189 (NCT02578680) trial is one of the most pivotal trials examining immunotherapy in patients with stage IV disease. How did this trial set the stage for future efforts?

Santos: KEYNOTE-189 was a landmark [trial] in NSCLC. In a subsequent follow-up of more than 23 months, the study still demonstrated positive results, with clinical meaningful outcomes, including OS and progression-free survival [PFS]. The combination of pembrolizumab [Keytruda] plus chemotherapy of either cisplatin or carboplatin, followed by maintenance therapy [comprised of] pembrolizumab and pemetrexed, was very well tolerated. [Additionally,] all the primary end points [of the trial] were positive.

A dual-immunotherapy approach was examined in the phase 3 CheckMate-227 trial (NCT02477826). Could you speak to the significance of this research?

After KEYNOTE-189, which showed that the addition of immunotherapy to chemotherapy improves OS, several clinical trials have shown clinical meaningful outcomes for our patients with stage IV lung cancer. CheckMate-227 [examined] the combination of nivolumab [Opdivo], which is a checkpoint inhibitor, and ipilimumab [Yervoy], another checkpoint inhibitor that focuses on the CTLA-4 pathway. For the first time, we have a combination of checkpoint inhibitors with no chemotherapy involved and improved OS over chemotherapy. Now, we have this option for patients who do not want to receive any chemotherapy whatsoever; we can offer them just pure immunotherapy.

Data from the trial led to the May 2020 FDA approval of nivolumab/ipilimumab for use in the frontline treatment of patients with metastatic NSCLC and PD-L1 positivity. Could you expand on how this regulatory decision impacted the paradigm?

Prior to CheckMate-227, we could only use immunotherapy alone if a patient had PD-L1 expression above 50% in the tumor. When we see a patient with lung cancer, we do a biopsy to test for PD-L1. Depending on the expression, we have different indications by the National Comprehensive Cancer Network to decide what we can do [in terms of treatment]. For those patients who have an expression of PD-L1 above 50%, we can use immunotherapy alone. However, for patients with a PD-L1 expression below 50%, we would have to combine with chemotherapy. Now, [because of] CheckMate-227, we can use immunotherapy alone in patients with a PD-L1 expression below 50%.

Then, in the phase 3 CheckMate-9LA trial (NCT03215706), chemotherapy was added to nivolumab/ipilimumab. What was the objective of this research?

The idea here was to achieve better outcomes. In this study, the primary end point was OS, and the trial demonstrated positive results for OS and for PFS. Importantly, by adding chemotherapy to the nivolumab/ipilimumab combination, when you stratify all patients by PD-L1 [expression], which is the best biomarker that we have for immunotherapy, this combination was positive for all the subgroups [analyzed].

The other thing worth mentioning is that the chemotherapy given in this study was very short. Instead of the classic set of 4 to 6 cycles of a platinum-based doublet that we [generally] use for patients with stage IV disease, in this study, we use 2 cycles. As such, the patient receives nivolumab/ipilimumab plus 2 cycles of chemotherapy, and then after those 2 cycles [of chemotherapy] are done, the patient will continue with nivolumab/ipilimumab alone.

Also, during the study, if a patient had adenocarcinoma or squamous cell carcinoma, the appropriate chemotherapy was assigned based on their histology. We know that histology matters for the type of chemotherapy we use.

What should be known about the safety of the chemoimmunotherapy approach?

The cycles of chemotherapy [in CheckMate-9LA] were given once every 3 weeks, so there is 3 weeks off in between cycles 1 and 2. No red flags were reported, and no added toxicities were observed beyond what we already knew [to be common] from nivolumab and ipilimumab, which is important to emphasize.

What are some other ongoing trials of interest that are further examining novel approaches with checkpoint inhibitors?

Several studies are coming up. One phase 3 study is looking at another checkpoint inhibitor called sintilimab [Tyvyt], [which] seems to be effective. The caveat is that we are waiting for the OS data [with this approach]. This study was done in the first-line treatment of [patients with] stage IV lung cancer. Cemiplimab-rwlc [Libtayo] is another checkpoint inhibitor [of interest]. The agent showcased] strikingly positive results, with a long-term median OS [observed in] patients with a PD-L1 expression above 50%.

What are some future directions for research?

What is more important is what we are doing in this space when a patient [progresses] on up-front immunotherapy. What we are doing now is looking to use, perhaps, another checkpoint inhibitor in combination with another pathway to overcome the resistance of the tumor to immunotherapy.

Editor’s Note: This interview was conducted prior to the February 22, 2021 FDA approval of cemiplimab for use in the frontline treatment of patients with advanced NSCLC with a PD-L1 expression level of 50% or higher.