Novel Chemoimmunotherapy Combinations Build on Established Treatment Standards in Lung Cancer

Lawrence E. Feldman, MD

Investigative combinations including immunotherapy, chemotherapy, and TKIs are widening the treatment paradigms in both small cell lung cancer (SCLC) and non–small cell lung cancer (NSCLC), according to Lawrence E. Feldman, MD.

“We are interested in agents that enhance the efficacy of PD-1 blockade [such as pembrolizumab (Keytruda)],” Feldman said. “[Immunotherapy combinations in lung cancer are] active areas of investigation, with several interesting clinical trials.”

In an interview with OncLive^®, Feldman, a professor of medicine in the College of Medicine at the University of Illinois Cancer Center, discussed shifting standards of care in SCLC, plus the implications of the phase 3 LEAP-006 (NCT03829319) and LEAP-008 (NCT03976375) trials in NSCLC. He also highlighted ongoing research in NSCLC being conducted at the University of Illinois Cancer Center surrounding pembrolizumab in combination with cabozantinib (Cabometyx).

OncLive^®: How has the standard of care in SCLC evolved with the addition of novel therapies?

Feldman: The major advance has been in extensive-stage [ES]–SCLC [involving] the use of immunotherapy combinations with chemotherapy. The 2 immunotherapy agents that have been added to chemotherapy include atezolizumab [Tecentriq] and durvalumab [Imfinzi], based on 2 recent studies. [The phase 3 IMpower133 trial (NCT02763579) investigating atezolizumab plus chemotherapy has] 2 years of follow-up, and the [phase 3 CASPIAN trial (NCT03043872) evaluating durvalumab plus chemotherapy has] 3 years of follow-up. The improvement in overall survival [(OS) observed with these therapies] seems to be holding up at these intervals.

How have the CASPIAN and IMpower133trials contributed to shifts in the SCLC landscape?

These 2 trials have led to the indication for chemoimmunotherapy in ES-SCLC. The CASPIAN trial was a worldwide trial with most of its patients in Europe and the United States, as well as in some other parts of the world. This trial evaluated durvalumab [or placebo] in combination with a platinum agent and etoposide, and the IMpower133 trial tested [carboplatin plus etoposide with or without] atezolizumab.

Both studies were similar in their results, [demonstrating a] median OS improvement. Importantly, the survival benefits from both from the immunotherapy combinations compared with chemotherapy [alone] have now [shown] long-term [benefit], but there’s still room for improvement.

Looking forward, what remaining unmet needs in SCLC would you like to see addressed in clinical trials?

We need to figure out why immunotherapy works in some patients but not in others. We also need to develop therapeutic agents that work with immunotherapy either in an additive or a synergistic fashion.

Currently, the immunotherapy/TKI combination of pembrolizumab plus lenvatinib (Lenvima) is being explored in NSCLC. What efficacy data have been reported thus far with this regimen, and what are your thoughts on this combination?

The LEAP-006 study is a 2-part phase 3 study [in first-line metastatic NSCLC]. In part 1, patients with NSCLC received chemotherapy plus pembrolizumab plus lenvatinib. This part is looking at toxicities, particularly dose-limiting toxicities. Lenvatinib plus pembrolizumab plus chemotherapy [has been shown to be] well tolerated. There were less than 3 dose-limiting toxicities that occurred in each arm of the study, and the study [regimen] was [found to be] safe.

Part 2 of this study, which is the randomized portion, is looking at platinum-based chemotherapy, pemetrexed [Alimta], and pembrolizumab with or without lenvatinib. The investigators concluded that the [the lenvatinib combination] was safe and tolerable [in part 1], and there was some antitumor activity seen. Enrollment for part 2 of this study is still ongoing.

Another study, the phase 3 LEAP-007 trial [NCT03829332], looked at pembrolizumab with or without lenvatinib in patients with a tumor proportion score of at least 1%. This trial did show improvement in objective response rates, but it was not considered a positive study.

How might findings from the LEAP-006 trial regarding immunotherapy/TKI combinations affect treatment for previously untreated patients with NSCLC?

The safety of the 4-drug combination seemed to be good. That’s a positive finding that allows us to feel reassured that, at least from a safety perspective, the combination can be tested. In general, we are looking at combinations of agents to add to immunotherapy to try to improve on the positive results that were seen in both SCLC and in NSCLC.

There have been a few ongoing trials investigating TKIs plus immunotherapy, but [additional trials are investigating] other agents that will help augment the positive results we already see with immunotherapy.

Pembrolizumab plus lenvatinib is now being compared with docetaxel in previously treated patients with metastatic NSCLC with progression after platinum-doublet chemotherapy. What are your thoughts on this combination?

The LEAP-008 trial is looking at pembrolizumab plus lenvatinib compared with docetaxel in second-line NSCLC. Docetaxel [alone] is the current standard of care in the second-line setting. This trial is studying whether lenvatinib could have a modulatory effect in patients with NSCLC who have progressed after platinum-doublet chemotherapy.

[This trial may find a way to improve the efficacy of] pembrolizumab in that setting compared with single-agent docetaxel. The current response rate for single-agent docetaxel is between 5% and 10%, and we know that agent can have toxicities. We’re looking for better treatments in the second-line setting, so LEAP-008 is a promising study.

What work is the University of Illinois Cancer Center doing in lung cancer?

We have a study that right now is a single-institution study at the University of Illinois Chicago, but it will also be at our affiliate institution, the Jesse Brown VA Medical Center. It’s currently undergoing review at the Institutional Review Board. We have [submitted] an investigational new drug application [to the FDA] for cabozantinib plus pembrolizumab in the first-line setting for patients with squamous cell carcinoma of the lung.

Patients in this [phase 2] study will receive standard therapy with platinum chemotherapy, a taxane, and pembrolizumab. In the maintenance setting, patients typically receive pembrolizumab alone. In our study, they will also receive cabozantinib, though at a lower dose than is typically used, such as 40 mg instead of 60 mg, [because of] toxicities, adverse effects, and tolerability. The [primary end point] will be progression-free survival.