Recent Progress in Squamous NSCLC and SCLC Moves Needle Forward

Janakiraman Subramanian, MD

In recent years, several advances have been made in the lung cancer space, particularly in squamous non—small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), said Janakiraman Subramanian, MD, and groundbreaking data from 2 key pivotal trials—KEYNOTE-407 and IMpower133—have resulted in practice-changing outcomes for these patients.

“Just seeing the pace of progress of how we treat, how we approach patients over the last 5 years has been so exciting,” said Subramanian. “We’ve all had to keep pace with the changes, and just this year, we’ve had so many phase III trial data coming out and getting published in the New England Journal of Medicine, not just in the immunotherapy space, but also in the targeted therapy space, which is very promising and very exciting.”

In the phase III KEYNOTE-407 trial, combining the PD-1 inhibitor pembrolizumab (Keytruda) with chemotherapy reduced the risk of death by 36% versus chemotherapy alone in patients with metastatic squamous NSCLC.¹

Those who received the pembrolizumab regimen had a median overall survival (OS) of 15.9 months (95% CI, 13.2—not evaluable) compared with just 11.3 months (95% CI, 9.5-14.8) with chemotherapy alone (HR, 0.64; 95% CI, 0.49-0.85; P = .0017). The addition of pembrolizumab also improved progression-free survival (PFS) in these patients. The median PFS was 6.4 months with the investigational regimen (95% CI, 6.2-8.3) versus 4.8 months (95% CI, 4.3-5.7) with chemotherapy alone (HR, 0.56; 95% CI, 0.45-0.70; P <.0001).

These data led to the October 2018 FDA approval of first-line pembrolizumab for use in combination with carboplatin and either paclitaxel or nab-paclitaxel (Abraxane) for the treatment of patients with metastatic squamous NSCLC, a new standard of care.

In the IMpower133 trial, the addition of atezolizumab (Tecentriq) to standard upfront carboplatin and etoposide was found to significantly prolong survival in patients with extensive-stage small cell lung cancer (SCLC).² After a median follow-up of 13.9 months, the median OS was 12.3 months (95% CI, 10.8-15.9) in those who received the atezolizumab regimen compared with 10.3 months (95% CI, 9.3-11.3) in those who received placebo (HR, 0.70; 95% CI, 0.54-0.91, P = .0069), which equates to a 30% reduction in the risk of death.

This is the first time in 20 years that a new initial treatment option for extensive-stage SCLC has delivered a clinically meaningful survival benefit. As such, the FDA granted a priority review designation to the supplemental biologics license application (sBLA) for the agent. The FDA action date for a decision on the sBLA is March 18, 2019.

OncLive: Could you discuss recent trials that have led to major advances in lung cancer treatment?

In an interview during the 2018 OncLive® State of the Science Summit^TM on Advanced Non—Small Cell Lung Cancer, Subramanian, a medical oncologist and director of thoracic oncology and director of the Center for Precision Medicine at St. Luke’s Cancer Institute, discussed ongoing advances and remaining challenges in the field of lung cancer.Subramanian: The KEYNOTE-407 study was [conducted] primarily [in patients with] squamous cell lung cancer and looked at giving chemotherapy plus pembrolizumab, which is a PD-1 inhibitor. Patients were randomized to receive carboplatin plus paclitaxel plus pembrolizumab versus carboplatin/paclitaxel alone. They also got placebo on that arm. They were looking at the co-primary endpoints with PFS and OS and patients were randomized to either arm, irrespective of their PD-L1 status.

Therefore, whether patients were PD-L1—negative or –positive, they were still able to go on the study and receive immunotherapy. What they clearly showed was that the OS was significantly better in patients on the immunotherapy arm. Similarly, the PFS was also better. Across all treatment parameters, adding immunotherapy for patients with squamous cell lung carcinoma improved their outcomes.

Adverse events were not anything unexpected from what we already knew about immunotherapy and chemotherapy combinations. Definitely, that is the next step in how we treat squamous cell lung carcinomas; until now, chemotherapy has been the primary first-line treatment, but this study has changed that. Now, that we are using chemotherapy combined with immunotherapy and that's becoming the standard of care in how we treat these patients.

[Two other important studies] were IMpower131 and IMpower133. In the SCLC study in which patients were randomized to receive carboplatin/etoposide plus atezolizumab or carboplatin/etoposide plus placebo.

It was very similar in design to the previous study; again, this was a large phase III study where patients with extensive-stage SCLC were randomized to the 2 arms. What they showed was, once again, that adding immunotherapy in the frontline setting to chemotherapy for patients with extensive-stage SCLC improved OS and PFS. Once again, that also is a new standard of care on how we treat patients with SCLC. Toxicities with this regimen were not anything unexpected and were found to be manageable.

In IMpower131, we looked at the combination of carboplatin/paclitaxel plus atezolizumab versus carboplatin/paclitaxel plus placebo. Of course, this was a more complex, 3-arm study, and they allowed 2 different versions of paclitaxel. Then, we had a placebo arm. Again, the primary endpoints were OS and PFS; there was a definite benefit in terms of PFS. In terms of OS, they haven't completed their analysis.

What other agents are making headway in this space?

What are some overall challenges that need to be addressed?

We only have the data from the first interim analysis, and what we saw was it did not show a significant difference in OS. However, it remains to be seen what the subsequent analysis will show. Interestingly, what we did find was at the 1-year interval, the 1-year survival was not significantly different between these 2 arms. However, as time went on, the 2-year survival seemed to show a separation between the curves and so what that study, at least at present, tells us is that there is definitely a group of patients with SCLC who benefit from chemotherapy /immunotherapy. Who these patients are, how best we select them, and how we deliver the appropriate treatment to them is the key issue that we will probably know better once the final results of that study read out. Whether this combination will also become a standard of care will depend on the final OS data.There are other immunotherapy agents [on the horizon]. Nivolumab is another one that we are waiting to see more data on. However, the more interesting part of this is, the field overall has come to the conclusion that immunotherapy should move to the frontline setting—either as a single-agent or in combination with chemotherapy. Then, that brings the dilemma of what to do after that for these patients. What are our subsequent options for them? That is a major dilemma—no question. There are now studies that are looking at new checkpoint inhibitors that are either completely novel or are in combination with current immunotherapy therapies; this is definitely something that we are looking at. There are other targeted agents that are being explored as well. That, is where the field is moving next.In SCLC, and squamous NSCLC for that matter, our understanding of the biology of the disease is still quite limited and that hamstrings us in a very significant manner. Not only that, we also need just a little bit of good fortune here to move the needle a little bit forward.

We need to learn from these patients—those who benefitted [from immunotherapy]. We need to have better tissue collection on our patients, which is one of the problems that we still struggle with. Particularly in patients with SCLC, there is very limited tissue collection and even the quality of samples that we collect are very limited, so we don't have actual good data on how the tumor evolves over time with different treatments. Knowing that information could change the paradigm of how we treat patients with SCLC. With these small, tiny biopsies we get, we are very limited by what information we have on these tumors, so a good tissue collection protocol [is needed].

We also need to enroll our patients on clinical trials so that we can get clinical outcomes data. Marrying these biological data with our clinical outcomes data is where we can continue to move the needle forward. It’s a limited success, but it's a promising success that we have. There have been numerous failed studies, but that shouldn't mean that we should stop. For all those failures, we have moved the needle a little bit. We should keep continuing with the effort to continue to move that needle forward.

References

1. Paz-Ares LG, Luft A, Tafreshi A, et al. Phase 3 study of carboplatin-paclitaxel/nab-paclitaxel (Chemo) with or without pembrolizumab (Pembro) for patients (Pts) with metastatic squamous (Sq) non-small cell lung cancer (NSCLC); KEYNOTE-407 investigators. J Clin Oncol. 2018;36(suppl; abstr 105). ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_suppl.105.
2. Liu S, Mansfield A, Szczesna S, et al. IMpower 133: primary PFS, OS and safety in a PH1/3 study of 1L atezolizumab + carboplatin + etoposide in extensive-stage SCLC; IMpower 133 investigators. In: Proceedings from the IASLC 19th World Conference on Lung Cancer; September 23-26, 2018; Toronto, Canada. Abstract PL02.07.