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Immunotherapy for SCLC
My Thoughts on the Evolving Role of Immunotherapy for SCLC

Released: April 04, 2019

Expiration: April 02, 2020

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Despite consistently poor outcomes, the treatment of extensive-stage small-cell lung cancer (SCLC) has remained stagnant for decades. Initial platinum-based chemotherapy achieves rapid and even complete responses, but these benefits are distressingly transient, with most patients progressing shortly after completing initial chemotherapy. With immunotherapy having fundamentally changed our approach to treating non-small-cell lung cancer, we have eagerly awaited its development in SCLC, a tumor characterized by a high mutational burden and predicted to benefit from immunotherapy. Finally, we have had 2 landmark FDA approvals introducing immunotherapy as a viable option for patients with SCLC: third-line nivolumab monotherapy and first-line atezolizumab in combination with chemotherapy.

CheckMate 032: Nivolumab With or Without Ipilimumab in Patients With Advanced SCLC and Disease Progression After Platinum-Based Chemotherapy
The multicohort phase I/II Checkmate 032 study gave us a glimpse of the potential for immunotherapy in this highly lethal disease. In pretreated patients, the PD-1 inhibitor nivolumab alone or in combination with the CTLA-4 inhibitor ipilimumab showed response rates of approximately 10% to 20%. Although these response rates were not astounding, there was an impressive durability observed.

As the study expanded, the subsets of patients treated in the third-line setting were separately analyzed. Here, the response rate was 11.9% with a median duration of response of 17.9 months—impressive by any measure. This led to FDA approval on August 16, 2018, of nivolumab for advanced SCLC with disease progression after platinum-based chemotherapy and at least 1 other line of therapy. Unfortunately, many patients with extensive-stage SCLC never make it to the third-line setting.

IMpower133: Addition of Atezolizumab to Carboplatin/Etoposide in Patients With Newly Diagnosed Extensive-Stage SCLC
Our greatest opportunity to have an impact on this highly lethal disease is in the first-line setting. This was studied in the IMpower133 study, a global, randomized, placebo-controlled phase III study that explored the impact of adding the PD-L1 inhibitor atezolizumab to carboplatin/etoposide for newly diagnosed SCLC. In this trial, patients received 4 cycles of standard carboplatin/etoposide and were randomized to receive atezolizumab or placebo concurrently and then as maintenance therapy. Atezolizumab was well tolerated and did not compromise the ability to deliver 4 full cycles of chemotherapy. The study met both of its primary endpoints, improved PFS (5.2 vs 4.3 months) with an HR of 0.77 and, of importance, improved OS (12.3 vs 10.3 months) with an HR of 0.70—both statistically significant and clinically meaningful. This led to the FDA approval of atezolizumab plus carboplatin/etoposide for first-line treatment of extensive-stage SCLC on March 18, 2019.

Why These Are Clinically Significant Findings
I am often asked to comment on what some clinicians interpret to be modest improvements with immuno-chemotherapy vs standard chemotherapy in extensive-stage SCLC. In IMpower133, there was no difference in the response rate with addition of atezolizumab to chemotherapy and the improvement in median OS was only 2 months more than that achieved with carboplatin/etoposide alone. Similarly, in Checkmate 032, the response rates were fairly low. I understand these concerns, but in my opinion, response is not our goal. Particularly in the first-line setting, response has never been the issue; it has been the durability of that response. In IMpower133, at the time of data analysis, 15% of responses were ongoing. In Checkmate 032, the median duration of response was equally striking.

Furthermore, the endpoint that matters most is survival, and the addition of atezolizumab to chemotherapy improved survival. Although a median improvement of 2 months may seem modest, an HR of 0.70 signifies a 30% reduction in the risk of death. This is the first trial in decades to affect survival in extensive-stage SCLC; there have been dozens of negative phase III trials that have failed to move the needle. SCLC is a recalcitrant disease, characterized by an aggressive and unrelenting course, and now for some, immunotherapy will provide a respite from that course.

How I am Using Immunotherapy in My Patients With SCLC
Based on the success of IMpower133, I currently advocate for combining atezolizumab with first-line carboplatin/etoposide for nearly all patients with extensive-stage SCLC. Although IMpower133 excluded patients with untreated brain metastases, I feel comfortable extrapolating from the study and using atezolizumab in these patients. I then incorporate brain radiation after chemotherapy. Although I would exclude the use of atezolizumab in patients with organ transplants or severe autoimmune conditions, I would at least consider its use in patients with mild autoimmune disease after discussion with the patient and other providers.

Future Directions
We certainly need to monitor long-term outcomes as these trials mature, as well as await results from the first-line phase III trials KEYNOTE-604 (pembrolizumab plus platinum-based chemotherapy) and CASPIAN (durvalumab with or without tremelimumab plus platinum-based chemotherapy followed by maintenance durvalumab with or without tremelimumab). Further advances will rely on biomarker development to identify the specific population that benefits from an immunotherapy approach and those who will need a different strategy. In the meantime, I am optimistic about the potential of immunotherapy for extensive-stage SCLC going forward.

Your Thoughts?
Have you begun using immunotherapy in your patients with SCLC? Please share your experience in the comments box below.
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