Improved OS Data Signal New Era With Immunotherapy in Small Cell Lung Cancer

Lawrence E. Feldman, MD

After decades of minimal progress, recent regulatory updates with checkpoint inhibitors have sparked excitement in extensive-stage small cell lung cancer (ES-SCLC) treatment, said Lawrence E. Feldman, MD.

"Immunotherapy and checkpoint inhibitors are here to stay in SCLC," said Feldman. "SCLC has been a dormant field for about 4 decades, but we are still seeing that they account for up to 15% of our lung cancer cases. It is refreshing to seeing these recent findings."

At the 2019 ESMO Congress, an update of the phase III IMpower133 trial reported that the median overall survival (OS) remained 12.3 months with the addition of atezolizumab (Tecentriq) to carboplatin plus etoposide compared with 10.3 months with carboplatin/etoposide alone at a median follow-up of 22.9 months (HR, 0.76; 95% CI, 0.60, 0.95; P = 0.0154).¹ Based on the primary IMpower133 data, the FDA approved the atezolizumab regimen in March 2019 as a first-line treatment for patients with ES-SCLC.

The phase III CASPIAN trial showed a similar OS improvement with durvalumab (Imfinzi) plus carboplatin/etoposide compared with carboplatin/etoposide alone in the first-line setting for patients with ES-SCLC. Median OS was 13.0 months versus 10.3 months, respectively (HR, 0.73; 95% CI, 0.59-0.91; P = .0047).² Additionally, in updated CASPIAN data presented at the 2019 ESMO Congress, the durvalumab regimen was also found to delay the development of new lesions and improve patient-reported outcomes versus etoposide and platinum-based therapy alone.³

In an interview during the 2019 OncLive^® State of the Science Summit™ on Lung Cancer, Feldman, a professor of clinical medicine at the University of Illinois Cancer Center, discussed the impact of these phase III data, ongoing trials, and other updates in SCLC treatment.

OncLive: How has SCLC treatment evolved in recent years?

Feldman: SCLC compromises about 15% of lung cancer cases overall, and is mainly seen in smokers. Now, we are encouraged to stage these patients as we do with non—small cell lung cancer (NSCLC) using the American Joint Committee on Cancer (AJCC) Staging System.

Having said that, we do differentiate between patients who have LS-SCLC versus ES-SCLC. For ES-SCLC, some of the recent trials, such as the IMpower133 trial using atezolizumab plus standard carboplatin/etoposide, and the CASPIAN trial of durvalumab versus platinum/etoposide alone, each compared with chemotherapy alone, showed an OS advantage with the addition of a checkpoint inhibitor. That has become the standard of care in terms of treating patients with ES-SCLC.

In limited-stage (LS)-SCLC, research with chemoradiation is ongoing. [The University of Illinois] is participating in the NRG LU005 trial looking at chemoradiation alone compared with atezolizumab plus chemoradiation.

The CheckMate-032 trial with nivolumab (Opdivo) alone or in combination with ipilimumab (Yervoy) is now listed in the National Comprehensive Cancer Network (NCCN) guidelines as a potential treatment for second-line treatment of patients with SCLC.

Also, we are participating in research studies combining immunotherapy in the second-line setting. Particularly, we have a Big Ten Cancer Research Consortium trial, which is looking at a drug called plinabulin in combination with ipilimumab and nivolumab.

Could you expand on the impact of immunotherapy?

The IMpower133 trial looked at patients with ES-SCLC receiving carboplatin/etoposide with or without atezolizumab. It showed about a 2-month OS advantage with the addition of atezolizumab. Those data changed the standard of care.

Just last month at the 2019 World Conference on Lung Cancer, results of the CASPIAN trial looking at a platinum-containing drug/etoposide with or without durvalumab were presented. Again, there was a 2- to 3-month median OS advantage with a significant P value and significant hazard ratio. CASPIAN confirmed that adding checkpoint inhibitors to the carboplatin/etoposide backbone is beneficial, particularly in terms of progression-free survival and OS. It was nice to see that both trials showed similar results and confirmed that checkpoint inhibitors can improve OS in those patients.

How has staging changed in SCLC?

Traditionally, we were taught to stage patients as either LS disease, which can be encompassed in one radiation field, or extensive disease, where patients have metastases outside of the chest typically, either in the brain, lungs, or liver. Now, we are encouraged to stage them using the Tumor, Node, Metastasis classification just like we do in NSCLC.

For patients with T1 or T2 disease, or maybe N1 or N2 disease, they may do better than patients with T4 or N3 disease. Even if it is LS disease, the prognosis is better in patients who have stage I or stage II disease compared with stage IIIA or IIIB disease. Mainly, it is helpful in terms of prognosis, and also it is important for the American College of Surgeons Commission on Cancer.

Having said that, we still approach the treatments of patients with LS- and ES-SCLC similarly. It is important to do proper AJCC staging, while at the same time determining if the patient has LS- or ES-SCLC.

What role does prophylactic cranial irradiation (PCI) have in SCLC treatment?

A meta-analysis in the late 1990s showed that PCI can improve OS and the occurrence of brain metastases. We have been doing PCI in LS-SCLC disease for many years. Then, we started also doing PCI in ES-SCLC. However, in 2017, there was a seminal publication in Lancet Oncology of a large Japanese trial showing that there was no difference in doing PCI versus observation in ES-SCLC.

That has changed practice, particularly in ES-SCLC where, at least at our institution, we follow patients with MRIs, and observe them, for example, every 3 months in the first year and then every 6 months in the second year. We follow them closely. If they do develop brain metastases, we can act early so patients are not subjected to the side effects of PCI, particularly in ES disease.

In LS-SCLC, there is more of a rationale for PCI, although we may want to observe in some cases. Many patients with LS-SCLC have fairly long survival rates of 2 to 3 years. We may want to avoid some of the neurocognitive adverse events that can come along with PCI.

What are some emerging strategies in second-line treatment?

The only FDA-approved drug in the second-line setting is topotecan. The CheckMate-032 trial showed that there was about 40% to 50% response rate adding checkpoint inhibitors, such as nivolumab or nivolumab plus ipilimumab, at different doses. There were 2 to 4 different dosages of the ipilimumab/nivolumab combination. No matter what dosages patients received, even with nivolumab alone, patients showed several high response rates in the 40% to 50% range. CheckMate-032 in particular led to a listing in the NCCN to allow use of checkpoint inhibitors in the second-line setting in SCLC.

Being at the University of Illinois, we are members the Big Ten Cancer Research Consortium. We are participating in a study at Rutgers Cancer Institute of New Jersey that is looking at nivolumab, ipilimumab, and plinabulin, which is an immunomodulator. That is a phase I/II trial, so the primary endpoints are safety and toxicity, but, of course, investigators are also looking at efficacy in terms of response.

References

1. Reck M, Liu SV, Mansfield AS, et al. IMpower133: updated overall survival (OS) analysis of first-line (1L) atezolizumab (atezo) + carboplatin + etoposide in extensive-stage SCLC (ES-SCLC). Ann Oncol. 2019;30(5 suppl; abstr 1736O). doi: 10.1093/annonc.mdz264.
2. Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small—cell lung cancer (CASPIAN): a randomized, controlled, open-label, phase 3 trial. The Lancet. 2019. doi: 10.1016/S0140-6736(19)32222-6.
3. Paz-Ares L, Goldman JW, Garassino MC, et al. PD-L1 expression, patterns of progression and patient-reported outcomes (PROs) with durvalumab plus platinum-etoposide in ES-SCLC: results from CASPIAN. Ann Oncol. 2019;30(suppl_5): mdz394.089. doi: 10.1093/annonc/mdz394.089.