Immunotherapy Restructures the SCLC Treatment Landscape

Benjamin P. Levy, MD

The standard of care for patients with small cell lung cancer (SCLC) has been trapped in a period of stagnation for the past several decades. However, meaningful improvements in outcomes with immunotherapy in recent years are finally starting to change the tide for the first-line treatment of these patients.

“Over the past 30 to 40 years, over 60 active agents have been tried with improvements in response rate and progression-free survival, but no improvement in overall survival,” Benjamin P. Levy, MD, said in a presentation at the 17th Annual Winter Lung Cancer Conference^®, hosted by Physicians’ Education Resource®, LLC. “This has historically [been an] aggressive disease with disappointing results. Immunotherapy clearly has been transformative in non—small cell lung cancer; it is the standard of care for most patients without a driver mutation in the first-line in combination with platinum chemotherapy and we see efficacy across various tumor types.”

SCLC has the characteristics of a disease that would be “ripe for the taking” with immunotherapy, Levy, an assistant professor of oncology and clinical director of Medical Oncology at Sidney Kimmel Cancer Center of Johns Hopkins Medicine, said during the meeting.¹

According to a prospective study of patients with extensive-stage (ES) SCLC (n = 432), 93% received first-line therapy, 50% received second-line therapy, and 22% received third-line therapy.² “Few patients receive third-line therapy,” Levy said. “I do not think that immunotherapy is going to play a meaningful role as a third-line [option] for these patients.”

The focus of immunotherapy utility for patients with SCLC is in the first-line setting, however promising data from second-line studies may also shake up the armamentarium.

IMpower133 and CASPIAN

Levy described the phase III IMpower133 trial (NCT02763579) examining the immune checkpoint inhibitor atezolizumab (Tecentriq) as “transformative” and “practice changing.” The trial randomized 403 treatment-naïve patients with ES-SCLC to receive carboplatin and etoposide with either atezolizumab (n = 201) or placebo (n = 202).

The median overall survival (OS) was 12.3 months in the atezolizumab group versus 10.3 months in the placebo group (HR, 0.70; 95% CI, 0.54-0.91; P = .007). A modest improvement in investigator-assessed progression-free survival (PFS) of 5.2 versus 4.3 months, respectively, was also observed (HR, 0.77; 95% CI, 0.62-0.96; P = .02).³

This data led to the approval of atezolizumab in combination with carboplatin and etoposide as a first-line treatment for adult patients with ES-SCLC in March 2019.⁴

Updated data presented at the European Society for Medical Oncology 2019 Congress demonstrated an improvement in OS for the first-line treatment with 22.9 months of follow-up. The 18-month OS rate demonstrated a survival increase of 13% in the atezolizumab arm (34%) compared with placebo (21%), further supporting the regimen as the new standard of care.⁵

Similar to IMpower133, improvements in OS were observed in the CASPIAN trial. Patients were randomized 1:1:1 to receive platinum chemotherapy and etoposide with either durvalumab (Imfinzi) or durvalumab plus tremelimumab versus platinum chemotherapy and etoposide alone. Data for durvalumab plus tremelimumab are not yet mature.

The median OS in patients treated with the durvalumab-plus-chemotherapy combination was 13.0 months versus 10.3 months in the chemotherapy-alone arm (HR, 0.73; 95% CI, 0.59-0.91; P = .0047).⁶

Tolerability of these regimens is similar to that seen in non—small cell lung cancer. “When you add immunotherapy to chemotherapy, you don’t see higher immune-related adverse events than you see with single-agent immunotherapy,” Levy said. “We need to be mindful of these immune-related adverse events [and] partner with our subspecialists, but the regimen is fairly well-tolerated.”

Despite improvements for patients with ES-SCLC with atezolizumab- and durvalumab-containing combinations, it is worth noting that KEYNOTE-604 (NCT03066778) exploring a similar protocol with pembrolizumab (Keytruda) did not meet the dual primary end point of statistically significant OS improvement and was a negative study. Results are expected at an upcoming meeting.⁷

Future directions for SCLC: The new second line

Uptake of second-line therapeutic options for patients with ES-SCLC has been slow going with topotecan (Hycamtin) sitting as the lone approved therapy in the space.8 Notably, the PD-1 inhibitor nivolumab (Opdivo) failed to beat topotecan head-to-head in the CheckMate331 trial (NCT02481830).¹

“[Developing strategies for SCLC] has been like throwing darts at a dart board for a long time, but I think things are changing,” Levy concluded. In listing some potential future directions for the field, Levy noted the recent promise seen with lurbinectedin.

Since the failure of nivolumab versus topotecan, lurbinectedin has become the “darling child” for second-line approaches for SCLC and could fulfill an unmet need in SCLC.¹

Available data for the marine-derived inhibitor of active transcription is from a phase II single-arm study (NCT02454972) as monotherapy in 105 patients. At median follow-up of 17.1 months, the overall response rate (ORR) was 35.2% (95% CI, 26.2%-45.2%) with a median duration of response of 5.3 months (95% CI, 4.1-6.4). The median OS was 9.3 months (95% CI, 6.3-11.8).⁸

Separating patients who were platinum sensitive (n = 60) and platinum resistant (n = 45) produced ORRs of 45.0% (95% CI, 32.1%-58.4%) and 22.2% (95% CI, 11.2%-37.1%), respectively. Further, patients in the platinum-sensitive group experienced a median OS of close to 1 year (11.9 months; 95% CI, 9.7-16.2) versus only 5.0 months (95% CI, 4.1-6.3) in patients who were platinum resistant.⁷

“This is a different ball game with lurbinectedin,” Levy said. A new drug application was filed with the FDA for the accelerated approval of the agent in December 2019 based on these data.⁸

References

1. Levy BP. Small cell lung cancer and neoendocrine tumors. Presented at: 17th Annual Winter Lung Cancer Conference, hosted by Physicians’ Education Resource, LLC; February 7-9, 2020; Miami Beach, FL.
2. Steffens CC, Elender C, Hutzschenreuter U, et al; TLK-Group (Tumor Registry Lung Cancer). Treatment and outcome of 432 patients with extensive-stage small cell lung cancer in first, second and third line - Results from the prospective German TLK cohort study. Lung Cancer. 2019;130:216-225. doi: 10.1016/j.lungcan.2019.02.026.
3. Horn L, Mansfield AS, Szczęsna A, et al; IMpower133 Investigators. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018;379(23):2220-2229. doi: 10.1056/NEJMoa1809064.
4. FDA approves atezolizumab for extensive-stage small cell lung cancer. FDA website. bit.ly/2OF2gN8. Published March 18, 2019. Accessed February 9, 2020.
5. Reck M, Liu SV, Mansfield AS, et al. IMpower133: updated overall survival (OS) anaylsis of first-line (1L) atezolizumab (atezo) + carboplatin + etoposide in extensive-stage SCLC (ES-SCLC). Ann Oncol. 2019;30(suppl 5;abstr 1736O). doi: 10.1093/annonc/mdz264
6. Paz-Ares L, DVorkin M, Chen Y, et al; CASPIAN Investigators. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet. 2019;394(10212):1929-1939. doi: 10.1016/S0140-6736(19)32222-6.
7. Merck’s Keytruda (pembrolizumab) in combination with chemotherapy significantly improved progression-free survival compared to chemotherapy alone as first-line treatment for extensive stage small cell lung cancer [press release]. Kenilworth, NJ: Merck; January 6, 2020. bwnews.pr/2SbtWvq. Accessed February 8, 2020.
8. Paz-Ares LG, Trigo Perez JM, Besse B, et al. Efficacy and safety profile of lurbinectedin in second-line SCLC patients: results from a phase II single-agent trial. J Clin Oncol. 2019;37(suppl 5; abstr 8505). doi: 10.1200/JCO.2019.37.15_suppl.8506.
9. PharmaMar has filed new drug application for lurbinectedin with the FDA for the treatment of relapsed small cell lung cancer [press release]. Madrid, Spain: PharmaMar; December 17, 2019. bit.ly/2unvbyG. Accessed February 8, 2020.

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