Chemoimmunotherapy Continues to Display Survival Benefits in Small Cell Lung Cancer

Yanyan Lou, MD, PhD

Atezolizumab (Tecentriq), durvalumab (Imfinzi), pembrolizumab (Keytruda), and nivolumab (Opdivo) have demonstrated improved survival in combination with etoposide and platinum (EP) in untreated extensive-stage small cell lung cancer (ES-SCLC), cementing checkpoint inhibition plus chemotherapy as a frontline standard, explained Yanyan Lou, MD, PhD.

IMpower133 was the first phase 3 trial to test the addition of a checkpoint inhibitor to chemotherapy in the first-line setting in ES-SCLC. Patients with untreated ES-SCLC were randomized to atezolizumab plus EP for 4 cycles followed by maintenance atezolizumab or placebo plus EP for 4 cycles followed by placebo maintenance.

Progression-free survival (PFS) and overall survival (OS) in the intention-to-treat population served as the co-primary end points of the study.

The median OS was 12.3 months in the atezolizumab arm vs 10.3 months in the placebo arm (HR, 0.70; 95% CI, 0.54-0.91; P = .007). The 1-year OS rates were 51.7% and 38.2%, respectively.

The 18-month OS rates were 34% and 21%, respectively, demonstrating sustained benefit with atezolizumab.¹

The median PFS was 5.2 months in the atezolizumab arm vs 4.3 months in the placebo arm (HR, 0.77; 95% CI, 0.62-0.96; P = .02). The 1-year PFS rates also favored atezolizumab, at 12.6% and 5.4%, respectively.

With regard to safety, the rates of grade 1/2 (36.9% vs 34.7%), grade 3/4 (56.6% vs 56.1%), and grade 5 adverse effects (AEs; 1.5% vs 1.5%) were comparable between the 2 arms, respectively.

The second phase 3 study, CASPIAN, randomized patients with untreated ES-SCLC to 1 of 3 arms: durvalumab plus tremelimumab plus EP for 4 cycles followed by durvalumab every 4 weeks; durvalumab plus EP for 4 cycles followed by durvalumab every 4 weeks; or EP for 4 to 6 cycles followed by optional prophylactic cranial irradiation.

Carboplatin and cisplatin were allowed, giving the treating physician more flexibility, said Lou.

“Compared with the IMpower133 study, the CASPIAN study seems to have a more potent control arm,” said Lou, associate professor of medicine, consultant, vice chair of Research in the Division of Hematology and Oncology, associate director of the Early Cancer Therapeutics Program at Mayo Clinic, in a presentation during a 2020 Institutional Perspectives in Cancer webinar on lung cancer.

In terms of baseline characteristics, the durvalumab/EP and EP-alone arms were well balanced, said Lou. However, the tremelimumab arm enrolled a greater percentage of patients with an ECOG performance status of 0 and brain metastases and liver metastases vs the durvalumab/EP and EP-alone arms.

The median OS was 12.9 months in the durvalumab/EP arm vs 10.5 months in the EP-alone arm (HR, 0.75; 95% CI, 0.62-0.91; P = .0032). The 1-year OS rates were 52.8% and 39.3%, respectively. The addition of durvalumab to EP continued to perform favorably vs EP alone in the 18-month (32.0% vs 24.8%) and 2-year analyses (22.2% vs 14.4%), respectively.²

“The [data] were very similar to the IMpower133 study,” said Lou.

The median PFS was 5.1 months in the durvalumab/EP arm vs 5.4 months in the EP-alone arm (HR, 0.80; 95% CI, 0.66-0.96). The 1-year (17.9% vs 5.3%), 18-month (13.9% vs 3.4%), and 2-year PFS rates (11.0% vs 2.9%) all favored the durvalumab/EP arm vs the EP-alone arm, respectively.

However, Lou cautioned against drawing definitive conclusions from these findings because the PFS data were not formally tested for statistical significance. Per the study design, statistical significance would only be tested if both OS analyses were positive, and the second comparison of tremelimumab/durvalumab/EP and EP alone, the P value (P = .0451) failed to reach the threshold for significance (P < .0418).³

“The durvalumab/EP and EP-alone arms had very similar [rates of] all-grade and grade 3/4 AEs, but the tremelimumab/durvalumab/EP arm clearly had more severe AEs and AEs leading to treatment discontinuation,” said Lou. “Adding tremelimumab to durvalumab and EP really did not add much clinical benefit but added increased toxicity.”

The phase 3 KEYNOTE-604 trial randomized patients with untreated ES-SCLC to pembrolizumab plus EP for 4 cycles followed by pembrolizumab every 3 weeks or placebo plus EP for 4 cycles followed by placebo every 3 weeks.⁴

Approximately 74% of patients in both arms had an ECOG performance status of 1, which was notably higher than in IMpower133 and CASPIAN, said Lou. Additionally, more patients in the experimental arm had brain metastases vs the IMpower133 and CASPIAN studies.

The median PFS was 4.8 months in the pembrolizumab arm vs 4.3 months in the placebo arm (HR, 0.73; 95% CI, 0.60-0.88), meeting the coprimary end point. The 1-year PFS rates were 15.9% and 5.0%, respectively. The 18-month PFS rates were 10.8% and 2.1%, respectively. 

Although OS favored the pembrolizumab arm, the P value (P = .0164) failed to reach the threshold for significance (P < .0128). The median OS was 10.8 months in the pembrolizumab arm vs 9.7 months in the placebo arm (HR, 0.80; 95% CI, 0.64-0.98). The 1-year OS rates were 45.1% and 39.6%, respectively. The 2-year OS rates were 22.5% and 11.2%, respectively.

The final study, ECOG ACRIN EA5161 was a phase 2 study that randomized patients with untreated ES-SCLC to nivolumab plus EP for 4 cycles followed by nivolumab every 2 weeks or EP for 4, every 3-week cycles.⁵

The PFS, which served as the primary end point, was 5.5 months with nivolumab vs 4.7 months with EP alone (HR, 0.68; 95% CI, 0.48-1.00; P = .047). The OS was 11.3 months and 8.5 months, respectively (HR, 0.67; 95% CI, 0.46-0.98; P = .038).

References

1. Horn L, Mansfield AS, Szczęsna A, et al. 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.
2. Liu SV, Horn L, Mok T, et al. IMpower133: Characterisation of long-term survivors treated first-line with chemotherapy ± atezolizumab in extensive-stage small cell lung cancer. Ann Oncol. 2020;31(suppl 4):S974-S987. doi:10.1016/annonc/annonc290
3. Paz-Ares LG, Dvorkin M, Chen Y, et al. Durvalumab ± tremelimumab + platinum-etoposide in first-line extensive-stage SCLC: updated results from the phase III CASPIAN study. J Clin Oncol. 2020;38(suppl 15):9002. doi:10.1200/JCO.2020.38.15_suppl.9002
4. Rudin CM, Awad MM, Navarro A, et al. KEYNOTE-604: pembrolizumab (pembro) or placebo plus etoposide and platinum (ep) as first-line therapy for extensive-stage (es) small-cell lung cancer (sclc). J Clin Oncol. 2020;38(suppl 15):9001. doi:10.1200/JCO.2020.38.15_suppl.9001
5. Leal T, Dowlati A, Lewis DA, et al. Randomized phase II clinical trials of cisplatin/carboplatin and etoposide alone or in combination with nivolumab as frontline therapy for extensive-stage small cell lung cancer: ECOG-ACRIN EA5161. J Clin Oncol. 2020;38(suppl 15):9000. doi:10.1200/JCO.2020.38.15_suppl.9000

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