Charles M. Rudin, MD, PhD

An important milestone in the treatment landscape of extensive-stage small cell lung cancer (ES-SCLC) has been trials of first-line chemoimmunotherapy. However, a study that requires better understanding of the methods and can be used to determine patients who are likely to experience durable benefits to therapy is currently concentrated, according to a virtual presentation during the 15th Annual New York Lung Cancers Symposium by Charles M. Rudin, MD, PhD.

“In the past couple years, the big news has been immunotherapy,” said Rudin, medical oncologist and chief of the Thoracic Oncology Service, co-director of the Druckenmiller Center for Lung Cancer Research, and Sylvia Hassenfeld Chair in Lung Cancer Research, at Memorial Sloan Kettering Cancer Center.

Frontline Treatment in ES-SCLC

The two high-impact trials that have led to the rise of immunotherapy in the frontline setting of ES-SCLC are the phase 3 IMpower133 and CASPIAN trials, said Rudin. In IMpower133, patients with untreated ES-SCLC were randomized to atezolizumab (Tecentriq) plus etoposide and platinum vs etoposide and platinum alone. The results indicated a 30% reduction in the risk of death with the addition of atezolizumab vs chemotherapy (HR, 0.70; 95% CI, 0.54-0.91; P = .007).¹ Moreover, the 12- and 18-month landmark overall survival (OS) analyses favored the chemoimmunotherapy combination vs chemotherapy alone, respectively (51.9% vs 39.0%; 34.0% vs 21.0%).

Data from the IMpower133 trial served as the basis for the March 2019 FDA approval of the combination as frontline therapy in ES-SCLC.

In CASPIAN, patients with untreated ES-SCLC were randomized to durvalumab (Imfinzi) plus platinum and etoposide vs platinum and etoposide alone. The addition of durvalumab led to a 27% reduction in the risk of death vs chemotherapy alone (HR, 0.73; 95% CI, 0.591-0.909; P = .0047).² Similarly, the 12- and 18-, as well as 24-month landmark OS analyses favored the chemoimmunotherapy combination vs chemotherapy alone , at 52.8% vs 39.3%; 32.0% vs 24.8%; and 22.2% vs 14.4%, respectively.

In March 2020, the FDA approved the combination of durvalumab plus platinum and etoposide for the frontline treatment of patients with ES-SCLC, according to the results from the CASPIAN trial.

Another phase 3 trial, KEYNOTE-604, randomized patients with untreated ES-SCLC to receive the addition of pembrolizumab (Keytruda) to platinum and etoposide or chemotherapy alone in the first-line setting.

At the time of data cutoff in December 2019, the median progression-free survival (PFS) was 4.8 months with pembrolizumab vs 4.3 months with chemotherapy alone, meeting the co-primary end point of the study (HR, 0.73; 95% CI, 0.60-0.88).³

However, the addition of pembrolizumab did not lead to a statistically significant improvement in OS, with a median OS of 10.8 months and 9.7 months in the pembrolizumab and chemotherapy-alone arms, respectively (HR, 0.80; 95% CI, 0.64-0.98; P = .0164).

Across the IMpower133, CASPIAN, and KEYNOTE-406 trials, the 12-month median PFS rates in the experimental arms were 12.6%, 17.9%, and 15.9% vs 5.4%, 5.3%, and 5.0% in the control arms, respectively.

Recurrent SCLC

Immunotherapy has also shown activity in the recurrent setting, evidenced by findings from the phase 1/2 CheckMate-032 trial, which demonstrated a median PFS of 1.4 months with nivolumab (Opdivo; n = 147) and 1.5 months with the combination of nivolumab and ipilimumab (Yervoy; n = 96) in patients with SCLC and disease progression on 2 prior lines of chemotherapy.4Although the median PFS was modest, the curves suggested that patients who responded to the combination experienced durable benefit, with 6-month PFS rates of 15.9% and 22.1%, respectively.

A similar trend was seen in a pooled analysis of the phase 1b KEYNOTE-028 and phase 2 KEYNOTE-158 trials, where patients who received pembrolizumab after 2 prior lines of therapy experienced a median PFS of 2.0 months but 12- and 24-month PFS rates of 16.9% and 13.1%, respectively.⁵

“The hockey stick appearance of the curves [is clear] where the curves just drop like a rock. Most of the patients do not benefit from this therapy, but then there’s a subset that clearly does,” said Rudin.

Although findings from these 2 trials served as the basis for the accelerated approvals of nivolumab and pembrolizumab as third-line treatment for patients with metastatic SCLC, the data are more indicative of the potential effects of immunotherapy than they are applicable for practicing clinicians now that immunotherapy has entered the first-line setting.

“In the third-line setting, we have these accelerated approvals for nivolumab and pembrolizumab, but we really don’t know how to give those now because we’re using PD-L1 checkpoint inhibitors in the first-line setting,” said Rudin.

Although immunotherapy has been the focus of discussion in ES-SCLC, other agents are entering the paradigm, explained Rudin, who cited lurbinectedin (Zepzelca) as a prime example of the potential actionability of alternative targets in the field.

“Lurbinectedin is a DNA-binder and an alkylating agent that affects transcription,” said Rudin.

The agent was evaluated in an open-label, single-arm, phase 2 basket trial (NCT-2454972) in patients with SCLC who had progressed on platinum-containing therapy. The results demonstrated an overall response rate (ORR) of 35.2% and a stable disease rate of 33.3%, which translated to a disease control rate of 68.6% (95% CI, 58.8%-77.3%).⁶

The median durations of response, PFS, and OS were 5.3 months (95% CI, 4.1-6.4), 3.5 months (95% CI, 2.6-4.3), and 9.3 months (95% CI, 6.3-11.8).

“The real advantage of this drug over topotecan is on the toxicity side as much or more than on the efficacy side, particularly in terms of the hematologic toxicities” said Rudin.

On June 15, 2020, the FDA granted an accelerated approved to lurbinectedin for the treatment of adult patients with metastatic SCLC with disease progression, following platinum-based chemotherapy.

“About 10% of patients with SCLC really derive meaningful and potentially durable benefit from the addition of immunotherapy, regardless of which of these PD-1/PD-L1 agents you’re using. The other 90% really do not,” said Rudin. “One of the challenges for our field is to define that 10% and to think about what to do about that 90%.”

Potential pathways forward in this regard could include blocking other immunologic checkpoints such as TIGIT, stimulating other immunologic players such as natural killer cells and macrophages, epigenetic priming, targeting DNA damage repair pathways, and developing other novel targets, concluded Rudin.

_References

1. _{Horn L, Mansfield AS, Szczesna A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Eng J Med. 2018;379(23):2220-2229. doi:10.1056/NEJMoa1809064}
2. _{Paz-Ares LG, 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 randomised, controlled, open-label, phase 3 trial. Lancet. 2019;394(10212):1929-1939. doi:10.1016/S0140-6736(19)32222-6}
3. _{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}
4. _{Ready NE, Ott PA, Hellmann MD, et al. Nivolumab monotherapy and nivolumab plus ipilimumab in recurrent small cell lung cancer: results from the CheckMate 032 randomized cohort. J Thor Oncol. 2020;15(3):426-435. doi:10.1016/j.jtho.2019.10.004}
5. _{Chung HC, Piha-Paul S, Lopez-Martin J, et al. Pembrolizumab after two or more lines of previous therapy in patients with recurrent or metastatic SCLC: results from the KEYNOTE-028 and KEYNOTE-158 studies. J Thor Oncol. 2020;15(4):618-627. doi:10.1016/j.jtho.2019.12.109}
6. _{Trigo J, Subbiah V, Besse B, et al. Lurbinectedin as second-line treatment for patients with small-cell lung cancer: a single-arm, open-label, phase 2 basket trial. Lancet Oncol. 2020;21(5):645-654. doi:10.1016/S1470-2045(20)30068-1}