Immunotherapy Makes Waves in Small Cell Lung Cancer

Alain C. Mita, MD

Until recently, the treatment armamentarium for extensive-stage small cell lung cancer (ES-SCLC) did not have significant advances, said Alain C. Mita, MD. In the last 2 years, however, the arrival of multiple immune checkpoint inhibitors has expanded the treatment paradigm in both the frontline and recurrent settings for this patient population.

"The venue of immune checkpoint inhibitors, particularly PD-1/PD-L1 inhibitors, is a step forward in the treatment of SCLC," said Mita. "These are the first treatments to show any improvement in survival for patients with SCLC in the last 20 years."

In March 2019, atezolizumab (Tecentriq) in combination with chemotherapy was approved for the initial treatment of adults with ES-SCLC, based on the 30% reduction in the risk of death with the combination versus chemotherapy alone that was demonstrated in the phase III IMpower133 trial (HR, 0.70; 95% CI, 0.54-0.91; P = .0069).¹ Updated findings continued to show a benefit in OS with the atezolizumab regimen (HR, 0.76; 95% CI, 0.60-0.95; P = .0154).²

Moreover, the PD-L1 inhibitor durvalumab (Imfinzi) was granted a priority review designation in December 2019, also for the frontline ES-SCLC setting, based on findings from the phase III CASPIAN trial. Results showed a 27% reduction in risk of death with durvalumab plus chemotherapy versus chemotherapy alone (HR, 0.73; 95% CI, 0.591-0.909; P = .0047).³

In the recurrent setting, a 12% overall response rate (ORR) reported from the phase I/II CheckMate-032 trial led to the August 2018 accelerated approval of nivolumab (Opdivo) for the treatment of patients with metastatic SCLC whose cancer had progressed after platinum-based chemotherapy and ≥1 other line of therapy.⁴

Finally, the phase II KEYNOTE-158 and Ib KEYNOTE-028 trials demonstrated a 19% ORR with single-agent pembrolizumab (Keytruda) in patients with SCLC whose disease progressed on or after platinum-based chemotherapy and ≥1 prior line of therapy.^5,6 As a result, pembrolizumab was granted FDA approval in June 2019 as a treatment for this patient population.

In an interview during the 2020 OncLive^® State of the Science Summit™ on Lung Cancer, Mita, an associate professor of medicine and co-director of Experimental Therapeutics at Cedars-Sinai Medical Center, discussed the impact of immunotherapy in the frontline and recurrent settings for patients with SCLC.

OncLive: What are the most significant treatment updates for patients with SCLC?

Mita: Atezolizumab in combination with chemotherapy is approved in the frontline setting of ES-SCLC. Durvalumab in combination with chemotherapy [is likely to be approved by June 2020]. For recurrent SCLC, nivolumab and pembrolizumab are currently approved.

How have immune checkpoint inhibitors changed the SCLC treatment landscape?

Immunotherapy opens the window for further opportunities exploring immunotherapy for limited-stage (LS)-SCLC, as well as other combinations for ES-SCLC.

The checkpoint inhibitors that have been approved in the recurrent setting are going to be important for future patients who have not benefitted from [this class of agents] as frontline therapy.

I do believe that their role [in the relapsed/refractory space] is going to diminish, because most patients will receive a frontline checkpoint inhibitor. It is not clear what role immunotherapy will have for patients who have already progressed on a checkpoint inhibitor.

Nevertheless, there is clearly a benefit with checkpoint inhibitors for the [majority] of patients who have never received one. They will receive at least 1 PD-L1 inhibitor in the future.

How could the potential approval of lurbinectedin in the second-line setting change the treatment paradigm?

Lurbinectedin is now available for patients with SCLC based on an [Expanded Access Program]. The drug is expected to get approved soon based on the most recent clinical trial data. We have to wait and see exactly what setting it will be approved for, but it will likely become part of our armamentarium soon.

What are your thoughts on the topline data with dinutuximab (Unituxin) as a treatment for patients with SCLC?

Unfortunately, the most recent data with dinutuximab showed that the phase III study missed its primary endpoint. As such, dinutuximab is not expected to become an available treatment any time soon.

What other trials in SCLC would you like to highlight?

At this time, the trials I am most excited about are those that are going to move these drugs in combination with concurrent chemoradiation as a treatment for patients with LS-SCLC. We [can’t] cure a number of these patients, so we hope that by adding an immune checkpoint inhibitor, we will increase the percentage of patients who are cured.

References

1. Liu S, Mansfield A, Szczesna A, et al. PL02.07 IMpower 133: primary PFS, OS, and safety in PH1/3 study of 1L atezolizumab + carboplatin + etoposide in extensive-stage SCLC. J Thor Oncol. 2018;13(10):S185-S186. doi: 10.1016/j.jtho.2018.08.013.
2. 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(suppl_5):v710-v717. doi: 10.1093/annonc/mdz264.
3. 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 study. Lancet. 2019;394(10212):1929-1939. doi: 10.1016/S0140-6736(19)32222-6.
4. Antonia SJ, Lopez-Martin JA, Bendell JC, et al. Checkmate 032: nivolumab (N) alone or in combination with ipilimumab (I) for the treatment of recurrent small cell lung cancer (SCLC). J Clin Oncol. 2016;34(suppl; abstr 100). doi: 10.1200/JCO.2016.34.15_suppl.100.
5. Chung HC, Lopez-Martin J, Kao S, et al. Phase 2 study of pembrolizumab in advanced small-cell lung cancer: KEYNOTE-158. J Clin Oncol. 2018;36(suppl; abstr 8506). doi: 10.1200/JCO.2018.36.15_suppl.8506.
6. Ott PA, Elez E, Hiret S, et al. Pembrolizumab in patients with extensive-stage small-cell lung cancer: results from the phase Ib KEYNOTE-028 study. J Clin Oncol. 2017;35(34):3823-3829. doi: 10.1200/JCO.2017.72.5069.