Novel treatments beyond the current chemoimmunotherapies are offering more treatment options in small cell lung cancer (SCLC), though real breakthroughs remain elusive, according to Ticiana Leal, MD, Associate Professor in the Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, and Director of the Thoracic Medical Oncology Program. Dr. Leal discussed advances in the treatment of small cell lung cancer at the 2023 Debates and Didactics in Hematology and Oncology Conference, sponsored annually by Emory’s Winship Cancer Institute and held in Sea Island, Georgia.1
New Checkpoint Inhibitors
The use of immune checkpoint inhibitors combined with chemotherapy has changed the first-line treatment approach in patients with extensive-stage small cell lung cancer. Although pembrolizumab and atezolizumab are the standard checkpoint inhibitors for these regimens, encouraging findings have emerged for a new PD-1 inhibitor: serplulimab.
Ticiana Leal, MD
Given in combination with platinum-based chemotherapy, serplulimab was evaluated as a first-line treatment in 585 patients with extensive-stage small cell lung cancer in the global phase III randomized, placebo-controlled ASTRUM-005 trial.2 The combination significantly improved median overall survival, which was 15.4 months with serplulimab plus chemotherapy and 10.9 months with chemotherapy alone (hazard ratio [HR] = 0.63; P < .001). The survival rate at 24 months was 43.1% vs 7.9%, respectively.
Dr. Leal noted that the median survival was impressive, but she pointed out a high proportion of never-smokers in a largely Asian population and questioned whether the results would translate into “real-world” experience. Whether this regimen moves forward to become a standard of care is not assured, she said.
Building Upon the Chemoimmunotherapy Backbone
Other novel approaches attempt to build upon the chemoimmunotherapy backbone. One approach exploits the TIGIT (T-cell immunoreceptor with immunoglobulin and ITIM domain) pathway that regulates T-cell–mediated and natural killer cell–mediated tumor recognition. TIGIT is the target of the monoclonal antibody tiragolumab.
In the phase III SKYSCRAPER-02 study, the use of tiragolumab in combination with atezolizumab, carboplatin, and etoposide was evaluated in untreated extensive-stage small cell lung cancer.3 Unfortunately, the study did not meet its co-primary endpoints of overall survival and progression-free survival; median progression-free survival was approximately 5.5 months in both arms and median overall survival was 13.6 months in both arms.
Another anti-TIGIT antibody, vibostolimab, is being evaluated in combination with pembrolizumab (as a coformulation, MK-7684A) and chemotherapy, compared with atezolizumab plus chemotherapy, as a first-line treatment in the phase III KEYVIBE-008 trial. The study aims to determine whether there will be a role for anti-TIGIT agents in this tumor type.
Addition of PARP Inhibitors
There is interest in determining the impact of adding PARP inhibitors to immunotherapy for maintenance as well as identifying predictive biomarkers for this approach. SWOG S1929 evaluated maintenance therapy with atezolizumab in combination with talazoparib in patients whose tumors express the SLFN11 gene (present in 50% of small cell lung cancers).4 In the study, patients with an SLFN11 immunohistochemistry (IHC) H-score of at least 1+ without progressive disease following induction therapy were randomly assigned to receive atezolizumab plus talazoparib or atezolizumab alone. The study met its primary endpoint, improving median progression-free survival from 2.8 months with atezolizumab alone to 4.2 months with talazoparib (HR = 0.70; P = .0561), although the overall survival benefit (8.5 vs 9.4 months, respectively; P = .30) was not significant.
“The benefit was modest, and in my opinion, additional studies are warranted in better understanding biomarker testing in SCLC, including SLFN11,” said Dr. Leal. Further analysis of the biomarker data may reveal signals for differential benefits, according to Dr. Leal. “I think this study highlighted that we can start selecting patients based on biomarkers—realizing that small cell lung cancer is not a ‘one-size-fits-all’ kind of disease and that we need to strategize treatment in a more rational way,” she added.
Treatment of Relapsed Disease
For relapsed disease, the preferred approach remains a platinum-based doublet rechallenge or enrollment in a clinical trial, based on the National Comprehensive Cancer Network® (NCCN®) Clinical Practice Guidelines in Oncology. However, Dr. Leal pointed out that not all patients are candidates for platinum-based chemotherapy rechallenge. The NCCN lists numerous alternative regimens, but they are largely suboptimal. “We need better strategies in the second line and beyond,” she commented.
Lurbinectedin, a selective inhibitor of oncogenic transcription, represents a treatment advance for patients with relapsed SCLC. Small cell lung cancer is frequently a transcriptional disease caused by deregulated oncogenic transcription factors. Lurbinectedin inhibits active transcription in tumor-associated macrophages and thereby downregulates interleukin (IL)-6, IL-8, CCL2 (C-C motif chemokine ligand 2), and vascular endothelial growth factor (VEGF).
In the phase II basket trial, lurbinectedin yielded a response rate of 35.2% in patients previously treated with one line of chemotherapy (prior immunotherapy was allowed).5 In this population of platinum-refractory and platinum-sensitive patients, median overall survival was 9.3 months, and 34.2% of patients were alive at 1 year. In the platinum-sensitive population, median overall survival was 11.9 months. Putting these results into perspective, Dr. Leal cited that the response rate observed with topotecan is between 6% and 11.8% in patients with refractory disease and 10% to 15% in patients with sensitive disease. Median survival time is between 3.6 and 5.4 months in patients with refractory disease and 5 and 8 months in patients with sensitive disease. Based on the study’s findings, single-agent lurbinectedin received accelerated approval by the U.S. Food and Drug Administration after disease progression on or after platinum-based chemotherapy.
Whether lurbinectedin might be more valuable in combination was the subject of the randomized phase III ATLANTIS study.6 In this trial, lurbinectedin was given with doxorubicin and compared with topotecan or cyclophosphamide, doxorubicin, and vincristine in relapsed patients who had prior platinum-based chemotherapy (prior immunotherapy was uncommon). The study did not meet the primary endpoint of overall survival. The median overall survival was approximately 10 months in either arm, and median progression-free survival was 4 months.
A post hoc analysis explored outcomes in patients who completed 10 cycles of the combination and then switched to lurbinectedin monotherapy,7 finding that these patients tended to maintain or improve their tumor response (including increases in complete responses). “Of note,” Dr. Leal said, “in a population that is refractory to prior therapy, median overall survival was 20.7 months, which is pretty impressive.”
The confirmatory phase III LAGOON trial has been initiated. It is randomly assigning 700 patients to receive lurbinectedin given as monotherapy or with irinotecan or investigator’s choice of topotecan or irinotecan.
Novel Strategies: Bispecific T-Cell Engagers and CAR Therapies
There is much interest in Delta-like ligand 3 (DLL3) as a target in small cell lung cancer, as it is expressed in 85% of these tumors. “We are looking at novel ways to target DLL3 now with bispecific T-cell engagers and chimeric antigen receptor (CAR) T-cell therapy. The CAR-T experience has been limited so far, but the bispecific T-cell engager strategy is moving forward in development,” Dr. Leal reported.
The bispecific T-cell engager antibody tarlatamab, which targets DLL3 and CD3, showed antitumor activity and response durability in heavily pretreated patients (50% had prior immunotherapy) in the DeLLphi-300 study.8 The confirmed response rate was 23%, the median duration of response was 13 months, and the median overall survival was 13 months. The phase II registrational DeLLphi-301 trial is evaluating tarlatamab in approximately 160 patients who have received at least three prior lines.
Tarlatamab is also being investigated in the front line, in combination with chemoimmunotherapy, and management of adverse side effects and administration are being optimized. At least three other DLL3-targeted T-cell engagers and a CAR T-cell product are currently in development as well.
Antibody-Drug Conjugates
“Another strategy that has been generating a lot of enthusiasm in small cell lung cancer is the development of antibody-drug conjugates,” Dr. Leal stated. At least half a dozen—most with different targets—are in development. They include sacituzumab govitecan-hziy and datopotamab deruxtean (TROP-2), ifinatamab deruxtecan and mirzotamab clezutoclax (B7-H3), ABBV-011 (a calicheamicin-based antibody-drug conjugate) and ABBV-706 (SEZ6), and tusamitamab ravtansine (CEACAM5). Early data are encouraging, according to Dr. Leal, and include a 58% response rate to the topoisomerase-1 inhibitor ifinatamab deruxtecan in an early-phase trial.
Identifying Small Cell Subtypes
“The discovery of transcriptional subsets is a major breakthrough,” Dr. Leal said, explaining their predominance might guide treatment selection in the future. Four key subtypes have been labeled: ASCL1, NEUROD1, POU2F3, and the inflamed subtype (SCLC-I).
The potential benefit of identifying the subtypes—essentially finding a biomarker—was demonstrated in a subset analysis of the IMpower133 trial; this study reported greater differential benefit with prolonged survival with atezolizumab plus chemotherapy in the SCLC-I subtype, although all subtypes derived greater benefit from the addition of immunotherapy to chemotherapy compared to chemotherapy alone.9 The SCLC-I–positive patients treated with atezolizumab plus chemotherapy had a median overall survival of 18.2 months, vs 10.4 months with chemotherapy (HR = 0.566). In other subtypes, median overall survival ranged from 9.6 to 11.6 months, similar to the range in the control arm.
“The complicating factor is the plasticity of small cell lung cancer,” Dr. Leal added, “as the subtypes evolve during treatment or upon disease progression, resistance arises. Circulating cell-free DNA testing might be useful in identifying the predominant subtype at the time of treatment selection…. This is the dream of the future.”
Dr. Leal added that other important questions are being explored and novel approaches tested in other studies. They include the following:
- Thoracic radiotherapy and radiotherapy to metastatic sites, with maintenance immunotherapy: NRG LU007 trial
- Immunotherapy for limited-stage small cell lung cancer: ADRIATIC, NRG/Alliance LU005, and MK 7339-013/KEYLYNK-013.
DISCLOSURE: Dr. Leal has served on the advisory board of Mirati Therapeutics, AstraZeneca, Merck, Takeda, EMD Serono, Eisai, and Jazz Pharmaceuticals; has served as a consultant to Merck, Daiichi Sankyo, Janssen, Eisai, Novocure, Amgen, Roche, Regeneron, and Catalyst; and has received institutional research funding from Pfizer, Advaxis, and Bayer.
REFERENCES
1. Leal T: Advances in small cell lung cancer therapy. 2023 Debates and Didactics in Hematology and Oncology Conference. Presented July 22, 2023.
2. Cheng Y, Han L, Wu L, et al: Effect of first-line serplulimab vs placebo added to chemotherapy on survival in patients with extensive-stage small cell lung cancer: The ASTRUM-005 randomized clinical trial. JAMA 328:1223-1232, 2022.
3. Rudin CM, Liu SV, Lu S, et al: SKYSCRAPER-02: Primary results of a phase III, randomized, double-blind, placebo-controlled study of atezolizumab + carboplatin + etoposide with or without tiragolumab in patients with untreated extensive-stage small cell lung cancer. 2022 ASCO Annual Meeting. Abstract LBA8507. Presented June 5, 2022.
4. Karim NFA, Miao J, Reckamp KL, et al: SWOG S1929: Phase II randomized study of maintenance atezolizumab versus atezolizumab + talazoparib in patients with SLFN11 positive extensive stage small cell lung cancer. 2023 ASCO Annual Meeting. Abstract 8504. Presented June 5, 2023.
5. Trigo J, Subbiah V, Besse B, et al: Lurbinectedin as second-line treatment for patients with small-cell lung cancer. Lancet Oncol 21:645-654, 2020.
6. Aix SP, Ciuleanu TE, Navarro A, et al: Combination lurbinectedin and doxorubicin versus physician’s choice of chemotherapy in patients with relapsed small-cell lung cancer (ATLANTIS): A multicentre, randomised, open-label, phase 3 trial. Lancet Respir Med 11:74-86, 2023.
7. Navarro A, Aix SP, Barneto-Aranda IC, et al: Analysis of patients with relapsed small cell lung cancer receiving single-agent lurbinectedin in the phase 3 ATLANTIS trial. 2022 ASCO Annual Meeting. Abstract 8524. Presented June 5, 2022.
8. Borghaei H, Paz-Ares L, Johnson M, et al: Phase 1 updated exploration and first expansion data for DLL3-targeted T-cell engager tarlatamab in small cell lung cancer (DeLLphi-300 study). 2022 World Conference on Lung Cancer. Abstract OA12.05. Presented August 8, 2022.
9. Gay CM, Stewart CA, Park EM, et al: Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities. Cancer Cell 39:346-360.e7, 2021.
