Author: Carl M. Gay, MD, PhD of MD Anderson Cancer Center

Dr. Carl Gay received our 2018 Young Investigator Award. He graciously agreed to write this summary of new research, including his own, that is poised to make a difference for people with small cell lung cancer.

A new era for the management of non-small cell lung cancer (NSCLC) was heralded by the discovery of EGFR mutations and the United States Food & Drug Administration (FDA) approval of the first targeted therapy (erlotinib)1-3 in 2004. Since that time, NSCLC patients have received increasingly personalized care thanks to improved biomarker testing and the development and approval of myriad targeted- and immune-based therapies. As personalized therapy options have grown, so has life expectancy for NSCLC patients.

Until recently, the outlook for SCLC patients contained little of the optimism gained from the personalized cancer therapy era. Attempts to identify targetable driver mutations had yielded little promise and drug development, despite countless attempts, had stalled short of approval. Thus, in contrast to the approach in NSCLC, wherein patients are matched to the best therapy on the basis of tests on their tumor’s DNA, RNA, and protein, SCLC patients were met with an often underwhelming and unsuccessful one-size-fits-all approach limited to just four FDA-approved chemotherapies (cisplatin/carboplatin, etoposide, and topotecan).

The past two-plus years, however, have brought new therapies and the promise of a personalized era for SCLC.

Recently Approved Therapies for SCLC

Two separate clinical trials were the first in more than three decades to demonstrate improved survival with any therapy for SCLC and resulted in rapid FDA approval for these agents for all patients. These trials (IMpower133 and CASPIAN) confirmed that the addition of immunotherapy (atezolizumab and durvalumab, respectively) to standard chemotherapy improved the life expectancy of patients with newly diagnosed, extensive-stage SCLC4,5. While the FDA also approved other immunotherapy agents (pembrolizumab and, until recently, nivolumab) for patients in later lines of therapy, most patients should now receive immunotherapy as part of their initial treatment strategy.

However, many patients fail to respond durably to immunotherapy, and the options are limited for patients who have progressed following chemotherapy in combination with immunotherapy. Until recently, the only option in this setting was the chemotherapy agent topotecan. But in June 2020, the FDA approved a new drug, lurbinectedin, for SCLC that relapsed despite frontline treatment. The initial data suggested that over 35% of patients experienced significant tumor reduction with lurbinectedin – a high mark in this otherwise refractory disease6. Patients receiving lurbinectedin lived for a median of over 10 months after initiating this therapy – again, a promising finding in a population that often saw very poor survival after their initial relapse. Studies to confirm that lurbinectedin outperforms other standards of care, such as topotecan, are necessary, but, for now, oncologists have yet another weapon in the battle against this disease.

Promising Future Therapies and Patient Selection

Several drug classes have demonstrated potential benefits for some relapsed SCLC patients.

  • PARP inhibitors (poly(ADP-ribose) polymerase is a protein that helps repair damaged DNA, in this case in the cancer cell).
  • Oral therapies that impair a cancer cell’s ability to repair its often flawed DNA and are approved for some breast cancer and ovarian cancer patients, have demonstrated response rates in excess of 40% when used in combination with oral chemotherapy agents7,8.

While efforts to demonstrate improved survival for all SCLC patients treated with PARP inhibitors fell short, investigators found that among patients whose tumors express a molecule called Schlafen-11 (SLFN11), the addition of a PARP inhibitor improved life expectancy8. SLFN11 can be detected using a simple assessment referred to as immunohistochemistry (IHC) and an assay for its detection has been validated and is being used in an ongoing trial for newly diagnosed SCLC patients (SWOG1929: A Phase II Study of Maintenance Atezolizumab Versus Atezolizumab in Combination with Talazoparib in Patients with SLFN11 Positive Extensive Stage Small Cell Lung Cancer). Researchers have also found that PARP inhibitors may enhance SCLC tumor responses to immunotherapy9, another potential strategy for prolonging responses for SCLC patients currently under investigation in clinical trials, including the one above. Trials are also underway investigating drugs aimed at restoring or maintaining the expression of SLFN1110 (A Phase I/II Study of DS-3201b and Irinotecan for Patients with Recurrent Small Cell Lung Cancer), again to try to prolong responses to chemotherapies and targeted therapies.

There is promising early data for other therapies in development, including drugs targeting other molecules highly expressed in SCLC tumors, including Delta-like ligand 3 (DLL3) (e.g. AMG757) and Aurora kinases (e.g. AZD2811). In the case of DLL3-targeting therapies, the presence of DLL3 itself assessed by IHC may allow physicians to select for those patients most likely to benefit from this therapy. Meanwhile, for Aurora kinases, investigators found that patients whose tumors have detectable (by IHC) expression of c-MYC derive the greatest benefit11.

More globally, recent evidence points to the inherent flaws in the one-size-fits-all approach to SCLC treatment assignment. Several investigators have highlighted heterogeneity among SCLC tumors – not necessarily based on their DNA (as in NSCLC), but instead based on their RNA12. For example, our recent work illustrates that SCLC tumors can be subdivided into four subtypes, which we called SCLC-A, SCLC-N, and SCLC-P, on the basis of expression of transcription factors ASCL1, NEUROD1, and POU2F3, respectively, and SCLC-I, or SCLC-Inflamed13.

Assigned to these subtypes by their gene expression profiles, SCLC patient tumors and models experience distinct responses to both standard therapies and experimental therapies based on subtype. For example, we have shown that while all SCLC patients benefit from the addition of immunotherapy to their frontline treatment, those patients identified as SCLC-I experience markedly improved durability of response compared to the other three groups. This knowledge not only allows investigators to identify patients for whom immunotherapy is most likely to offer maximal benefit but also those patients that urgently need therapeutic strategies aimed at improving responses to immunotherapy, such as PARP inhibitors. Elsewhere, SCLC-P models respond most favorably to PARP inhibitors, SCLC-P and SCLC-N tumors respond most favorably to Aurora kinase inhibitors, and SCLC-A tumors express the highest levels of DLL3 – just to revisit a few drug classes mentioned earlier.

Patients Should Seek Out Clinical Trials

Patients with SCLC, for now, are still subject to the one-size-fits-all approach in the standard of care setting. However, as mentioned, trials are underway to assess some novel therapies and, most importantly, novel biomarkers to better match patients to more effective therapies. Physicians should encourage SCLC patients, and patients should feel empowered to request, seek out, and enroll in clinical trials that aim to usher this disease into the personalized era.

References

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10 Gardner, E. E. et al. Chemosensitive Relapse in Small Cell Lung Cancer Proceeds through an EZH2-SLFN11 Axis. Cancer Cell 31, 286-299, doi:10.1016/j.ccell.2017.01.006 (2017).

11 Owonikoko, T. K. et al. Randomized Phase II Study of Paclitaxel plus Alisertib versus Paclitaxel plus Placebo as Second-Line Therapy for SCLC: Primary and Correlative Biomarker Analyses. J Thorac Oncol 15, 274-287, doi:10.1016/j.jtho.2019.10.013 (2020).

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13 Gay, C. M. et al. Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities. Cancer Cell, doi:10.1016/j.ccell.2020.12.014 (2021).