Therapy Selection in Small Cell Lung Cancer With Disease Progression After Platinum-Based Therapy

Platinum-based therapies, commonly used for SCLC, unfortunately prove ineffective for certain patients. As a result, ongoing clinical trials are diligently investigating alternative treatments to identify potential options for this specific patient population.
 
Misty Shields, MD, PhD, is a thoracic oncologist and assistant professor of clinical medicine in the Department of Medicine and Division of Hematology/Oncology at Indiana University School of Medicine in Indianapolis. Her clinical research interests in relation to patients with SCLC include clinical trials featuring novel therapies and approaches. In this article, Dr Shields discusses the efficacy and safety of lurbinectedin compared with other therapies, the use of liquid biopsies, and the impact of early palliative care approaches on quality of life and survival.

The National Comprehensive Cancer Network (NCCN) recommends clinical trials for all patients with SCLC.¹ Are you particularly enthusiastic about any trials in this space, because of either innovative approaches or preliminary data that has been released?

Over 200 trials are actively recruiting for patients with SCLC. I am excited to see the results from a phase 2, single-arm study (ClinicalTrials.gov identifier: NCT04010357) investigating the role of abemaciclib — an oral cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor — in 29 patients with chemo-refractory retinoblastoma (Rb) wild-type extensive-stage SCLC (ES-SCLC). “Platinum-refractory” in this study is defined as no response after 1 to 2 cycles of chemotherapy or relapse after completion of platinum-based chemotherapy. The primary outcome of this study is objective response rate, with secondary outcomes including progression-free survival (PFS) at 6 months, overall survival (OS), safety, adverse events, and duration of response. Rb testing will be confirmed as wild type by either next-generation sequencing or liquid biopsy for ctDNA.
 
The majority of SCLCs include the biallelic inactivation of TP53 and RB1; however, in a small subset (6%) of SCLCs, RB1 is proficient.^2,3 Preclinical research identified a distinct Rb-proficient subset by immunohistochemistry and genomic analysis by next-generation sequencing through assessment of Rb expression, RB1 alterations, and p16 low/cyclin D1 high profile, where there may be potential utility of CDK4/6 inhibitors such as abemaciclib for these patients.³ This study highlights the powerful translational connection of a bench-to-bedside approach for a personalized and mechanism-based regimen for a subgroup of SCLC.

For patients with disease progression after etoposide plus a platinum derivative (EP) who are not eligible for rechallenge or clinical trials, lurbinectedin and topotecan seem to be the therapies of choice.⁴ How does the efficacy and safety profile of lurbinectedin compare to that of topotecan, and what factors contribute to physician decision making about how to use these therapies in these patients?

Direct comparison of single-agent lurbinectedin with topotecan has not yet been performed in ES-SCLC. However, tolerability of these 2 chemotherapy agents can be extrapolated from the phase 3 CORAIL study (ClinicalTrials.gov identifier: NCT02421588) in platinum-resistant ovarian cancer. In the CORAIL study, 442 patients were randomly assigned in a 1:1 fashion to receive either lurbinectedin 3.2 mg/m² intravenous (IV) infusion every 3 weeks (q3wk) vs control arm topotecan 1.5 mg/m² IV days 1 to 5 q3week or pegylated liposomal doxorubicin (PLD) 50 mg/m² IV q4week, with a primary endpoint of PFS. Median PFS was 3.5 months (95% CI, 2.1–3.7) in the lurbinectedin arm compared with 3.6 months (95% CI, 2.7–3.8) in the control arm (P =0.6294; homologous recombination [HR] =1.057). Grade 3 or greater toxicities were most frequent in the control arm (64.8%) compared with lurbinectedin (47.9%; P =0.0005). This study demonstrated that lurbinectedin, albeit in relapsed or refractory ovarian cancer, has comparable efficacy and a more tolerable toxicity profile compared with topotecan and PLD.⁵
 
Variables to consider when deciding between these 2 regimens are laboratory parameters such as hematologic “reserve” and comorbidities (history of gastrointestinal disease), as well as geographic proximity from the cancer center or clinic and social support and transportation for frequent trips (day 1 q3week vs days 1 to 5 q3week schedule).
 
In my opinion, the use of topotecan in the oncology setting is widely variable. Topotecan is not unanimously well received for use by thoracic oncologists given its unfavorable toxicity profile and intensive treatment schedule.

How does lurbinectedin modulate the tumor microenvironment in SCLC, and what implications might this have for its use in combination therapy?

Lurbinectedin is a synthetic alkaloid that binds DNA and disrupts DNA–protein interactions, thereby inhibiting active transcription of proteins in cancer cells.⁶ Preclinical studies have demonstrated lurbinectedin’s ability to modulate the tumor microenvironment by induction of apoptosis in peripheral monocytes circulating in the blood and tumor-associated macrophages.^6–8 Specifically, lurbinectedin decreases expression of inflammatory chemokines, including chemokine (C-C motif) ligand 2 (CCL2), and it may induce immunogenic cell death by the release of damage-associated molecular patterns.⁶
 
Preclinical models suggest synergy of lurbinectedin with anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) and anti-programmed cell death 1 ligand (anti-PD-1) blockade.⁶ This has led to support of the actively recruiting phase 3, open-label, randomized study with lurbinectedin in combination with atezolizumab, compared with atezolizumab alone (ClinicalTrials.gov identifier: NCT05091567), administered as a maintenance therapy in ES-SCLC following first-line induction therapy. Primary endpoints of this first-line maintenance study include PFS and OS.

ICIs have seen mixed success in the treatment of SCLC, with approvals for first-line treatment following positive results in the IMpower133 (ClinicalTrials.gov identifier: NCT02763579), CASPIAN (ClinicalTrials.gov identifier: NCT03043872), and KEYNOTE-604 (ClinicalTrials.gov identifier: NCT03066778) phase 3 trials, but trial failures and withdrawals for second- and third-line usage.^9–13 What is the current situation for ICI use in platinum-resistant SCLC patients? Are any trials ongoing for this indication?

It seems that the application of ICIs in SCLC would truly be ideal for a homerun. However, the response of ICIs in SCLC is lacking; effects are very modest. How do we identify and leverage therapy for these patients? Work from Gay et al may highlight an inflamed signature to identify patients who will benefit from ICIs.¹⁴ However, prospective validation is needed to develop a reliable predictive biomarker for ICIs in SCLC.
 
The role of ICIs in second-line therapy and beyond is unclear. In fact, in the NCCN guidelines for SCLC, if a patient demonstrates progression on maintenance immunotherapy, the ongoing use of ICIs is discouraged at the time of relapse. What is unique about the immune landscape in SCLC? PD-L1 expression is low or absent in SCLC. SCLC harbors a cold T-cell receptor repertoire and demonstrates immune escape through downregulation of major histocompatibility complex (MHC) class I expression, resulting in decreased antigen presentation.¹⁵ A field of active research is exploring the role of MHC class I antigen presentation in non-neuroendocrine subtypes and leveraging these pathways to prime immunogenicity in SCLC.
 
The addition of the anti-T cell immunoreceptor with Ig and ITIM domains (TIGIT) antibody tiragolumab to atezolizumab plus platinum-based chemotherapy in first-line therapy, studied in Skyscraper-02 (ClinicalTrials.gov identifier: NCT04256421), was quite lackluster. Skyscraper-02 failed to hit its coprimary endpoint of improving OS. More investigation is needed to characterize why this approach fell short.
 
Emerging trials in this space include novel adjuncts to modulate the immune response to ICIs, thereby enhancing T-cell recognition with therapeutics, such as epigenetic regulators and antibody drug conjugates (ADCs). In fact, a phase 1 study (ClinicalTrials.gov identifier: NCT03639194) is actively investigating the role of a novel seizure-related homolog 6 (SEZ6) ADC, called ABBV-011, alone or in combination with budigalimab (ABBV-181) in relapsed or refractory SCLC. Moreover, can the use of bispecific T-cell engagers such as delta-like ligand 3 (DLL3) — AMG 757 or BI 764532 — essentially force the immune system to engage and recognize DLL3-positive SCLC by design? I am eagerly awaiting the results of these studies.

The novel antibody-drug conjugate targeting DLL3, rovalpituzumab tesirine (Rova-T), was withdrawn by the manufacturer after it showed no survival benefit for patients with SCLC in the first-line treatment settings.¹⁶ For lung cancer, generally, we have seen waves of approved molecularly targeted therapies in the past few years. Why has it been so difficult to develop targeted therapies for SCLC, and are there any that you are excited to follow in development?

We must consider many variables when extrapolating findings in a preclinical manner to clinical trials for use in patients. These variables may be contributing to the number of “negative trials” we have experienced to date in SCLC.
 
Preclinical studies must be designed with an achievable dose and schedule that is suitable for patients. Leaving a drug at high levels on cancer cells in a lab for weeks is not useful unless a patient can be dosed in a similar way, such as via daily oral use or continuous pump administration. We must also be mindful of pharmacokinetics and pharmacodynamics, such as maximal achievable concentrations and drug clearance and elimination through the liver and kidney, when designing these models in the lab for future applications in patients.
 
Another major barrier to studying SCLC is access to specimens. Truly, “tissue is the issue” in SCLC, because most patients do not undergo surgical resection given the proclivity for early metastatic spread in SCLC. The majority of patients with SCLC will undergo biopsy with a fine-needle aspiration or core-needle biopsy that is limited furthermore by crush artifact and necrosis due to a highly proliferative background of tumor.
 
We are incredibly fortunate to have the preclinical SCLC cell line models established in the 1970s to 1990s, which have led to innumerable advances in SCLC. However, these models have many limitations, including lack of dynamic features such as capture by time and space. Newer mouse models of SCLC are exciting for studying SCLC; however, they fail to replicate the heterogeneity demonstrated in patient specimens.¹⁷ Patient-derived xenografts are very exciting to capture acquired mechanisms of resistance but can be time-consuming and require maintenance of colonies.

Can any biomarkers currently predict resistance to platinum-based chemotherapies or guide treatment approaches for patients who have progressed after platinum-based therapy?

This question highlights an area of great unmet need in the treatment of SCLC. We know that SCLC consists of at least 4 neuroendocrine subtypes (NeuroD1, ASCL1, POU2F3, and YAP1 vs an inflamed signature). Moreover, heterogeneity and subtype plasticity exist and can transform with selective pressures, such as after platinum-based chemotherapy.^18,19 More clinical validation of these subtypes is needed, and it needs to address when to test (at diagnosis, at relapse, or longitudinally), how to test for the neuroendocrine subtypes (RNA sequencing, methylation arrays, or immunohistochemistry), the interpretation for its clinical application, and whether distinct therapeutic vulnerabilities exist.
 
No validated predictive biomarkers for platinum resistance exist for clinical use in SCLC. There has been recent interest in Schlafen 11 (SLFN11) as a potential predictive biomarker for the combination of poly (ADP-ribose) polymerase (PARP) inhibitors with alkylating agent temozolomide after platinum-based therapy in ES-SCLC.²⁰ Validation of this biomarker in a prospective manner is actively underway.

A recent paper looked at the genetic profiles of 3600 SCLC cases, the largest published cohort to date.²¹ Does this paper provide any insight into how patients might be further stratified to improve outcomes? Do ctDNA (liquid biopsy) approaches currently have any uses in monitoring of SCLC patients?

This paper demonstrates strength in numbers to highlight unique features of SCLC, leveraging a large dataset of available information from genetic testing performed in both community and academic settings in patients with SCLC.
 
In my opinion, longitudinal liquid biopsies, with their ability to capture numerous features from a patient simultaneously, are the future of SCLC. Liquid biopsies will be powerful aids in detecting emerging resistance if the right platforms are employed, not only including exon and the rare intron coverage of these techniques, but also capturing data simultaneously on methylation signatures, subtype classification, and circulating tumor cell enumeration. This, combined with clinical annotation such as where a patient is in the treatment, which treatment they are receiving, and how their radiographic evaluation of disease burden over time correlates, will be beneficial.

Would you like to mention anything else on this topic?

We know early palliative care involvement in non-small cell lung cancer means that patients live longer.^22,23 With SCLC, the cadence of the disease can be overwhelming, as these patients are quite symptomatic at diagnosis and the focus is typically on starting treatment as soon as possible. Most patients’ cancer-related symptoms do improve initially, as SCLC is very sensitive to treatment. However, due to factors we do not quite understand, the disease comes back, and then it may be too late for effective palliative care because we do not have those pathways in place.
 
Integrating palliative care early for patients with SCLC is important. Palliative care can provide an additional layer of support to help with cancer-related symptoms and help keep patients on therapy and reduce care delays or hospitalizations. Patients can experience side effects from their treatments, so we have to think about how we maintain the fitness of patients to allow them to get the therapies they need, live longer, and be with their families.
 
This Q&A was edited for clarity and length.

Disclosures

Misty Shields, MD, PhD, reported an affiliation with Jazz Pharmaceuticals.

References

1. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Small Cell Lung Cancer. Fort Washington, PA: NCCN; 2022. Ver. 3.2023. Accessed May 24, 2023. https://www.nccn.org/guidelines/nccn-guidelines/guidelines-detail?category=1&id=1462  
 
2. George J, Lim JS, Jang SJ, et al. Comprehensive genomic profiles of small cell lung cancer. Nature. 2015;524(7563):47-53. doi:10.1038/nature14664
 
3. Febres-Aldana CA, Chang JC, Ptashkin R, et al. Rb tumor suppressor in small cell lung cancer: combined genomic and IHC analysis with a description of a distinct Rb-proficient subset. Clin Cancer Res. 2022;28(21):4702-4713. doi:10.1158/1078-0432.CCR-22-1115
 
4. Toublanc AC, Guecamburu M, Veillon R, Rosellini P, Girodet PO, Zysman M. Second-line lurbinectedin as a new treatment option for small-cell lung cancer: preliminary results in real-clinical practice. Thorac Cancer. 2022;13(15):2248-2252. doi:10.1111/1759-7714.14464
 
5. Gaillard S, Oaknin A, Ray-Coquard I, et al. Lurbinectedin versus pegylated liposomal doxorubicin or topotecan in patients with platinum-resistant ovarian cancer: a multicenter, randomized, controlled, open-label phase 3 study (CORAIL). Gynecol Oncol. 2021;163(2):237-245. doi:10.1016/j.ygyno.2021.08.032
 
6. Patel S, Petty WJ, Sands JM. An overview of lurbinectedin as a new second-line treatment option for small cell lung cancer. Ther Adv Med Oncol. 2021;13. doi:10.1177/17588359211020529
 
7. Allavena P, Belgiovine C, Digifico E, Frapolli R, D’Incalci M. Effects of the anti-tumor agents trabectedin and lurbinectedin on immune cells of the tumor microenvironment. Front Oncol. 2022;12. doi: 10.3389/fonc.2022.851790
 
8. Belgiovine C, Bello E, Liguori M, et al. Lurbinectedin reduces tumour-associated macrophages and the inflammatory tumour microenvironment in preclinical models. Br J Cancer. 2017;117(5):628-638. doi:10.1038/bjc.2017.205
 
9. Liu SV, Reck M, Mansfield AS, et al. Updated overall survival and PD-L1 subgroup analysis of patients with extensive-stage small-cell lung cancer treated with atezolizumab, carboplatin, and etoposide (IMpower133). J Clin Oncol. 2021;39(6):619-630. doi:10.1200/JCO.20.01055
 
10. 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 randomised, controlled, open-label, phase 3 trial. Lancet. 2019;394(10212):1929-1939. doi:10.1016/S0140-6736(19)32222-6
 
11. Rudin CM, Awad MM, Navarro A, et al. Pembrolizumab or placebo plus etoposide and platinum as first-line therapy for extensive-stage small-cell lung cancer: randomized, double-blind, phase III KEYNOTE-604 study. J Clin Oncol. 2020;38(21):2369-2379. doi:10.1200/JCO.20.00793
 
12. Bristol-Myers Squibb announces phase 3 CheckMate-331 study does not meet primary endpoint of overall survival with Opdivo versus chemotherapy in patients with previously treated relapsed small cell lung cancer. News release. Bristol-Myers Squibb. October 12, 2018. Accessed April 9, 2023. https://news.bms.com/news/details/2018/Bristol-Myers-Squibb-Announces-Phase-3-CheckMate–331-Study-Does-Not-Meet-Primary-Endpoint-of-Overall-Survival-with-Opdivo-Versus-Chemotherapy-in-Patients-with-Previously-Treated-Relapsed-Small-Cell-Lung-Cancer/default.aspx
 
13. Merck provides update on Keytruda^® (pembrolizumab) indication in metastatic small cell lung cancer in the US. News release. Merck. March 1, 2021. Accessed April 9, 2023. https://www.merck.com/news/merck-provides-update-on-keytruda-pembrolizumab-indication-in-metastatic-small-cell-lung-cancer-in-the-us/
 
14. 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. 2021;39(3):346-360.e7. doi:10.1016/j.ccell.2020.12.014
 
15. Chen M, Chen R, Jin Y, et al. Cold and heterogeneous T cell repertoire is associated with copy number aberrations and loss of immune genes in small-cell lung cancer. Nat Commun. 2021;12(6655). doi:10.1038/s41467-021-26821-8
 
16. AbbVie discontinues rovalpituzumab tesirine (Rova-T) research and development program. News release. AbbVie. August 29, 2019. Accessed April 9, 2023. https://news.abbvie.com/news/press-releases/abbvie-discontinues-rovalpituzumab-tesirine-rova-t-research-and-development-program.htm
 
17. Ireland AS, Micinski AM, Kastner DW, et al. MYC drives temporal evolution of small cell lung cancer subtypes by reprogramming neuroendocrine fate. Cancer Cell. 2020;38(1):60-78.e12. doi:10.1016/j.ccell.2020.05.001
 
18. Baine MK, Hsieh MS, Lai WV, et al. SCLC subtypes defined by ASCL1, NEUROD1, POU2F3, and YAP1: a comprehensive immunohistochemical and histopathologic characterization. J Thorac Oncol. 2020;15(12):1823-1835. doi:10.1016/j.jtho.2020.09.009
 
19. Owonikoko TK, Dwivedi B, Chen Z, et al. YAP1 expression in SCLC defines a distinct subtype with T-cell–inflamed phenotype. J Thorac Oncol. 2021;16(3):464-476. doi:10.1016/j.jtho.2020.11.006
 
20. Coleman N, Zhang B, Byers LA, Yap TA. The role of Schlafen 11 (SLFN11) as a predictive biomarker for targeting the DNA damage response. Br J Cancer. 2021;124(5):857-859. doi:10.1038/s41416-020-01202-y
 
21. Sivakumar S, Moore JA, Montesion M, et al. Integrative analysis of a large real-world cohort of small cell lung cancer identifies distinct genetic subtypes and insights into histological transformation. Cancer Discov. Published online April 16, 2023. doi:10.1158/2159-8290.CD-22-0620
 
22. Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med. 2010;363(8):733-742. doi:10.1056/NEJMoa1000678
 
23. Sullivan DR, Chan B, Lapidus JA, et al. Association of early palliative care use with survival and place of death among patients with advanced lung cancer receiving care in the Veterans Health Administration. JAMA Oncol. 2019;5(12):1702-1709. doi:10.1001/jamaoncol.2019.3105
 
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