Progress on New Therapies Stirs Hope in SCLC

Joshua K. Sabari, MD

During the past 15 years, breakthrough discoveries have revolutionized the treatment landscape for most patients with lung cancer, progress that has helped fuel an overall drop in cancer mortality.^1,2 However, options remain limited for the subgroup of patients with small cell lung cancer (SCLC).

Against this backdrop, the treatment paradigm for patients with SCLC is evolving slowly beyond standard chemotherapy. Immune checkpoint inhibitor (ICI) combinations with chemotherapy have been incorporated into first-line treatment protocols for patients with extensive-stage SCLC (ES-SCLC) and the approval of lurbinectedin (Zepzelca), a novel form of chemotherapy, has expanded options for progressive disease.

Meanwhile, data for novel ICI combinations presented at recent medical conferences strengthen the case for such strategies in ES-SCLC, experts say. Additionally, efforts to study disease variation have uncovered molecular drivers of SCLC subtypes that may be useful in developing targeted therapies.

“Small cell lung cancer, despite being an uncommon disease, is one of the more aggressive cancers we know. It has a poor overall survival, and, despite making many survival-extending advances, both in targeted therapeutics as well as immunotherapy in non–small cell [lung cancer], we haven’t really done that well in the small cell [lung cancer] population,” Joshua K. Sabari, MD, said during an OncLive^® educational webinar in July 2022.3 Sabari is an assistant professor in the Department of Medicine at NYU Grossman School of Medicine in New York, New York.

“Clearly, more needs to be done. We need to understand the biology of this disease better, but as that research takes place, we need to follow best treatment practices as we now understand them,” Sabari said.

Taofeek Owonikoko, MD, PhD

That includes diagnosing patients and initiating therapy as early as possible during the course of disease, and closely monitoring responses for signs of recurrence and brain metastases, Sabari said. Lung cancer experts who participated in a recent OncLive Peer Exchange^® expressed excitement about an increasing number of clinical trials for patients with SCLC and the potential for research to yield novel, more effective therapies. However, they also noted that many patients are not benefiting from currently available options.⁴

“When you look at the US population of patients diagnosed with small cell lung cancer, 40% of them may not get any treatment at all,” Taofeek Owonikoko, MD, PhD, said. He is chief of the Division of Hematology/Oncology at the University of Pittsburgh School of Medicine in Pennsylvania and associate director for translational research at UPMC Hillman Cancer Center.

“That reflects the belief by most of our non-oncology colleagues in other specialties such as pulmonary and internal medicine that once you have a diagnosis of small cell there’s no effective treatment, [the patient] shouldn’t even bother going through any treatment,” Owonikoko said. “...Maybe over time, with education with our peers and colleagues, we are going to be able to change that paradigm.”

The SCLC Landscape

An estimated 236,740 patients are expected to receive a diagnosis of lung cancer in the United States in 2022, with approximately 85% of those cases classified as non–small cell lung cancer (NSCLC) and 15% as SCLC.⁵

Improvements in detection and treatment have helped drive down the mortality rates from lung cancer, significantly contributing to an overall decline in cancer mortality of 2% per year from 2015 through 2019, according to the American Cancer Society.6 However, most of the lung cancer gains are attributed to treatment advances for patients with NSCLC, because ICIs and molecularly targeted therapies have transformed the paradigm.⁷

The discrepancy in outcomes for the 2 major subtypes is reflected in the 5-year relative survival rate, which is 26% for patients with NSCLC and 7% for those with SCLC.7 With treatment, median overall survival (OS) for patients with SCLC ranges from 6 months to 24 months, depending on the extent of disease and stage at diagnosis.⁵

Among patients with new SCLC diagnoses, approximately 12,000 are expected to present with limited-stage disease whereas about 23,000 will have extensive-stage disease. In limited- stage disease, the tumor is confined to 1 hemithorax, the mediastinum, or the supraclavicular nodes, such that the tumor fits within a single radiation field. Any disease that cannot be safely confined to a single radiation field is defined as extensive.^5,8

For patients with limited-stage SCLC, the goal of treatment is often curative through chemotherapy plus thoracic radiation therapy and, for some patients, surgical resection. For the majority of patients who are diagnosed with ES-SCLC, preferred systemic primary treatment involves combining a PD-L1 inhibitor, either atezolizumab (Tecentriq) or durvalumab (Imfinzi), with a chemotherapy doublet, according to National Comprehensive Cancer Network guidelines.9 Although the risk of relapse is high, more than 60% of patients consistently respond to cytotoxic therapies, including many patients with metastatic disease.¹⁰

Front Line ICI Approvals

Several studies have now demonstrated an improvement in overall survival with the addition of ICI therapy to chemotherapy in the front line, although most of the gains are relatively modest.

The FDA approved atezolizumab in combination with carboplatin and etoposide for the f irst-line treatment of adults with ES-SCLC in March 2019. A year later, the agency gave the go-ahead for durvalumab in combination with etoposide and either carboplatin or cisplatin as a first-line treatment for patients with ES-SCLC.^11,12

Jared Weiss, MD

“If we look back on the past decade, the biggest advance is the addition of PD-L1 inhibitory therapy being added to the standard platinum etoposide regimen,” Jared Weiss, MD, said during the OncLive Peer Exchange^® program. “If you look at the evolution of frontline therapy before that, it was based on toxicity advantages and convenience advantages. These matter, but PD-L1 is our first survival advantage in a long time.” Weiss is an associate professor of medicine-oncology at UNC Lineberger Comprehensive Cancer Center in Chapel Hill, North Carolina.

The FDA approved the atezolizumab regimen based on findings from the phase 3 IMpower133 trial (NCT02763579) for 403 patients who had received no prior chemotherapy for extensive-stage disease and had ECOG performance status 0 or 1.¹¹

Median OS was 12.3 months (95% CI, 10.8-15.9) for patients receiving atezolizumab with chemotherapy and 10.3 months (95% CI, 9.3-11.3) for participants receiving placebo plus chemotherapy (HR, 0.70; 95% CI, 0.54-0.91; P = .0069). Median progression-free survival (PFS) was 5.2 months (95% CI, 4.4-5.6) with atezolizumab compared with 4.3 months (95% CI, 4.2-4.5) with placebo (HR, 0.77; 95% CI, 0.62-0.96; P = .0170). The objective response rate (ORR) was 60% with the atezolizumab regimen vs 64% with chemotherapy alone.¹¹

Charles M. Rudin, MD, PhD

The combination of durvalumab plus chemotherapy gained approval based on OS results from 537 patients treated in the phase 3 CASPIAN trial (NCT03043872). The median OS was 13.0 months (95% CI, 11.5-14.8) in the durvalumab plus chemotherapy arm compared with 10.3 months (95% CI, 9.3-11.2) in the chemotherapy-alone arm (HR, 0.73; 95% CI, 0.59-0.91; P = .0047).¹²

Investigator-assessed median PFS was 5.1 months (95% CI, 4.7-6.2) in the durvalumab arm and 5.4 months (95% CI, 4.8-6.2) in the chemotherapy-alone arm (HR, 0.78; 95% CI, 0.65-0.94). The ORR was 68% in the durvalumab group vs 58% with chemotherapy alone.¹²

Both ICI regimens maintained an OS benefit in updated findings reported in 2021. The median OS was 12.3 months (95% CI, 10.8-15.8) vs 10.3 months (95% CI, 9.3-11.3), respectively, for the atezolizumab-based and chemotherapy-alone regimens in IMpower133 (HR, 0.76; 95% CI, 0.600.95; P = .0154). At 18 months, the OS rate among patients who received atezolizumab was 34.0% compared with 21.0% for participants treated with chemotherapy alone.¹³

Similarly, the median OS rate was 12.9 months (95% CI, 11.3-14.7) with durvalumab plus chemotherapy compared with 10.5 months (95% CI, 9.3-11.2) for chemotherapy alone in updated findings from CASPIAN (HR, 0.75; 95% CI, 0.62-0.91; P = .0032). The addition of durvalumab to chemotherapy resulted in a 32.0% OS rate at 18 months vs 24.8% with chemotherapy alone. (CASPIAN also included a third arm in which patients received durvalumab, the CTLA-4 inhibitor tremelimumab, and platinum-etoposide therapy, but that regimen did not significantly improve OS).¹⁴

Although the addition of PD-L1 inhibitors to standard chemotherapy represents a step forward for the SCLC paradigm, many patients do not respond to these therapies, Charles M. Rudin, MD, PhD, noted during the program.

“When they do work, they can be transformative,” Rudin said. “There are patients who have durable responses even in extensive-stage disease so these [therapies] can really change a person’s fate. That’s something that was a long time coming and has clearly redefined our standard of care.”

Rudin is chief of the thoracic oncology service, codirector of the Druckenmiller Center for Lung Cancer Research, and the Sylvia Hassenfeld Chair in Lung Cancer Research at Memorial Sloan Kettering Cancer Center in New York, New York. He is a leading investigator into the use of ICIs in patients with SCLC.

First Line Pembrolizumab

In August 2022, Rudin and colleagues presented long-term follow-up results from the phase 3 KEYNOTE-604 study (NCT03066778) at the 2022 World Conference on Lung Cancer sponsored by the International Association for the Study of Lung Cancer.¹⁵ The study tested the first-line use of pembrolizumab (Keytruda), a PD-1 inhibitor, combined with a chemotherapy doublet vs chemotherapy alone for patients with stage IV SCLC with no prior systemic therapy or unstable brain metastases and an ECOG performance score of 0 or 1. The dual primary end points were PFS and OS.

In all, 453 patients were randomly assigned to receive pembrolizumab (n = 228) or placebo (n = 225) plus etoposide with carboplatin or cisplatin every 3 weeks for 4 cycles. These regimens were followed in the experimental arm by pembrolizumab monotherapy and by placebo in the control arm for up to 31 cycles with optional prophylactic cranial irradiation. However, approximately 15% of patients in the chemotherapy-alone group subsequently received ICI therapy.

In previously reported findings, there was a trend toward an OS improvement with the pembrolizumab-containing regimen, but the outcome did not meet a prespecified threshold for statistical significance (HR, 0.80; 95% CI, 0,640.98; P = .0164).¹⁵

In the updated data, the median OS in the intention-to-treat (ITT) population after approximately 3.5 years’ follow-up was 10.8 months (95% CI, 9.2-12.9) among patients who received pembrolizumab compared with 9.7 months (95% CI, 8.6-10.7) for chemotherapy alone (HR, 0.76; 95% CI, 0.63-0.93). The median PFS in the ITT population was 4.8 months (95% CI, 4.3-5.4) with pembrolizumab and 4.3 months (95% CI, 4.2-4.5) for chemotherapy alone (HR, 0.70; 95% CI, 0.57-0.85).¹⁵

Of note, 18 patients who completed 35 cycles of pembrolizumab therapy had better outcomes. The median OS was not reached (NR; 95% CI, 16.6NR) and the 2-year OS rate was 72.2% (95%CI, 39.5%-89.2%), which corresponded to approximately 4 years after randomization.

In presenting the data, Rudin emphasized that 15.5% of patients treated with the pembrolizumab regimen were still alive at 36 months vs 5.9% of participants who received chemotherapy alone. “We’re seeing about a tripling of 3-year survival,” Rudin said. “Although both of these curves are lower than we would like them to be, to me it’s a substantial benefit and similar to what we’ve seen with other checkpoint inhibitors for this disease.”

Moreover, he noted, 6.9% of patients in the pembrolizumab arm maintained a PFS benefit at 3 years, including 10.1% with a duration of response (DOR) of at least 42 months. “These patients are remaining progression-free at the tail of the curve for multiple years now,” Rudin said, adding that such an approach could be a “transformative thought” for patients.

Next steps for pembrolizumab-based combinations for patients with ES-SCLC include the phase 3 KEYVIBE-008 study (NCT05224141) as first-line therapy. The study is evaluating MK-7684A, a coformulation of vibostolimab and pembrolizumab, plus etoposide with platinum chemotherapy vs atezolizumab plus chemotherapy followed by MK-7684A or atezolizumab, respectively. Vibostolimab is a monoclonal antibody directed at the TIGIT immune checkpoint.¹⁷

Investigational ICI Approaches

In another study, Rudin and colleagues sought to determine whether the addition of tiragolumab, a TIGIT inhibitor, to atezolizumab plus chemotherapy would improve outcomes for patients with treatment-naïve ES-SCLC. Investigators randomly assigned 490 patients to tiragolumab (n = 243) or placebo (n = 247) combined with atezolizumab, carboplatin, and etoposide in the phase 3 SKYSCRAPER-02 trial (NCT04256421).¹⁸

The use of tiragolumab failed to improve OS and PFS in all patients who received treatment (HR, 1.02 and 1.08, respectively) and in the primary analysis set of participants without a presence or history of brain metastases at baseline (HR, 1.04 and 1.11), according to findings presented at the 2022 American Society of Clinical Oncology Annual Meeting in June (2022 ASCO).¹⁸

However, investigators noted that the median OS outcomes in the control arm of atezolizumab plus chemotherapy confirmed its place as a first-line standard of care. The median OS was 12.9 months (95% CI, 12.1-14.5) in the full analysis set and 13.6 months (95% CI, 12.3-15.2) in the primary analysis set.¹⁸

As development of FDA-approved ICIs continues for SCLC indications, the novel PD-1 inhibitor serplulimab (HLX10) has demonstrated an OS benefit in combination with chemotherapy as a frontline treatment for patients with ES-SCLC in research conducted in China and several other countries. Interim findings from the phase 3 ASTRUM-005 study (NCT04063163) were presented at the 2022 ASCO.¹⁶

In the study, 585 patients were randomly assigned 2:1 to receive either serplulimab (n = 389) or placebo (n = 196) with carboplatin plus etoposide, followed by serplulimab monotherapy or placebo, respectively. Key eligibility criteria included no prior systemic therapy for ES-SCLC and an ECOG performance score of 0 or 1.

After a median follow-up of 12.3 months, the median OS in the serplulimab group was 15.4 months (95% CI, 13.3-not evaluable) compared with 10.9 months (95% CI, 10.0-14.3) in the placebo arm (HR, 0.63; 95% CI, 0.49-0.82); P < .001). The median PFS was 5.7 months (95% CI, 5.5-6.9) with the serplulimab regimen vs 4.3 months (95% CI, 4.2-4.5) with placebo plus chemotherapy (HR, 0.48; 95% CI, 0.38-0.59). The ORR was 80.2% with serplulimab and 70.4% with chemotherapy alone.¹⁶

In April 2022, the FDA granted orphan drug status for serplulimab as a treatment for SCLC, which qualifies the drug for certain financial incentives, according to Shanghai Henlius Biotech, Inc, the company developing the drug.19 In China, the National Medical Products Administration approved serplulimab for microsatellite instability–high solid tumors in March 2022 and is considering a new drug application for the agent in first-line ES-SCLC.¹⁶

Second-Line Failures and Advances

Although ICI therapy is solidifying a place in the frontline treatment of ES-SCLC, its efficacy as monotherapy for progressive disease has faded. In 2018, the FDA granted an accelerated approval for nivolumab (Opdivo), a PD-1 inhibitor, as a second-line therapy for patients with metastatic SCLC whose disease progressed after treatment with platinum-based chemotherapy and at least 1 other line of therapy, based on response rates and DOR data from the phase 1/2 CheckMate-032 trial (NCT01928394). However, Bristol Myers Squibb withdrew the indication in December 2020 after data from confirmatory studies failed to support a benefit.²⁰

A similar scenario unfolded with pembrolizumab, which also received an accelerated approval as a second-line therapy in patients with metastatic SCLC that progressed after prior chemotherapy in June 2019, based on tumor response rate and from cohort G of the phase 2 KEYNOTE-158 trial (NCT02628067) and cohort C1 of the phase 1 KEYNOTE-028 (NCT02054806) study. Merck withdrew the indication in March 2021 after findings from subsequent clinical trials did not confirm an OS improvement.²¹

Meanwhile, lurbinectedin was introduced into the treatment landscape for second-line therapy in June 2020. Until then, the only FDA-approved option for second-line therapy for SCLC was topotecan (Hycamtin), a topoisomerase I inhibitor that gained its initial indication in the malignancy in 1998.^22,23

Lurbinectedin is an alkylating drug that binds to DNA, setting off a cascade of events that may disrupt DNA binding proteins and repair pathways, resulting in cell death. The agent also may affect the tumor microenvironment through several mechanisms that cause apoptosis of peripheral blood monocytes and tumor-associated macrophages, decrease expression of the inflammatory chemokines, and reduce tumor angiogenesis.^22,24

The FDA granted an accelerated approval for lurbinectedin in adults with metastatic SCLC with disease progression on or after platinum-based chemotherapy based on findings from the phase 2 PM1183-B-005-14 trial (Study B-005; NCT02454972).²⁵

Among 105 patients treated during the study, the investigator-assessed ORR was 35% (95% CI, 26%-45%) and the median DOR was 5.3 months (95% CI, 4.1-6.4). Outcomes were better for the cohort of 60 patients who had platinum-sensitive SCLC, defined as recurrence or progression 90 days or longer after the last dose of platinum-containing therapy. For these patients, the investigator-assessed ORR was 45% (95% CI, 32%-58%) and the median DOR was 6.2 months (95% CI, 3.5-7.3).^22,24

In December 2021, investigators launched the confirmatory phase 3 LAGOON trial (NCT05153239), which was designed to establish the efficacy of lurbinectedin for full FDA approval. The trial, which has a target enrollment of approximately 700 patients, is randomly assigning participants to 1 of 3 arms: lurbinectedin monotherapy at 3.2 mg/m2 intravenously (IV); lurbinectedin at 2.0 mg/m2 IV plus irinotecan 75 mg/m2 IV; investigator’s choice of topotecan at 2.3 mg/m2 orally or 1.5 mg/m2 IV, or irinotecan at 350 mg/m2 IV. The primary end points are OS and PFS.²⁶

The Search for Molecular Targets

In NSCLC, the development of tyrosine kinase inhibitors has made treatment for the tumor type a prime example of molecularly targeted therapy.² However, similar progress has proved elusive in SCLC. Nearly all cases of SCLC are associated with smoking and its mutational profile reflects the impact of tobacco carcinogens in driving disease. Whereas NSCLC is driven by activating oncogenic alterations, the development of SCLC involves the dual inactivation of the tumor suppressor genes TP53 and RB1.¹⁰

“Genetically, what we see across the board in patients with small cell lung cancer is inactivation or loss of TP53, a gene responsible for fixing other abnormalities. We also see loss of RB1 or retinoblastoma, and these 2 alterations are very difficult to target in patients with small cell lung cancer,” Sabari said. “Unlike EGFR mutations, for example, which we can act upon with tyrosine kinase inhibitors, there are no FDA-approved therapies for these alterations in small cell.”

Although genomic analysis is not yet used to develop prognoses or drive treatment, investigators have identified 4 distinct subtypes of SCLC based on differential levels of transcription factor expression: ASCL1 (SCLC-A subtype), POU2F3 (SCLC-P), NEUROD1 (SCLC-N), and YAP1 (SCLC-Y). The subtypes account for approximately 70%, 16%, 11%, and 2% of cases, respectively.²⁷

In 2021, investigators identified an inflamed subtype (SCLC-I) characterized by low expression of ASCL1, NEUROD1, and POU2F3, according to Carl M. Gay, MD, PhD, and colleagues at The University of Texas MD Anderson Cancer Center in Houston. An analysis of SCLC circulating tumor cells in xenograft models showed that the SCLC-I subtype is more likely to respond to ICI therapy whereas the other subtypes might respond to inhibitors targeting PARP, aurora kinases, or BCL-2.²⁸

“Based on these separate classifications of small cell lung cancer, we’re starting to tease out potential subsets of patients who may benefit from specific therapies,” Sabari said. “More recently, there is a paper from Carl Gay’s group at MD Anderson that takes this to the next level to seek a more inflamed subtype of small cell lung cancer [in which] patients may benefit further from immunotherapy than others. Again, these subclassifications are not currently used in clinical practice, but they may help in the future with prognosis, treatment, and, more importantly, the development of clinical trials for specific subsets of patients.”

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