Novel Frontline Combinations Influence Later-Line Treatment Strategies in SCLC

Taofeek Owonikoko, MD, PhD

Small cell lung cancer (SCLC) has continued to evolve in recent years, in part from immunotherapy (IO)/chemotherapy combinations in the frontline setting with atezolizumab and durvalumab, respectively.¹ For the secondline setting, the addition of lurbinectedin (Zepzelca) has shown intriguing data while also raising questions about the agent’s optimal role in this population. These newer strategies and therapeutics in were discussed in detail during an OncLive Peer Exchange^®, which was moderated by Taofeek Owonikoko, MD, PhD, professor of medicine in the Division of Hematology-Oncology of the University of Pittsburgh and chief of hematology and oncology at the University of Pittsburgh Medical Center Hillman Cancer Center.

Nearly 240,000 new patients will be diagnosed with lung cancer in 2023 in the United States; SCLC accounts for 14% of lung cancers and is a usually more aggressive subtype.² When diagnosed with SCLC, which commonly peaks between aged 75 and 79 years in men and women, 94% of patients have disease that has spread beyond the lungs. The incidence of all lung cancers, including SCLC, peaks about 5 years earlier in African American men compared with White men. Regarding outcomes, the 2-year survival rate in SCLC has increased to 19% and 16% in 2017 to 2018 among women and men from 10% and 8% in 1975 to 1976, respectively.

While progress in outcomes has been greater in non–small cell lung cancer, recent advances, including molecularly targeted therapies against EGFR and ALK, checkpoint inhibitors that boost immune response, improved staging, and video-assisted surgery have all contributed to progress in treatment of all types of lung cancer, including in SCLC.² Owonikoko added, however, that outcomes for SCLC remain dismal, as most patients are diagnosed with incurable, extensive-stage disease.

Challenges Surround Early Diagnosis in SCLC

Konstantinos Leventakos, MD, an assistant professor of medicine and oncology at Mayo Clinic in Rochester, Minnesota, added that the biggest challenge in SCLC is that it is fast growing in nature and that more efficient screening methodologies would be useful in identifying the disease earlier. “Have we seen patients being diagnosed with SCLC through screening? Yes, but whether we have seen a meaningful reduction in the mortality because we were able to recognize many patients in early stages are data that we don’t yet have. So while oncologists are pro-screening because it saves lives, more personalized and more SCLC specific strategies are needed.”

Patients should also be treated sooner for pneumonia for an extended time, particularly smokers, and an earlier biopsy could aid in earlier diagnoses. “Once there is a histologic confirmation of SCLC, immediate referral to oncology is required, and the health care system should be ready to accommodate fast referrals for patients with SCLC,” Leventakos said.

Jacob Sands, MD, a thoracic medical oncologist at Dana-Farber Cancer Institute and assistant professor of medicine at Harvard Medical School, agreed that lung screening is the best way to improve SCLC outcomes as it allows earlier-stage intervention.

Defining the Role of Biomarkers in SCLC Diagnosis and Treatment

Anne Chiang, MD, PhD, an associate professor and associate cancer center director of clinical initiatives at Yale School of Medicine, explained that PD-L1 expression must be assessed prior to determining treatment for an individual patient with SCLC.

First-Line IO Combinations in ES-SCLC

The panel reflected on a patient case of a 68-year-old male with SCLC who was also identified to have pleural hepatic and brain metastases. Despite the heavy disease burden, the patient had an ECOG performance status of 0 and started treatment with nivolumab (Opdivo), carboplatin, etoposide. After 2 cycles, as well as following completion of 4 cycles, there was progressive improvement in the pleural pericardial effusions, reduction in the overall metastatic burden, and significant shrinkage in the hepatic metastases. Overall, the patient experienced minimal toxicity with the regimen and a clear improvement in terms of the associated symptoms.

Having a response to treatment after 2 cycles, followed by a deeper response after cycle 4 was uncommon, making Sands optimistic about this particular patient case. However, Chiang said this scenario was typical in her practice.

While Chiang said most patients with SCLC are metastatic, similar to this individual patient, they can have responses to treatment. “We have a responsibility to these patients to prepare them for what may come next. In most cases, there is recurrence. There’s a window to talk to our patients and make sure that they understand and can prepare without giving up hope, for what may come next.”

Frontline standard-of-care (SOC) options for SCLC treatment include the combination of atezolizumab, carboplatin, and etoposide; the second option is platinum plus etoposide and durvalumab (Imfinzi). Both options are FDA approved and widely used, the panel noted. “These are both PD-L1 inhibitors and patients like hearing that these are not toxins,” Sands said.

The indication for atezolizumab was based off findings from the phase 3 IMpower133 trial (NCT02763579), in which the PD-L1 inhibitor plus chemotherapy improved median overall survival to 12.3 months compared with 10.3 months in the chemotherapy plus placebo arm (HR, 0.70; 95% CI, 0.54-0.91; P = .007).³

Having cisplatin available, as well as patients who have hemocytopenia because of bone marrow involvement, would put the durvalumab plus platinum/etoposide regimen as his preference in the frontline setting.

In the limited-stage disease setting, Leventakos said data are limited for incorporating immunotherapy. Moreover, in the absence of a clinical trial, standard treatment for those with limited-stage disease is concurrent chemoradiation, which usually comprises cisplatin with etoposide. Leventakos cited frequent situations of starting with 1 cycle of chemotherapy and catch up with radiation in the following cycle or as soon as possible. Also, in the case of a resected SCLC nodule, adjuvant cisplatin, preferably with etoposide, would be his approach.

CASPIAN Takes It Up a Notch in SCLC

The phase 3 CASPIAN trial (NCT03043872) explored the efficacy and safety of durvalumab alone or combined with tremelimumab (Imjudo) and platinum-based chemotherapy followed by durvalumab maintenance therapy vs chemotherapy alone as a first-line treatment for patients with ES-SCLC.⁴ Preliminary findings did demonstrate an overall survival (OS) improvement with the immunotherapy regimen, but it was not found to be statistically significant. However, updated data showed that the durvalumab combination continued to show an improved overall survival (OS) vs chemotherapy alone.⁵ Specifically, in longer study follow-up, which was a median follow-up of 39.4 months, the median OS at 3 years was 12.9 months vs 10.5 months, respectively (HR, 0.71; 95% CI, 0.60-0.86; P = .0003), and the 3-year OS rate was 17.6% vs 5.8%, respectively.

In the other arm of the CASPIAN trial, durvalumab/tremelimumab plus etoposide/cisplatin chemotherapy (EP) also continued to improve OS vs chemotherapy alone. Median OS was 10.4 months (HR, 0.81; 95% CI, 0.67-0.97; P = .0200), and the 36-month OS rate was 15.3%. At 3 years, three times more patients with SCLC were estimated to be alive when given durvalumab plus chemotherapy versus chemotherapy alone, with most patients still receiving durvalumab at the data cutoff. These data established durvalumab plus chemotherapy as the first-line SOC for patients with extensive-stage (ES)–SCLC.⁵

“I love showing my patients the tail of the curve for the CASPIAN trial. I show it to them because it’s important that they know that they could be living in 3 years, even if they have disease that has spread to the brain,” Chiang said. “The CASPIAN trial showed us that you can triple the survival from 6% to 18%. We’re working on clinical trials to try to improve that even more.”

First-line durvalumab plus chemotherapy benefited the OS and progression-free survival (PFS) irrespective of the presence of brain metastases in patients with SCLC, supporting its SOC use.⁶

In the durvalumab plus chemotherapy arm of the trial, adverse events (AEs) were reported by few patients before starting treatment in both arms. Baseline AE rates were maintained in both arms up to 24 weeks after starting treatment, except for itchy skin, which increased from 13% at baseline to 34% at cycle 6 in the durvalumab/chemotherapy arm and 12% at baseline to 42% at cycle 8 in the chemotherapy-alone arm. Dizziness increased from 16% to 40% at cycle 5 in the durvalumab/chemotherapy arm.

Shaking Up Second-Line SCLC Treatment

In a second case scenario, the panel highlighted a 78-year-old female patient who was initially admitted for weight loss and dysphasia. A PET scan showed a significant fluorodeoxyglucose avidity in the mass and a 4R node, and the biopsy led to a SCLC diagnosis. The patient was initially treated for limited-stage disease with concurrent carboplatin and etoposide with radiation, but a recurrence occurred after 7 months. The patient then completed 4 cycles of chemotherapy and atezolizumab before starting maintenance treatment with the PD-L1 inhibitor. Her disease progressed again about 5 months after starting treatment. Lurbinectedin was then started, but following further disease progression, lurbinectedin therapy was discontinued.

Lurbinectedin received FDA approval in June 2020 for the treatment of adult patients with metastatic SCLC with disease progression on or after platinum-based chemotherapy. The decision was based off findings in the multicenter, open-label, multicohort PM1183-B-005-14 trial (Study B-005; NCT02454972), which comprised 105 patients with metastatic SCLC.

Results showed that lurbinectedin led to an overall response rate of 35.2% and a disease control rate of 68.6%.⁷

Second-line options, beyond lurbinectedin, can include a standard chemotherapy doublet, Leventakos said, but treatment in the second-line setting is not being offered as much as it should. “The old classic second-line treatment in the [United States] is an inhibitor with topotecan, while other countries might use irinotecan. In the US, topotecan was the main second-line treatment. Lurbinectedin has changed the second-line setting.”

“Lurbinectedin is a great tool for us. Patients tolerate it well and we’ve had good responses. It’s the second-line tool for most patients. It would be great if we could combine lurbinectedin with immunotherapy,” Chiang said.

Cell viability testing in SCLC models confirm high SLFN11–expressing cell lines are 4 times more sensitive to lurbinectedin compared with low SLFN11–expressing cell lines, suggesting a potential biomarker for lurbinectedin.⁸

However, in the relapsed setting, the combination of lurbinectedin plus doxorubicin did not improve OS vs control in patients with relapsed SCLC, though it did demonstrate a favorable hematologic safety profile.⁹

Overall, activity with lurbinectedin has led to the ongoing, randomized phase 3 LAGOON study (NCT05153239) which is evaluating lurbinectedin alone or lurbinectedin/irinotecan vs investigators choice or irinotecan in patients with relapsed SCLC.¹⁰

“This is an exciting time for SCLC. We’re developing this idea that we can have precision medicine, that there’s not just 1 uniform SCLC, that there are subtypes that we can leverage and hope to be able to understand why some of the trials in the past were negative. Perhaps we didn’t capture the right population,” Chiang concluded. Overall, we are starting to develop some real inroads into helping our patients with SCLC.”

References

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• Cancer Facts and Figures 2023. American Cancer Society. Accessed August 23 2023. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2023/2023-cancer-facts-and-figures.pdf
• Horn L, Mansfield AS, Szczęsna A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018;379(23):2220-2229. doi:10.1056/NEJMoa1809064
• Durvalumab ± tremelimumab in combination with platinum-based chemotherapy in untreated extensive-stage small cell lung cancer (CASPIAN) (CASPIAN). ClinicalTrials.gov. Updated July 19, 2023. Accessed September 19, 2023. https://clinicaltrials.gov/study/NCT03043872
• Paz-Ares LG, Chen Y, Reinmuth N, et al. Durvalumab, with or without tremelimumab, plus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer: 3-year overall survival update from CASPIAN. ESMO Open. 2022;7(2):100408. doi:10.1016/j.esmoop.2022.100408
• Chen Y, Paz-Ares LG, Dvorkin M, et al. First-line durvalumab plus platinum-etoposide in extensive-stage (ES)-SCLC (CASPIAN): Impact of brain metastases on treatment patterns and outcomes. J Clin Oncol. 2020;38(suppl 15):9068-9068. doi:10.1200/JCO.2020.38.15_suppl.9068
• Trigo J, Subbiah V, Besse B, et al. Lurbinectedin as second-line treatment for patients with small-cell lung cancer: a single-arm, open-label, phase 2 basket trial. Lancet Oncol. 2020;21(5):645-654. doi:10.1016/S1470-2045(20)30068-1.
• Kundu K, Cardnell RJ, Zhang B, et al. SLFN11 biomarker status predicts response to lurbinectedin as a single agent and in combination with ATR inhibition in small cell lung cancer. Transl Lung Cancer Res. 2021;10(11):4095-4105. doi:10.21037/tlcr-21-437
• 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. 2023;11(1):74-86. doi:10.1016/S2213-2600(22)00309-5
• Besse B, Paz-Ares LG, Peters S, et al. A phase III study of lurbinectedin alone or in combination with irinotecan vs investigator’s choice (topotecan or irinotecan) in patients with relapsed small cell lung cancer (SCLC; LAGOON trial). J Clin Oncol. 2023;41(suppl 16; abstract TPS8613). doi:10.1200/JCO.2023.41.16_suppl.TPS8613