Investigators Set Sights on Novel Agents Following Negative Studies in Relapsed Small Cell Lung Cancer

Primo “Lucky” Lara Jr., MD

New agents in development including ABBV-011 and BL-B01D1 seek to turn the tides of relapsed extensive-stage small cell lung cancer (ES-SCLC), explained Primo “Lucky” Lara Jr., MD, who added that although chemoimmunotherapy has earned its right as the frontline standard of care, both classes of agents have yet to demonstrate benefit in second or later lines.

“In patients with reasonable performance status, the best option remains clinical trials participation,” Primo “Lucky” Lara Jr, MD, director of the University of California (UC) Davis Comprehensive Cancer Center, professor of medicine and executive associate dean at the UC Davis School of Medicine said in a presentation delivered at the 24th Annual International Lung Cancer Congress®.¹

In 2020, lurbinectedin (Zepzelca) received accelerated approval from the FDA, joining topotecan as an approved second-line therapy. Topotecan received approval in 1996, and in 2006 demonstrated an improvement in overall survival (OS) vs best supportive care alone (HR, 0.64; 95% CI, 0.45-0.90; P =.0104),² whereas lurbinectedin was approved based on response data from a phase 2 trial. In the overall population (n = 105), the objective response rate (ORR) was 35.2% (95% CI, 26.2%-45.2%), the benefit of which was driven largely by patients with a chemotherapy-free interval of 90 days or more (platinum-sensitive; ORR, 45.0%; 95% CI, 32.1%-58.4%).³ A similar pattern was seen in terms of duration of response (DOR), which was 6.2 months in patients with platinum sensitivity vs 4.7 months in those with platinum-resistant disease.

Median OS was 9.3 months (95% CI, 6.3-11.8) overall, and 5.0 months (95% CI, 4.1-6.3) and 11.9 months (95% CI, 9.7-16.2) in patients with a chemotherapy-free interval less than 90 days and 90 days or greater, respectively. A subsequent study showed that the magnitude of benefit seemed to grow the longer patients’ chemotherapy-free interval was, with an ORR of 60.0% via investigator assessment, median DOR of 5.5 months (95% CI, 2.9-11.2), and median OS of 16.2 months (95% CI, 9.6-not reached) in patients with a chemotherapy-free interval of 180 days or more.⁴

However, the activity of the agent does not come without toxicity, Lara explained, stating that 16% of patients experienced grade 3 or 4 treatment-related adverse effects (TRAEs) in the pivotal trial published in Lancet Oncology, including fatigue, febrile neutropenia, pneumonia, and diarrhea. “This is a cytotoxic [agent]. It sounds like a new targeted agent, but it’s not. It’s a cytotoxic agent derived from a marine creature. It cleaves to double stranded DNA brakes, which is your classic cytotoxic agent, so its toxicities mirror that of what we would expect with chemotherapy,” Lara said.

Lara also noted that when tested in combination with doxorubicin as second-line therapy in the phase 3 ATLANTIS trial (NCT02566993), the combination failed to demonstrate an improvement in OS vs topotecan or cyclophosphamide, doxorubicin, and vincristine (HR, 0.967; 95% CI, 0.815-1.148; P =.7032).⁵ The “next shot on goal” is the phase 3 LAGOON trial (NCT05153239), Lara said, which will evaluate lurbinectedin in combination with irinotecan vs irinotecan alone in the relapsed setting.

Subsequent attempts at improving the activity of lurbinectedin include the phase 1/2 LUPER trial (NCT04358237), Lara said, which evaluated lurbinectedin in combination with pembrolizumab (Keytruda) in the relapsed setting. However, with dose-limiting toxicity that resulted in median duration of treatment of 2.1 months (range, 0-11.8) and an ORR of only 31%, the combination never moved forward in development.⁶

The phase 3 CheckMate 451 trial (NCT02538666) evaluated a pure immunotherapy approach, with maintenance nivolumab (Opdivo) with or without ipilimumab (Yervoy) vs placebo. However, both confidence intervals for OS with nivolumab with ipilimumab (HR, 0.92; 95% CI, 0.75-1.12; P =.3693) and nivolumab alone (HR, 0.84; 95% CI, 0.69-1.02) crossed 1.00, failing to show benefit.⁷ Additionally, when nivolumab was put up against topotecan in the second-line setting in the phase 3 CheckMate 331 trial (NCT02481830) in immunotherapy-naïve patients, a long established standard of care, the PD-1 inhibitor failed to improve OS (HR, 0.86; 95% CI, 0.72-1.04; P =.11).⁸

After several failed attempts with chemotherapy and immunotherapy, investigators have turned their attention to antibody-drug conjugates (ADC). At the 2023 ASCO Annual Meeting, Daniel Morgensztern, MD, presented data from a first-in-human phase 1 trial (NCT03639194) with the seizure-related homolog protein 6 (SEZ6)-targeted ADC ABBV-011, which consists of an anti-SEZ6 IgG1 monoclonal antibody SC17, noncleavable LD19.¹⁰ linker, and calicheamicin payload.

In explaining the rationale behind the agent’s investigation, Lara stated that the protein is highly expressed in SCLC and other neuroendocrine cancers, with limited expression in most healthy tissues and non-neuroendocrine cancers.

Among 98 evaluable patients treated with the agent, most of which had extensive-stage disease and 2 prior lines of therapy, including prior immunotherapy, the ORR was 19% (95% CI, 12%-29%), and the clinical benefit rate was 69% (95% CI, 59%-78%).9 Notably, 37% (95% CI, 27%-47%) of patients experienced clinical benefit for at least 12 weeks. Response on study was evaluated in 40 patients and showed a median treatment duration of 12 weeks (range, 2-63), and a median DOR of 4.2 months (95% CI, 2.6-6.7). At data cutoff, 8% of patients remained on treatment. Notably, there was not a significant difference in activity between platinum-sensitive and platinum-resistant patients, Lara said.

The most common AEs included fatigue, nausea, decreased appetite, decreased platelet count, vomiting, aspartate aminotransferase increase, constipation, and gamma-glutamyl transferase

increase. Treatment-emergent hepatoxicities included hyperbilirubinemia, ascites, alanine aminotransferase increase, veno-occlusive liver disease, and portal hypertension. 

Another ADC that has entered the research realm is BL-B01D1, a first-in-class EGFR- and HER3-directed ADC that is thought to enable broad-spectrum and pan-tumor killing. The agent is bounded to a novel topoisomerase I inhibitor payload via a cleavable linker.

In a first-in-human phase 1 trial (NCT05194982) encompassing non–small cell lung cancer (n = 87), nasopharyngeal carcinoma (n = 28), SCLC (n = 7), head and neck squamous cell carcinoma (n = 15), and other (n = 2), data from which were presented by Li Zhang, MD, at the 2023 ASCO Annual Meeting, the ORR in the small cell population was 14.3% (95% CI, 0.36%-57.9%), with a DCR of 85.7% (95% CI, 42.1%-99.6%).10 In the overall study population (n = 195), most patients experienced a TRAE (any grade, 92%; grade ≥3, 57%). Frequent TRAEs included leukopenia, anemia, neutropenia, and thrombocytopenia. Notably, interstitial lung disease was not seen.

In conclusion, Lara stated, “Platinum-based therapy plus a PD-L1 inhibitor is the frontline standard of care, either atezolizumab [Tecentriq] or durvalumab [Imfinzi], with the platinum doublet. Maintenance immunotherapy and combination immune checkpoint inhibitors have missed the mark. In the second-line setting lurbinectedin is FDA approved. Topotecan is also FDA approved. Re-challenging with a platinum-based doublet is also fine as long as you have a long treatment-free interval. [Though], we still have to work on putting patients on trials.”

References

1. Lara P Jr. Extensive-stage small cell lung cancer in the 2nd line and beyond setting. Presented at: 24th Annual International Lung Cancer Congress; July 27-29, 2023; Huntington Beach, CA.
2. O’Brien MER, Ciuleanu TE, Tsekov H, et al. Phase III trial comparing supportive care alone with supportive care with oral topotecan in patients with relapsed small-cell lung cancer. J Clin Oncol. 2006;24(34):5441-5447. doi:10.1200/JCO.2006.06.5821
3. 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/S1470-3045(20)30068-1
4. Subbiah V, Paz-Ares L, Besse B, et al. Antitumor activity of lurbinectedin in second-line small cell lung cancer patients who are candidates for re-challenge with the first-line treatment. Lung Cancer. 2020;150:90-96. doi:10.1016/j.lungcan.2020.10.003
5. Paz-Ares L, Ciuleanu TE, Navarro A, et al. Lurbinectedin/doxorubicin versus CAV or topotecan in relapsed SCLC patients: phase III randomized ATLANTIS trial. Presented at: International Association for the Study of Lung Cancer 2021 World Conference on Lung Cancer; September 8-14, 2021; Virtual. Abstract PL02.03.
6. Calles A, Navarro A, Doger B, et al. A phase 1/2 trial of lurbinectedin (L) in combination with pembrolizumab (P) in relapsed small cell lung cancer (SCLC): The LUPER study. J Clin Oncol. 2022; 40 (suppl 16):8581. doi: doi.10.1200/JCO.2022.40.16_suppl.8581
7. Owonikoko T, Kim H, Govindan R, et al. Nivolumab (nivo) plus ipilimumab (ipi), nivo, or placebo (pbo) as maintenance therapy in patients (pts) with extensive disease small cell lung cancer (ED-SCLC) after first-line (1L) platinum-based chemotherapy (chemo): Results from the double-blind, randomized phase III CheckMate 451 study. Presented at: 2019 European Lung Cancer Congress; April 11 to 13, 2019; Geneva, Switzerland. Abstract LBA1.
8. Reck M, Vicente D, Ciuleanu T, et al. Efficacy and safety of nivolumab (nivo) monotherapy versus chemotherapy (chemo) in recurrent small cell lung cancer (SCLC): Results from CheckMate 331. Ann Oncol. 2018;29(10):X43. doi:10.1093/annonc/mdy511.004
9. Morgensztern D, Ready NE, Johnson ML, et al. First-in-human study of ABBV-011, a seizure-related homolog protein 6 (SEZ6)–targeting antibody-drug conjugate, in patients with small cell lung cancer. J Clin Oncol. 2023;41(suppl 16):3002. doi:10.1200/JCO.2023.41_suppl.16.3002
10. Zhang, L, Ma Y, Zhao Y, et al. BL-B01D1, a first-in-class EGFRxHER3 bispecific antibody-drug conjugate (ADC), in patients with locally advanced or metastatic solid tumor: Results from a first-in-human phase 1 study. J Clin Oncol. 2023;41(suppl 16):3001. doi:10.1200/JCO.2023.41.16_suppl.3001