Recently, the addition of immunotherapy to chemotherapy regimens has demonstrated increased survival in patients with ES-SCLC, and immunotherapy plus chemotherapy is now the standard of care for patients with extensive-stage disease. 

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Tarlatamab

Tarlatamab (AMG 757) is a half-life extended, bispecific T-cell connector that targets CD3 and delta-like ligand 3 (DLL3). DLL3 is an atypical Notch ligand that is overexpressed in most forms of SCLC tumours but is not present in normal adult tissues.  

Tarlatamab functions independently of MHC-I expression to trigger immune responses, resulting in T-cell mediated tumour lysis, according to authors of a review in Frontiers in Oncology.[1]

In May, the United States Food and Drug Administration (FDA) granted accelerated approval to tarlatamab-dlle after a phase 2 DeLLphi-301 study (NCT05060016) assessed the antitumor activity and safety of two different doses of tarlatamab in patients with relapsed ES-SCLC who had previously been treated with two or more lines of therapy.[2][3]

Overall, 220 patients received tarlatamab. They received a step dose of 1 mg of tarlatamab on day 1 of cycle 1, after which they were administered a target dose of either 10 mg or 100 mg on days 8 and 15 of cycle 1 and then every 2 weeks thereafter in 28-day cycles until disease progression occurred.

Among patients assessed for antitumor activity and survival, median follow-up was 10.6 months in the 10-mg group and 10.3 months in the 100-mg group. An objective response occurred in 40% of the patients in the 10-mg group and 32% in the 100-mg group.

In the 10-mg group, the median progression-free survival was 4.9 months; in the 100-mg group, it was 3.9 months. Overall survival estimates at 9 months were 68% and 66% of patients, respectively.

The most common treatment-related AEs (TRAEs) were cytokine-release syndrome, which occurred in 51% of the patients in the 10-mg group and in 61% of those in the 100-mg group. Other TRAEs included decreased appetite (in 29% and 44% of patients, respectively) and pyrexia (in 35% and 33% of patients, respectively). Only 3% of patients discontinued tarlatamab because of TRAEs.

Investigators concluded, “tarlatamab had durable antitumor activity in patients with heavily pretreated small-cell lung cancer. Results from this trial can be viewed favourably in the context of real-world studies of drugs for third-line use and beyond, in which objective responses occurred in 14 to 21% of the patients, median response durations were less than 3 months, and median overall survival durations were less than 6 months.”

Note: This trial only included ECOG 0 and 1 patient. 

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Rova-T

Clinical outcomes involving treatment with rovalpituzumab tesirine (Rova-T) have been disappointing, wrote researchers in the Journal of Thoracic Oncology.[3] This has been the conclusion despite an initial fervour revolving around Rova-T monotherapy in early phase 1 trials in SCLC.

Rova-T is an antibody-drug conjugate that consists of a DLL3-targeting antibody bound to a cytotoxic agent pyrrolobenzodiazepine via a protease-cleavable linker. In the TAHOE trial, investigators examined the efficacy and safety of Rova-T vs topotecan as second-line (2L) therapy in patients with SCLC expressing high levels of DLL3. Results were published in the Journal of Thoracic Oncology.[4]

In this RCT, Rova-T (0.3 mg/kg) was administered intravenously on day 1 of a 42-day cycle for two cycles to 296 patients. Two additional cycles were offered to patients who met protocol-defined criteria for continued dosing. Topotecan was administered to 148 patients. The median age of the patients was 64 years, and 77% had extensive disease at initial diagnosis.

“Compared with topotecan, which is the current standard second-line chemotherapy, Rova-T exhibited an inferior OS and higher rates of serosal effusions, photosensitivity reaction, and peripheral oedema in patients with SCLC,” the authors wrote. 

"A considerable unmet therapeutic need remains in this population."

— Authors, Journal of Thoracic Oncology [3]

The use of Rova-T with immune checkpoint inhibitors, however, has shown evidence of efficacy. An open-label, phase 1–2 study assessed the safety and efficacy of Rova-T, plus the immune checkpoint inhibitor nivolumab with or without ipilimumab in 42 patients with previously treated ES-SCLC.[5] Antitumour activity was observed, although all patients experienced one or more treatment-emergent adverse events.

Cohort 1 was administered 0.3 mg/kg Rova-T every 6 weeks for two cycles, plus 360 mg of IV-administered nivolumab (two 3-week cycles beginning on week 4). Cohort 2 received the same dosage of Rova-T as cohort 1, along with 1 mg/kg nivolumab (four 3-week cycles) and 1 mg/kg ipilimumab (commencing week 4). Starting at week 10, both cohorts received 480 mg of nivolumab every 4 weeks. The ORR was 30% (cohort 1, 27.6%; cohort 2, 36.4%). All responses were partial.

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GD2 strategies

Disialoganglioside (GD2) is highly expressed in SCLC tumour cells and is considered a good target for chimeric antigen receptor T cells (CART), according to an article in Cancer Research Communications.[6]

Although GD2-directed CARTs (GD2-CART) kill various GD2-expressing tumors, they exhibit limited toxicity vs SCLC. This could change with recent innovations.

Researchers recently introduced GD2-CAR into induced pluripotent stem cells (iPSC)-derived rejuvenated cytotoxic T lymphocytes (GD2-CARrejT). GD2-CARrejTs are more aggressive against SCLC cells than GD2-CARTs.

Research has shown that dual blockade of TIGIT and programmed death-1 (PD-1) magnified the cytotoxicity of GD2-CARTs to a variable degree. This indicates that low TIGIT and PD-1 expression by GD2-CARrejTs is an integral factor for robust cytotoxicity against SCLC.

"Not only for robust cytotoxicity but also for availability as ‘off-the-shelf’ T-cell therapy, iPSC-derived GD2-CARrejTs are a promising novel treatment for SCLC."

— Authors, Cancer Research Communications [6]

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SEZ6

1. Seizure-related homolog protein 6 (SEZ6) is a transmembrane protein expressed in SCLC tumours that has shown promise in treating SCLC. ABBV-011 is an antibody-drug conjugate that aims SEZ6 by leveraging a calicheamicin payload. This strategy has demonstrated antitumor activity in preclinical models of SCLC.[7]
2. Preliminary results involving monotherapy dose-escalation and dose-expansion cohorts of the first-in-human ABBV-011 study also demonstrated the antitumour activities of this agent.
3. In this phase 1, open-centre, multilabel trial (n=99), the maximum tolerated dose was not met, and the drug was well-tolerated by 40 patients at 1.0 mg/kg.
4. The confirmed ORR was 25%, with 10 partial responses. The median duration of response was 4.2 months. The median PFS was 3.5 months. The clinical benefit rate was 65% (10 partial responses and 16 stable diseases).

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Disclaimer: This story is contributed by Naveed Saleh and is a part of our Global Content Initiative, where we feature selected stories from our Global network which we believe would be most useful and informative to our doctor members.