Immunotherapy Instills Renewed Promise in SCLC

David R. Spigel, MD

Chief Scientific Officer

Sarah Cannon Research Institute

Nashville, TN

With the emergence of immunotherapy-based regimens in earlier lines of treatment and the potential use of novel agents, such as bispecific antibodies (including bispecific T-cell engagers [BitEs]) and antibody-drug conjugates (ADCs), medical oncologist David R. Spigel, MD, feels bullish about the future in both extended- and limited-stage small cell lung cancer (SCLC).

“We have made strides in immune-based strategies in [SCLC], and it gives us hope that we are going to have better opportunities to use the new classes of drugs,” Spigel, chief scientific officer at the Sarah Cannon Research Institute in Nashville, Tennessee, told Targeted Therapies in Oncology during an interview. Recent developments have squarely placed immunotherapy as a potential cornerstone in SCLC.

Limited-Stage SCLC

In the limited-stage setting, consolidation treatment with durvalumab (Imfinzi) after treatment with concurrent platinum-based chemotherapy and radiotherapy improved survival and was shown to have a favorable safety profile, according to findings from the phase 3 ADRIATIC study (NCT03703297).

After receiving platinum-based chemoradiotherapy, patients were randomly assigned to receive durvalumab (1500 mg) and placebo, durvalumab (1500 mg) plus tremelimumab (75 mg), or placebo and placebo every 4 weeks for 4 cycles. This was followed by durvalumab (durvalumab with or without tremelimumab arms) or placebo every 4 weeks for a maximum of 24 months or until investigator-determined progression or intolerable toxicity. The first 600 patients were randomly assigned in a 1:1:1 ratio; subsequent patients were randomly assigned 1:1 to durvalumab or placebo.

“The rationale for evaluating durvalumab was prompted from its use in stage IV extensive-stage disease,” Spigel said. “The other factor that factored into this rationale is that durvalumab has become a standard in locally advanced non–small cell lung cancer, which is similar to limited-stage SCLC.”

During the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois, Spigel et al1 reported at the interim analysis of the durvalumab vs placebo arm that after a median follow-up of 37.2 months (range, 0.1-60.9), the median overall survival (OS) in patients treated with durvalumab (n = 264) was 55.9 months (95% CI, 37.3-not evaluable) vs 33 months (95% CI, 25.5-39.9) in patients treated with placebo (n = 266). This translated to a 27% reduction in the risk of death (HR, 0.73; 95% CI, 0.57-0.93; P = .0104).

Further, after a median follow-up of 27.6 months (range, 0-55.8), the median progression-free survival (PFS) was 16.6 months (95% CI, 10.2-28.2) with durvalumab vs 9.2 months (95% CI, 7.4-12.9) with placebo, equating to a 24% reduction in the risk of disease progression or death (HR, 0.76; 95% CI, 0.61-0.95; P = .0161).

The findings demonstrate the benefit of moving immunotherapy into earlier stages of SCLC. “That’s a major change in care and represents a breakthrough in limited-stage SCLC in close to 3 decades,” Spigel said. “Durvalumab as consolidation treatment after concurrent chemoradiotherapy demonstrated statistically significant and clinically meaningful improvement in both OS and PFS compared with placebo in patients with LS [limited-stage] SCLC.”

“The ADRIATIC study has changed the standard of care and now includes subsequent durvalumab immunotherapy after the completion of concurrent chemoradiation, when a staging scan has shown that the patient had progression,” Alissa J. Cooper, MD, said, during an interview with Targeted Therapies in Oncology. The benefit was observed regardless of which chemotherapy patients received for their concurrent chemoradiation. Cooper is a thoracic medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York, and was not involved in the trial.

An important finding from the trial involved pneumonitis and radiation pneumonitis among patients, Cooper said. “The ADRIATIC trial demonstrated that there wasn’t a substantial amount of added toxicity in addition to what patients had already experienced from concurrent chemoradiation,” Cooper said. “In particular, radiation can cause pneumonitis, but investigators reported that the addition of durvalumab did not lead to substantially increased rates of pneumonitis as compared with placebo.” (TABLE 11).

Durvalumab was well tolerated and adverse events were consistent with known safety profiles, with no new signals observed, according to the investigators. The findings from ADRIATIC lead to further questions about the optimal duration of immunotherapy with regard to the early-stage setting, locally advanced setting, or the metastatic setting. “We still have a lot to learn about how much immunotherapy is necessary for tumors to have a response and to have a durable response,” Cooper said.

Further, ADRIATIC reported that patients received a median of 9 cycles of durvalumab, which resulted in a significant magnitude of benefit. “Could we see more benefit if patients received more cycles?” asked Cooper. “If we follow these patients longer, might we recommend either a de-escalation of therapy, fewer cycles recommended, or an escalation of therapy with more cycles recommended? We just don’t have the data on that yet.”

FDA Approval for Tarlatamab

Tarlatamab-dlle (Imdelltra), a BiTE that targets the delta-like ligand 3 and CD3, received an accelerated approval from the FDA on May 16, 2024. The agent is indicated for patients with SCLC whose disease has progressed on or after platinum-based chemotherapy. It is the first BiTE approved for a major solid tumor and the first therapeutic option for the treatment of extended-stage SCLC (ES-SCLC).² Findings from the phase 2 DeLLphi-301 trial (NCT05060016) provided the basis for the approval.³ With 3 recent clinical and regulatory developments, the use of immunotherapy in treating patients with small cell lung cancer has been established as a standard of care in extended-stage and limited-stage disease.

The 3-part, open-label, international trial evaluated the antitumor effects, safety, adverse events profile, and pharmacokinetics of the agent in patients who had been previously treated with 2 or more lines of therapy.³ The primary end point was confirmed objective response and secondary end points were duration of objective response, disease control, duration of disease control, PFS, and OS.

There were also exploratory end points and these included cytokine levels, DLL3 expression in tumor tissue, immune-related biomarkers, and patient- reported outcomes.³

Part 1 (n = 180) was a dose-comparison assessment in which patients received 10 mg of tarlatamab (n = 88) or 100 mg of tarlatamab (n = 88). An independent dose- selection committee reviewed the data and recommended the target dose for patients in part 2 (n = 12) and 3 (n = 34). As of the data cut-off of June 27, 2023, the median duration of treatment was 5.1 months (range, 0.0-15.2) in the 10-mg group and 3.7 months (range, 0-15.2) in the 100-mg group.3 Investigators reported that the median follow-up was 10.6 months (95% CI, 9.2-11.3) in the 10-mg group and 10.3 months (95% CI, 9.2-11.5) in the 100-mg group.

The percentage of patients with an objective response as assessed by blinded independent central review was 40% (97.5% CI, 29%-52%) in the 10-mg group and 32% (97.5% CI, 21%-44%) in the 100-mg group (TABLE 2).3 Further, the median PFS was 4.9 months (95% CI, 2.9-6.7) in the 10-mg group and 3.9 months (95% CI, 2.6-4.4) in the 100-mg group.³

“In heavily pretreated patients, the response rate was 40%,” Cooper said. “But what was even more important was that some patients achieved a durable response that was ongoing at 12 months.” SCLC usually responds readily to therapies but then tends to recur or progress quickly on those therapies or shortly thereafter, Cooper said.

When patient-reported outcomes were analyzed, it revealed a trend for improvement from baseline in global health status in the 10-mg and 100-mg groups, according to investigators.³

Improvements in chest pain, dyspnea, and stabilization of cough were seen in both groups and analyses of time-to-deterioration in patients who had undergone treatment for longer than 2 months showed no further clinical deterioration in global health status, chest pain, dyspnea, and cough.³

Patients with SCLC lack approved therapies in the third-line and beyond. Findings from DeLLphi-301 are important relative to second-line standard-of-care treatment options such as topotecan, which has shown objective responses in 17% and 24% of patients, a median duration of response of 3.6 months and 4.2 months, and a median OS of 6.3 months and 7.8 months in past studies.^4,5

Extensive-Stage Disease

Immunotherapy has been evaluated in extensive-stage (ES) SCLC with pivotal trials evaluating either atezolizumab (Tecentriq) or durvalumab when added to platinum-based therapies. In 2019, the FDA approved atezolizumab for the firstline treatment of adults with ES-SCLC based on findings from the IMpower133 trial (NCT02763579).^6,7

In IMpower133, patients were randomly assigned to receive carboplatin and etoposide with either atezolizumab (n = 201) or placebo (n = 202) for four 21-day cycles, followed by a maintenance phase during which they received either atezolizumab or placebo (according to the previous random assignment) until they had unacceptable toxic effects, disease progression, or no additional clinical benefit.⁷

The primary end points were OS and PFS in the intention-to-treat population and tumor assessments were conducted at screening, every 6 weeks for the first 48 weeks and every 9 weeks thereafter until disease progression.7 At a median follow-up of 13.9 months, the median OS was 12.3 months in the atezolizumab group and 10.3 months in the placebo group (HR, 0.70; 95% CI, 0.54-0.91; P= .007). The stratified HR for death for OS was 0.70 (95% CI, 0.54-0.91; P = .007), investigators reported.

Similar to the median OS, the median PFS favored the treatment arm, at 5.2 months vs 4.3 months, respectively (HR, 0.77; 95% CI, 0.62-0.96; P = .02).7 For PFS, the stratified HR for disease progression or death was 0.77 (95% CI, 0.62-0.96; P = .02).

Adverse events due to any component of the trial regimen were observed in 94.9% of patients in the atezolizumab arm compared with 92.3% in the control arm.

Neutropenia, anemia, and decreased neutrophil count were the most common grade 3 or 4 adverse events.

Durvalumab received FDA approval on March 27, 2020, in combination with etoposide and either carboplatin or cisplatin as f irst-line treatment in patients with ES-SCLC.

CASPIAN Trial

The approval was based on findings from the CASPIAN trial (NCT03043872).^8,9 Patients in CASPIAN were randomly assigned to receive durvalumab and etoposide, durvalumab and tremelimumab plus etoposide, or etoposide monotherapy. Specifically, treatment-naive patients with ES-SCLC received 4 cycles of durvalumab plus either cisplatin or carboplatin every 3 weeks followed by maintenance durvalumab every 4 weeks until progression or up to 6 cycles of cisplatin or carboplatin every 3 weeks. The primary end point was OS in the intention-to-treat population.

Durvalumab plus platinum- etoposide was associated with a significant improvement in OS, with an HR of 0.73 (95% CI, 0.59-0.91; P = .0047).

Median OS was 13 months (95% CI, 11.5-14.8) in the durvalumab plus platinum-etoposide group vs 10.3 months (95% CI, 9.3-11.2) in the platinum-etoposide group, with 34% (95% CI, 26.9%-41.0%) vs 25% (95% CI, 18.4%-31.6%) of patients alive at 18 months.⁹

Investigator-assessed PFS showed an HR of 0.78 (95% CI, 0.65-0.94), with median PFS of 5.1 months (95% CI, 4.7-6.2) in the durvalumab plus chemotherapy arm and 5.4 months (95% CI,4.8-6.2) in the chemotherapy alone arm.

The investigator-assessed confirmed objective response rate was 68% (95% CI, 62%-73%) in the durvalumab plus chemotherapy arm and 58% (95% CI, 52%-63%) in the chemotherapy alone arm.⁸

Emerging Therapies

ABBV-706, which is an antibody-drug conjugate (ADC), has generated some interest among clinicians.

During the 2024 ASCO Annual Meeting, findings from a phase 1 dose escalation study (NCT05599984) were presented.¹⁰

The trial evaluated ABBV-706 as monotherapy or in combination with budigalimab, a PD-1 inhibitor; carboplatin; or cisplatin. Primary end points were safety, pharmacokinetics, and preliminary efficacy.¹⁰

The investigators evaluated 49 patients with solid tumors (SCLC, n = 22; central nervous system tumors, n = 5; neuroendocrine tumors, n = 22). The agent was administered at a dose of 1.3 to 3.5 mg/kg every 3 weeks in 21-day cycles.¹⁰

The investigators reported a confirmed objective response rate of 21% with 7 partial responses: 40% (6 of 15) for patients with SCLC and 6% (1 of 18) for patients with neuroendocrine tumors. The overall response rate without confirmation was 45%, and the clinical benefit rate was 97%.¹⁰

Regarding safety, investigators reported that cytopenia was dose dependent, with febrile neutropenia reported in 1 patient at a dose of 2.5 mg/kg and gastrointestinal toxicity at grade 1 or 2. The investigators concluded that the agent demonstrated a manageable safety profile. Further evaluation is ongoing.

Another ADC, GSK5764227 (GSK227; HS-20093), received breakthrough designation from the FDA in patients with ES-SCLC.¹¹ Data presented during this year’s ASCO annual meeting showed tumor shrinkage occurring in 96.2% of patients ( 50 of 52) with evaluable targeted lesions.¹² Additionally, tumor shrinkage of 50% or more, or deep responses, occurred in 44.2% of patients. Median OS was not reached, and responses were reported regardless of B7-H3 expression. Investigators reported that a phase 3 study comparing efficacy and safety of GSK227 vs standard therapy in relapsed SCLC is planned.

REFERENCES:

1. Spigel DR, Cheng Y, Cho BC, et al. ADRIATIC: durvalumab (D) as consolidation treatment (tx) for patients (pts) with limited-stage small-cell lung cancer (LS-SCLC). J Clin Oncol. 2024;42(suppl 17):LBA5. doi:10.1200/JCO.2024.42.17_ suppl.LBA5

2. FDA grants accelerated approval to tarlatamab-dlle for extensive stage small cell lung cancer. FDA. May 16, 2024. Accessed August 27, 2024. https://tinyurl.com/bddwjpk2

3. Ahn MJ, Cho BC, Felip E, et al; DeLLphi-301 Investigators. Tarlatamab for patients with previously treated smallcell lung cancer. N Engl J Med. 2023;389(22):2063-2075. doi:10.1056/NEJMoa2307980

4. von Pawel J, Schiller JH, Shepherd FA, et al. Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol. 1999;17(2):658-667. doi:10.1200/JCO.1999.17.2.658

5. von Pawel J, Jotte R, Spigel DR, et al. Randomized phase III trial of amrubicin versus topotecan as second-line treatment for patients with small-cell lung cancer. J Clin Oncol. 2014;32(35):4012-4019. doi:10.1200/JCO.2013.54.5392

6. FDA approves atezolizumab for extensive-stage small cell lung cancer. FDA. March 18, 2019. Accessed August 28, 2024. https://tinyurl.com/2s2dk6dv

7. 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

8. FDA approves durvalumab for extensive-stage small cell lung cancer. FDA. March 30, 2020. Accessed August 28, 2024. https://tinyurl.com/y7u9xust

9. Paz-Ares L, Dvorkin M, Chen Y, et a; CASPIAN Investigators. 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):19291939. doi:10.1016/S0140-6736(19)32222-6

10. Chandana SR, Choudhury NJ, Dowlati A, et al. Firstin-human study of ABBV-706, a seizure-related homolog protein 6 (SEZ6)–targeting antibody-drug conjugate (ADC), in patients (pts) with advanced solid tumors. J Clin Oncol. 2024;42 (suppl 16):3001. doi:10.1200/JCO.2024.42.16_suppl.3001

11. GSK receives US FDA Breakthrough Therapy Designation for its B7-H3-targeted antibody-drug conjugate in relapsed or refractory extensive-stage small-cell lung cancer. News release. GSK. August 20, 2024. Accessed August 20, 2024. https://tinyurl.com/4e2yecs7

12. Wang J, Duan J, Sun Y, et al. ARTEMIS-001: data from a phase 1a/b study of HS-20093 in patients with relapsed small cell lung cancer (SCLC). J Clin Oncol. 2024;42(suppl 16):8093. doi:10.1200/JCO.2024.42.16_suppl.8093