New Guideline Recommends Chemotherapy With Immunotherapy in Advanced SCLC

Illustration of human lungs

Updated guidelines acknowledge that patients with advanced small cell lung cancer (SCLC) receiving chemotherapy plus immunotherapy followed by maintenance immunotherapy have longer-term survival than those receiving chemotherapy alone. However, this approach does not apply to patients with an EGFR mutation. In addition, guidelines include the use of lurbinectedin (Zepzelca) in the second line for relapsed SCLC. These updates were developed with an expert panel assembled by the American Society of Clinical Oncology and Ontario Health.¹

“The primary clarification is that in limited-stage small cell lung cancer, initiating chemotherapy promptly is crucial. These individuals are prone to rapid disease progression and can deteriorate quickly. The objective is to commence chemotherapy as soon as possible, and then consider incorporating radiation therapy [in] the second cycle,” Gregory Peter Kalemkerian, MD, said in an interview with Targeted Therapies in Oncology.

Kalemkerian is a clinical professor, associate division chief for faculty development and education, and the associate director of the hematology/oncology fellowship program at University of Michigan Health in Ann Arbor. He also assisted in the review of data spanning 1990 to 2022 that informed the updated guideline recommendations.

Regarding EGFR-mutant adenocarcinoma, the decision to continue with an EGFR tyrosine kinase inhibitor (TKI), typically osimertinib (Tagrisso), remains a topic of debate. “Personally, I lean toward continuation based on my observations,” Kalemkerian explained. “I believe that the adenocarcinoma EGFR-mutant–sensitive clone is still present, and some tumors are responsive, whereas others transform into small cell. Using the EGFR TKI with chemotherapy is something that I do for these patients,” he explained.

Data from several trials contributed to the updated recommendations, including the phase 3 IMpower133 trial (NCT02763579), which showed that patients with extensive-stage SCLC derived benefit from the addition of atezolizumab (Tecentriq), regardless of PD-L1 immunohistochemistry or plasma-based tumor mutational burden status.² In the study, patients were randomly assigned to receive either carboplatin plus etoposide (VePesid) with the addition of atezolizumab (n = 201) or carboplatin plus etoposide with placebo (n = 202). In a recent review update, the median follow-up duration for overall survival (OS) was 22.9 months, during which 302 deaths were recorded. The median OS was 12.3 months in the experimental arm and 10.3 months in the control arm with an HR of 0.76% (95% CI, 0.60 -0.95; P = .0154). At 18 months, 34% and 21% of patients were alive in the respective arms.

Patients received 4 cycles of carboplatin. Each cycle lasted 21 days and on day 1, the drug was administered intravenously (IV) at a rate of 5 mg per mL/min, and the area under the concentration-time curve was measured. This was administered along with IV etoposide on days 1 through 3 at a dose of 100 mg/m² and 1200 mg of atezolizumab IV or placebo on day 1. Maintenance atezolizumab or placebo followed until unacceptable toxicity, disease progression, or loss of clinical benefit. The 2 primary end points of the study included progression-free survival (PFS) and OS assessed by an investigator. Both PFS and OS were significant at the interim analysis and updated rates and exploratory biomarker analyses were also conducted.

Another trial that contributed to the guideline update was the open-label phase 3 CASPIAN study (NCT03043872), which evaluated 805 patients with extensive-stage SCLC. Patients were randomly assigned 1:1:1 in the first line to receive either durvalumab (Imfinzi) plus either cisplatin or carboplatin, durvalumab plus tremelimumab (Imjudo) plus cisplatin or carboplatin, or cisplatin or carboplatin alone.³

As of March 22, 2021, the median follow- up was 39.4 months and the group receiving durvalumab plus cisplatin or carboplatin showed improved OS (12.9 months) vs cisplatin or carboplatin alone (10.5 months) with an HR of 0.71% (95% CI, 0.60%-0.86%; P = .0003). The 36-month OS rate was 17.6% vs 5.8%, respectively.

The group receiving durvalumab plus tremelimumab plus cisplatin or carboplatin continued to numerically improve OS vs cisplatin or carboplatin alone (HR, 0.81%; 95% CI, 0.67%-0.97%; P = .0200). The median OS was 10.4 months and the 36-month OS rate was 15.3%. At the data cutoff, 27 patients in the durvalumab plus cisplatin or carboplatin group and 19 patients in the durvalumab plus tremelimumab plus cisplatin or carboplatin group continued to receive durvalumab treatment. When comparing the survival rates at 3 years, it was estimated that 3 times as many patients treated with durvalumab plus cisplatin or carboplatin were alive compared with those treated with cisplatin or carboplatin alone. “There are a number of meta-analyses that we looked at for the addition of immunotherapy and extensive-stage SCLC that also informed the guidelines with positive data,” Kalemkerian explained. “There are trials from China that demonstrated similar improvements with other immunotherapy checkpoint inhibitors that are not yet approved in the United States,” and there were many negative trials that informed the guidelines as well, Kalemkerian said. For patients with relapsed SCLC, Kalemkerian mentioned a phase 2 trial (NCT02454972), “which is fairly large (over 100 patients), but we are still awaiting the phase 3 data with lurbinectedin at this time,” he said.⁴

Although there is OS benefit with the addition of immunotherapy, treatment still needs improving, Kalemkerian explained. “Many providers—because SCLC is an aggressive disease with a high mutational tumor burden—were expecting immunotherapy to do a bit better than it did.” That said, there is a long path ahead, but agents such as lurbinectedin and approaches that adjust the tumor milieu to make it more immune sensitive are being explored.

REFERENCES:

1. Khurshid H, Ismaila N, Bian J, et al. Systemic therapy for small-cell lung cancer: ASCO-Ontario Health (Cancer Care Ontario) guideline. J Clin Oncol. 2023;41(35):5448-5472. doi:10.1200/JCO.23.01435

2. Liu SV, Reck M, Mansfield AS, et al. Updated overall survival and PD-L1 subgroup analysis of patients with extensive-stage small-cell lung cancer treated with atezolizumab, carboplatin, and etoposide (IMpower133). J Clin Oncol. 2021;39(6):619-630. doi:10.1200/JCO.20.01055

3. Paz-Ares L, Chen Y, Reinmuth N, et al. Durvalumab, with or without tremelimumab, plus platinum-etoposide in firstline 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

4. 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