Small cell lung cancer (SCLC) represents approximately 15 percent of all cases of lung cancer in the United States and remains one of the most challenging thoracic malignancies with an estimated 5-year overall survival (OS) of 6.5 percent. Approximately two out of three people with SCLC have extensive stage (ES) disease, which is characterized by the poorest prognosis.
Several Phase III randomized clinical trials have highlighted the benefit of adding immune checkpoint inhibitors to first-line standard chemotherapy in advanced SCLC patients, including the KEYNOTE-604 study (NCT03066778). Recently, long-term follow-up results from this Phase III trial were published in the Journal of Thoracic Oncology (2022; https://doi.org/10.1016/j.jtho.2022.07.063).
KEYNOTE-604 is a double-blind, placebo-controlled study that included patients with ES-SCLC who have not previously been treated with a systemic therapy and had a ECOG performance status of 0 or 1. A total of 453 eligible patients were randomly assigned 1:1 to receive pembrolizumab at 200 mg or placebo for 35 cycles maximum + 4 cycles of standard-dose etoposide + platinum (EP).
Among both cohorts, 228 patients received a pembrolizumab + EP combination and 225 were administered placebo + EP. The dual primary endpoints were OS and progression-free survival (PFS) in the pembrolizumab + EP group (intent-to treat [ITT] population). Key secondary endpoints included overall response rate (ORR), duration of response (DOR), and safety.
The data from the latest analysis was conducted at a median (range) time from randomization to data cutoff of 43.3 (37.8-52.3) months. The majority of patients discontinued study treatment, most due to progressive disease (92% in the pembrolizumab group and 99.1% in the placebo group). A total of 54.8 percent of patients in the pembrolizumab + EP group and 66.2 percent in the placebo + EP group received subsequent therapy (11.2% vs. 22.1% received a subsequent immune checkpoint inhibitor).
The median OS was 10.8 months (95% CI, 9.2-12.9) with pembrolizumab, compared with 9.7 months (95% CI, 8.6-10.7) with placebo. The 36-month OS rate in the pembrolizumab group was 15.5 percent compared with 5.9 percent (HR, 0.76; 95% CI, 0.63-0.93) in the placebo group, reducing the risk for death by 24 percent. The median PFS was 4.8 months (95% CI, 4.3-5.4) with pembrolizumab, compared with 4.3 months (95% CI, 4.2-4.5) with placebo. Also, the 36-month PFS rate was 6.9 percent for participants who received pembrolizumab + EP versus 0.5 percent for those given placebo + EP (HR, 0.70; 95% CI, 0.57-0.85).
Furthermore, from randomization to database cutoff, 18 patients in the ITT population completed all 35 cycles of pembrolizumab; however, only 14 lived through the final assessments. For patients who completed 35 cycles of pembrolizumab, the ORR was 100 percent (95% CI, 81.5%-100%; two complete responses, 16 partial responses), and median (range) DOR was not reached (14.1-46.8+ months). Two-year OS rate was 72.2 percent (95% CI, 39.5%-89.2%). Grade 3-5 adverse events occurred in 78.9 percent of patients in the pembrolizumab + EP group and 77.1 percent of patients in the placebo + EP group.
Oncology Times connected with Bryan James Schneider, MD, FASCO, and Angel Qin, MD, to discuss some of the barriers to treatment in SCLC, their thoughts of the KEYNOTE-604 study, and hopes for the future in this space. Schneider is Associate Professor of Internal Medicine in the Division of Hematology/Oncology and Qin is Clinical Assistant Professor, both at the University of Michigan.
Oncology Times: What are some of the treatment challenges for patients with metastatic SCLC?
Schneider: “The two biggest challenges clinicians face are what to do with patients with platinum refractory/resistant disease and how to manage brain metastases. Patients initially treated with platinum/etoposide + immunotherapy who progress during or shortly after completion of the chemotherapy have very difficult disease to manage and subsequent treatment options have a very low likelihood of providing meaningful clinical value.
“In addition, up to 60 percent of patients will develop brain metastases during the course of the disease, and this is usually multifocal that oftentimes limits the use of stereotactic radiation. As many of these patients are over the age of 70, whole-brain radiation can be very debilitating and often worsens their quality of life.”
Qin: “Additionally, most clinical trials continue to not include patients with small cell lung cancer. Therefore, treatment options for patients remain limited. The survival benefits of these treatments are also often modest at best. Trials that do include small cell lung cancer as a cohort often do not have eligibility criteria that are reflective of the patient population, i.e., excluding patients with brain metastases.”
Oncology Times: What do these findings of the KEYNOTE-604 study mean for patients?
Qin: “I don't think that the results of KEYNOTE-604 change our treatment paradigm for our patients with ES-SCLC. Both the CASPIAN (NCT03043872) and IMpower133 (NCT02763579) studies had confirmed the OS benefit of adding a checkpoint inhibitor to frontline platinum/etoposide with continued maintenance of immunotherapy. While the median OS was not as impressive with the addition of pembrolizumab, nevertheless, the OS benefit was still present. Furthermore, with longer follow-up, we saw that patients who completed 35 cycles of pembrolizumab had exceptional durable response, with median overall survival not yet reached.”
Schneider: “In broad strokes, I think it confirms the modest clinical benefit with the addition of pembrolizumab to platinum-based chemotherapy that we observed with the addition of atezolizumab to frontline chemotherapy. No new safety concerns were identified. For eligible patients, the addition of immune checkpoint therapy to platinum-based chemotherapy remains a very reasonable frontline option. This study also supports what we've seen with SCLC patients treated with other immune checkpoint inhibitors: about 10-15 percent of patients seem to have benefit regardless of the specific agent.”
Oncology Times: Are there any ongoing studies/novel drugs being tested within this space that you are particularly excited about?
Schneider: “Honestly, it is hard to be overly enthusiastic about any novel drugs given that, despite 4 decades of research in this space, we continue to use platinum and etoposide as the backbone treatment for our newly diagnosed patients. This has been extremely frustrating, especially since for most patients the disease is quite sensitive to initial chemotherapy and patients have a “honeymoon period” where they feel well, but this is often short lived. Extensive research to identify actionable genomic driver alterations has been disappointing, and we rarely see the durable clinical responses with immune checkpoint therapy when compared to many of our non-small cell lung cancer patients.”
Qin: “I am intrigued by the results of the DeLLphi-300 study, which was presented at the World Conference on Lung Cancer in August of this year. This was a Phase I study that examined tarlatamab, which is a bispecific T-cell engager targeting DLL3. The study, conducted in patients with relapsed/refractory small cell lung cancer, showed an ORR of 23 percent. In the limited-stage setting, there are also ongoing studies to incorporate immunotherapy into concurrent chemo-radiation; the NRG cooperative group is looking to add atezolizumab to concurrent chemo-radiation followed by atezolizumab maintenance. The KEYLYNK-013 study is also adding olaparib to pembrolizumab as maintenance after concurrent chemo-radiation and pembrolizumab.”
Oncology Times: What are some of the unanswered questions you still see in the field of metastatic SCLC?
Schneider: “At this point, it is unlikely that we are going to find a genomic driver alteration in SCLC like EGFR or ALK that is targetable with a single therapeutic agent. Many of the gene alterations in small cell lung cancer result in dysfunction of tumor suppressor genes that are currently not viable therapeutic targets. Identifying who will benefit from currently available immunotherapy agents and then enhancing the ability of the rest of the patients to respond to these treatments are key research topics for the immediate future.
“Given the significant advances in immunotherapy seen in melanoma and non-small cell lung cancer, the hope would be to enhance the tumor microenvironment in small cell lung cancer to facilitate better efficacy of our current immune checkpoint inhibitors. Whole genome sequencing, transcriptional profiling, and immune phenotyping of SCLC have shown early promise for identifying molecular subsets that predict improved responses to immune checkpoint inhibitors and may hopefully lead to novel targeted therapies.”
Qin: “I think there has been intriguing work published regarding subtypes of SCLC based on gene expression. We do not yet know if those subtypes should be treated differently. The updates of the KEYNOTE-604 study also show a subset of patients who have an exceptional durable response to immunotherapy. We also do not know what it is about the biology of their cancer that enables this impressive response. But identifying these patients [and] understanding their unique cancer biology will help shed light on strategies that can be employed to potentially improve durability of response in more patients.”
Dibash Kumar Das is a contributing writer.
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