Two separate randomized phase III trials have established atezolizumab (IMpower1331 and durvalumab (CASPIAN2) as first-line treatments for extensive-stage (ES) SCLC in combination with chemotherapy followed by these same checkpoint inhibitors (CPIs) as maintenance on the basis of improvements in OS and PFS outcomes. Hence, the question for clinicians is whether there is a difference between these two anti–PD-L1 antibodies or if, instead, both agents can be used interchangeably as first-line treatment for patients with ES-SCLC. In the IMpower133 study, the chosen platinum-based agent was carboplatin; conversely, both cisplatin and carboplatin were allowed at the investigator’s choice in the CASPIAN study. Both atezolizumab and durvalumab were given every 3 weeks in combination with chemotherapy during the induction phase; at maintenance, atezolizumab was given every 3 weeks while durvalumab every 4 weeks until the disease progressed or effects became intolerable.
Key studies in ES-SCLC were presented during the 2020 ASCO Virtual Scientific Program, including updates on several key studies. Longer-term follow-up data for the CASPIAN study3 was presented, which included the final data for Arm A, in which durvalumab and tremelimumab (an anti-CTLA4 antibody) plus chemotherapy was compared with chemotherapy alone (Arm C). The randomized phase II EA5161 study,4 in which nivolumab plus chemotherapy was compared with chemotherapy alone as first-line management of ES-SCLC. A prespecified analysis of OS and PFS for subgroups of patients with and without brain metastases from the CASPIAN study also was presented5, as well as KEYNOTE-604,6 a double-blind, phase III comparison of pembrolizumab and etoposide plus a platinum-based agent versus placebo and etoposide plus a platinum-based agent as first-line therapy for ES-SCLC. Based on the results of these studies, we have a better insight on the actual status of CPIs in the management of SCLC.
CASPIAN Study Updates
Dr. Paz-Ares provided the planned updated analysis of OS for combination durvalumab/etoposide/chemotherapy versus chemotherapy alone, as well as the first results for combination durvalumab/tremelimumab/chemotherapy versus chemotherapy alone, from the CASPIAN study.3 In 2019, durvalumab/chemotherapy showed an advantage in OS over chemotherapy alone for patients with ES-SCLC (HR 0.73; 95% CI: 0.59-0.91; p = 0.0047).2 Recall that CASPIAN had three arms; patients with ES-SCLC who had not previously received treatment were randomly assigned 1:1:1 to: combination durvalumab (1,500 mg), tremelimumab (75 mg), and chemotherapy every 3 weeks; combination durvalumab (1,500 mg) and chemotherapy every 3 weeks; or to chemotherapy alone every 3 weeks. After induction therapy, maintenance treatment consisted of 1,500 mg of durvalumab every 4 weeks until disease progression for those cohorts in which durvalumab was given in the induction phase. In the chemotherapy-alone arm, patients received up to six cycles of chemotherapy and optional prophylactic cranial irradiation (PCI) and were then observed off treatment. In the updated analysis, durvalumab/chemotherapy continued to demonstrate an OS improvement over chemotherapy alone, with an HR of 0.75 (95% CI: 0.62-0.91; nominal p = 0.0032); median OS was 12.9 versus 10.5 months for durvalumab/chemotherapy and chemotherapy alone, respectively. At 2-year follow-up, 22.2% of patients who received durvalumab/chemotherapy survived versus 14.4% in the chemotherapy-alone arm.
The final analysis for durvalumab/tremelimumab/chemotherapy revealed an improved (numerically) OS over chemotherapy alone; however, it did not reach statistical significance per the prespecified statistical plan (HR 0.82; 95% CI: 0.68-1.00; p = 0.0451; p ≤ 0.0418 required for statistical significance). Median PFS (4.9 months vs. 5.4 months) and ORR (58.4% vs. 58.0%) were similar for both groups. Nonetheless, the 12-month PFS rate was numerically higher for durvalumab/tremelimumab/chemotherapy (16.9% vs. 5.3%). Incidence of all-cause adverse events for grades 3 and 4 were 62.3%, 70.3%, and 62.8% for durvalumab/chemotherapy, durvalumab/tremelimumab/chemotherapy, and chemotherapy alone, respectively. With these results, CASPIAN consolidated the use of durvalumab in combination with chemotherapy as a first-line option for ES-SCLC, while tremelimumab in combination failed to add any benefit to chemotherapy compared to chemotherapy alone.
In addition, Chen et al.5 presented data on patients with brain metastases who were enrolled in the CASPIAN study. This is an important issue as those who received either of the experimental arms of the study did not receive PCI, while the chemotherapy-alone group did (optional at the physician’s discretion). Patients who had either asymptomatic or treated and stable brain metastases were eligible for enrollment. Brain imaging was not mandated at screening or during treatment. OS and PFS analyses in this group of patients were prespecified. Twenty-eight out of 268 (10.4%) patients in the durvalumab/chemotherapy arm and 27 out of 269 (10.0%) in the chemotherapy-only group had known brain metastases; only three patients (of those with baseline brain metastases) in each arm received radiotherapy to the brain prior to study entry. The combination of durvalumab/chemotherapy improved OS in patients with or without brain metastases at baseline (HR 0.69; 95% CI: 0.35-1.31 and HR 0.74; 95% CI: 0.59-0.93, respectively). Similarly, PFS was also improved with durvalumab/chemotherapy regardless of the presence (HR 0.73; 95% CI: 0.42-1.29) or not (HR 0.78; 95% CI: 0.64-0.95) of baseline brain metastases. Interestingly, among patients without known brain metastases at baseline, new brain metastases at first progression of disease were seen in similar proportions for durvalumab/chemotherapy (20/240; 8.3%) and chemotherapy alone (23/242; 9.5%) groups, even though 19 patients (7.9%) in the chemotherapy-alone group received PCI previously.
The bottom line is that 48 of 268 (17.9%) and 49 of 269 (18.2%) patients with or without known brain metastases at baseline received radiotherapy to the brain subsequent to study treatment in the durvalumab/chemotherapy and chemotherapy-alone arms, respectively. OS and PFS were improved in the group who received durvalumab/chemotherapy over chemotherapy alone in both the intention-to-treat population as well as in a prespecified group with brain metastases at baseline. In fact, the rates of new brain metastases were similar between arms despite PCI being allowed only in the chemotherapy-alone arm.
EA5161 Study Update
Dr. Leal et al. presented the results of the EA5161 study, in which nivolumab in combination with etoposide and one of the platinum-based agents cisplatin or carboplatin, at investigator’s choice, was given to patients with ES-SCLC who had not received previous treatment.4 This was a phase II study in which patients were randomly assigned 1:1 to nivolumab plus chemotherapy every 21 days for four cycles, followed by maintenance nivolumab every 2 weeks until progression or up to 2 years (arm A); or chemotherapy alone every 21 days for four cycles, followed by observation (arm B). PCI was allowed at the investigator’s discretion. The primary endpoint was PFS, and secondary endpoints included OS, ORR, and safety. In the intent-to-treat population of 160 patients, nivolumab/chemotherapy significantly improved PFS compared with chemotherapy alone (HR 0.65; 95% CI: 0.46-0.91; p = 0.012); mPFS was 5.5 versus 4.6 months for nivolumab/chemotherapy and chemotherapy alone, respectively. OS was also improved with nivolumab/chemotherapy versus chemotherapy alone (HR 0.67; 95% CI: 0.46-0.98; p = 0.038); mOS was 11.3 versus 8.5 months for nivolumab/chemotherapy and chemotherapy alone, respectively. ORR was numerically superior for nivolumab/chemotherapy, although not statistically significant. In terms of safety, the incidence of treatment-related grades 3 and 4 adverse events were 77% versus 62% for nivolumab/chemotherapy and chemotherapy alone, respectively. Dr. Leal et al. concluded that the nivolumab/chemotherapy combination to treat patients with ES-SCLC significantly improved PFS and OS.
Unanswered Questions
The ASCO 2020 Virtual Scientific Program ultimately revealed answers to some questions about the role of CPIs in ES-SCLC, but other questions remain unanswered. In terms of CPI efficacy in combination with chemotherapy, the outcomes for mPFS, mOS, 12-month OS, and 24-month OS are very similar for all three studies conducted in the first-line setting. Two of these studies were phase III trials in which primary and secondary endpoints were met, even with longer follow-up, as recently noted in the CASPIAN study7. Moreover, in a Cochrane analysis that included 32 randomized trials for SCLC,11 treatment outcome prior to CPI use in ES-SCLC revealed 12- and 24-month overall survival rates of 29.37% and 6.93%, respectively. If we focus on the 12- and 24- month OS from the five analyses mentioned above, in which patients with ES-SCLC received the most modern therapy (CPI plus chemotherapy), 12- and 24-month OS range from 43.8% to 52.8% and 22% to 23.5%, respectively. Certainly, there has been an improvement in OS with the introduction of CPI to the treatment algorithm for ES-SCLC. Hence, the role of CPI has been clearly established and should be considered part of standard of care in this clinical scenario.
Is this CPI efficacy driven by the concurrent use of CPIs and chemotherapy, or by the use of CPI maintenance phase? The IMpower133, CASPIAN, EA5161, and KEYNOTE-604 studies were not designed to answer this question. However, when we look at the survival curves from these five analyses, separation started to occur after patients finished their concurrent therapy and started maintenance CPI. This observation might lead us to believe that the benefit stems from CPI maintenance; however, we must be cautious with this kind of interpretation. In fact, a few years ago, the CheckMate-451 trial investigated the role of CPI maintenance after induction chemotherapy for ES-SCLC9. In CheckMate-451, 834 patients with ES-SCLC were enrolled; those whose cancer had not progressed after four cycles of chemotherapy were randomly assigned in a 1:1:1 ratio to nivolumab/ipilimumab (an anti-CTLA4 antibody), nivolumab alone, or placebo. With respect of OS, neither nivolumab/ipilimumab nor single agent nivolumab alone proved superiority over maintenance placebo.9 Hence, we do not have a clear-cut answer for this question. For the time being, however, we recommend concurrent CPI/chemotherapy as induction followed by CPI maintenance.
What is the importance of anti-CTLA4 blockage in the management of ES-SCLC? Based on the new CASPIAN data (durvalumab/tremelimumab/chemotherapy) presented at ASCO as well as CheckMate-451, we can say that anti-CTLA4 does not appear to be an effective immunotherapy-based strategy in SCLC, and we should not pursue further studies in the absence of predictive biomarkers. What about the role of anti–PD-1 antibodies in the first-line treatment of ES-SCLC? Two separate presentations addressed the effect of anti–PD-1 antibodies: a randomized phase II trial, EA5161; and a phase III trial, KEYNOTE-604. EA5161 met its primary and secondary endpoints; however, there is no plan for an immediate confirmatory phase III trial, and the data are insufficient to change clinical practice. Briefly, KEYNOTE-604 showed a positive impact on PFS and a trend in favor of OS by adding pembrolizumab to chemotherapy for ES-SCLC. Unfortunately, it did not meet the prespecified threshold for success, and the study was statistically negative for OS advantage. However, EA5161 and KEYNOTE-604 will serve as a platform for future trials that attempt to introduce anti–PD-1 blockade in the first-line therapy of ES-SCLC.
Finally, we have learned that we need better biomarkers in SCLC. PD-L1 in tissue and tumor mutation burden in both blood and tissue have not been discriminant in SCLC, as was shown in at least three clinical trials, including CheckMate-032 and KEYNOTE-158 for the case of PD-L1 as biomarker and IMpower133 in the case of tumor mutation burden. Differential expression of the transcription regulators ASCL1 and NeuroD1 has been proposed to define molecular subtypes of patients with SCLC. In a study of 285 patients with SCLC, next-generation sequencing using MSK-IMPACT was applied to profile these SCLC cases, and then immunohistochemistry to assess for ASCL1 (A) or NeuroD1 (N) key transcription factors. From this group, 155 patients had evaluable treatment data in response to first-line chemotherapy. ORR, PFS, and OS were analyzed for four different SCLC subtypes: A-/N-, A+/N-, A-/N+, and A+/N+. The study revealed differences among these molecular subtypes and concluded that these subgroups defined by ASCL1 and NeuroD1 encompass characteristics that may predict patient outcomes. Other additional key transcription factors such as POU2F3 and YAP1 are being assessed in this study. In a prior study, a YAP1 subset of SCLC was shown to be enriched for T-cell–inflamed phenotype and associated with long-term survival; it may also be predictive of clinical benefit of immunotherapy.10 Without question, more research is needed to identify better prognostic and predictive biomarkers in patients with SCLC.
References:
1. Horn L, Mansfield AS, Szczesna A, et al. First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer. IMpower133 Study Group. N Engl J Med. 2018; 379(23):2220-9. doi: 10.1056/NEJMoa1809064. Epub 2018 Sep 25.
2. Paz-Ares L, Dvorkin M, Chen Y, et al. 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. CASPIAN investigators. Lancet. 2019; 394(10212):1929-39. doi: 10.1016/S0140-6736(19)32222-6. Epub 2019 Oct 4.
3. Paz-Ares LG, Dvorkin M, Chen Y, et al. Durvalumab ± tremelimumab + platinum-etoposide in first-line extensive-stage SCLC (ES-SCLC): updated results from the phase III CASPIAN study. J Clin Oncol. 2020;38(suppl). Abstract 9002.
4. Leal T, Wang Y, Dowlati A, et al. Randomized phase II clinical trial of cisplatin/carboplatin and etoposide (CE) alone or in combination with nivolumab as frontline therapy for extensive-stage small cell lung cancer (ES-SCLC): ECOG-ACRIN EA5161. J Clin Oncol. 2020;38(suppl). Abstract 9000.
5. Chen Y, Paz-Ares LG, Dvorkin M, et al. First-line durvalumab plus platinum-etoposide in extensive-stage (ES)-SCLC (CASPIAN): impact of brain metastases on treatment patterns and outcomes. J Clin Oncol. 2020;38(suppl). Abstract 9068.
6. Rudin CR, Awad MM, Navarro A, et al. KEYNOTE-604: pembrolizumab (pembro) or placebo plus etoposide and platinum (EP) as first-line therapy for extensive-stage (ES) small-cell lung cancer (SCLC). J Clin Oncol. 2020;38(suppl). Abstract 9001.
7. Owonikoko TK. Chemo-immunotherapy in small cell lung cancer: many questions remain. Abstract presented at: 2020 ASCO Virtual Scientific Program; May 29-31, 2020.
8. Amarasena IU, Chatterjee S, Walters JA, Wood-Baker R, Fong KM. Platinum versus non-platinum chemotherapy regimens for small cell lung cancer. Cochrane Database Syst Rev. 2015; 2015(8):CD006849. doi: 10.1002/14651858.CD006849.pub3.
9. Owonikoko T, Kim HR, 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. Ann Oncol. 2019; 30(Suppl 2):II77.
10. Owonikoko TK, Dwivedi B, Chen Z, et al. YAP1 positive small-cell lung cancer subtype is associated with the T-cell inflamed gene expression expression profile and confers good prognosis and longterm survival. J Clin Oncol. 2020; 38(suppl). Abstract 9019.
