Although platinum-based chemotherapy given concurrently with a PD-L1 inhibitor has become the standard of care for the frontline treatment of patients with extensive-stage small cell lung cancer, investigators have found that maintenance immunotherapy and combination strategies have fallen short of expectations.
Although platinum-based chemotherapy given concurrently with a PD-L1 inhibitor has become the standard of care for the frontline treatment of patients with extensive-stage small cell lung cancer (ES-SCLC), investigators have found that maintenance immunotherapy and combination strategies have fallen short of expectations, according Primo N. Lara, Jr MD.1
“Platinum-based chemotherapy concurrent with a PD-L1 inhibitor, either atezolizumab (Tecentriq) or durvalumab (Imfinzi), is the frontline standard of care. Maintenance immunotherapy and combination immune checkpoint inhibitors, such as durvalumab and tremelimumab, have missed the mark,” said Lara, the executive associate Dean for Cancer Programs, School of Medicine, at UC Davis Comprehensive Cancer Center. “In the second-line or beyond setting, pembrolizumab (Keytruda) and nivolumab (Opdivo) [have been] approved. As we always say, if you have a patient who is in fair shape, send [them] to us for a clinical trial."
During the 21st Annual International Lung Cancer Congress®, a program developed by Physicians’ Education Resource® (PER®), LLC, Primo, who is also the Codman-Radke Endowed Chair in Cancer Research, a professor, and the director of the UC Davis Comprehensive Cancer Center, highlighted the latest advances made with immunotherapy in SCLC, research done in the maintenance setting, and approaches for the second-line setting and beyond.
The standard of care for patients with ES-SCLC is platinum-based chemotherapy plus a PD-L1 inhibitor, and this approach was examined in the IMpower133 study. Specifically, in pivotal phase 3 trial, investigators examined the efficacy of atezolizumab in combination with carboplatin and etoposide.2
The trial enrolled 500 patients with histologically documented ES-SCLC who not received prior treatment for their disease and had an ECOG performance score of 0 or 1. Patients with an autoimmune disease or who had active central nervous system (CNS) metastases were excluded from the trial. Patients were randomized 1:1 to receive either atezolizumab, carboplatin, and etoposide or carboplatin, etoposide, and placebo. The co-primary endpoints of the trial were overall survival (OS) and progression-free survival (PFS).
Results showed a notable median OS survival benefit for patients on the atezolizumab arm, with an HR of 0.70, translating to a 30% reduction in risk of death. Patients on this arm also experienced a more favorable median PFS (HR = 0.77). Most of the patient subgroups analyzed in the trial benefited from atezolizumab, according to Lara.
The addition of atezolizumab to chemotherapy did not result in a significant increase in response. The overall response rate (ORR) was 64.4% in the placebo arm compared with 60.2% in the atezolizumab arm. However, those in the atezolizumab arm did experience a slightly higher complete response rate versus those on the placebo arm, at 2.5% versus 1.0%, respectively, noted Lara.
Updated results from an exploratory analysis presented during the 2020 AACR Virtual Annual Meeting II showed that the combination of atezolizumab plus carboplatin/etoposide continued to demonstrate an improvement in OS versus chemotherapy alone in the frontline treatment of this patient population, regardless of PD-L1 expression and blood tumor mutational burden (TMB).3
In the global, randomized, multicenter phase 3 CASPIAN study, investigators examined the addition of durvalumab to tremelimumab and etoposide (n = 268) versus either durvalumab plus etoposide (n = 268) or etoposide alone (n = 269) in a total of 805 treatment-naïve patients with WHO performance status of 0 or 1, a life expectancy of ≥12 weeks, and measurable disease per RECIST v1.1 criteria.4 Notably, patients with asymptomatic or treated and stable brain metastases were permitted.
Earlier findings from the trial showed that the addition of durvalumab to chemotherapy reduced the risk of death by 27% versus chemotherapy alone (HR = 0.73; 95% CI, 0.59 – 0.91; P = .0047). The median PFS was similar between the arms, at 5.1 months with durvalumab versus 5.4 months without (HR, 0.78; 95% CI, 0.65-0.94); however, analysis of the 12-month PFS rate indicated a large advantage that favored durvalumab, at 17.5% versus 4.7%.
Updated findings presented during the 2020 ASCO Virtual Scientific Program, showed that the addition of durvalumab to chemotherapy continued to show an improvement in OS in this patient population. Specifically, at a median follow-up of 25.1 months, the median OS was 12.9 months in patients who received the combination therapy compared with 10.5 months in those who only received chemotherapy (HR, 0.75; 95% CI, 0.62-0.91; P = .0032).5
The combination was also found to have a probability of median OS rate of 52.8% at the 12-month mark compared with 39.3% in the chemotherapy-only cohort. The rates were 32.0% versus 24.8% at 18 months and 22.2% versus 14.4% at the 24-month mark, respectively. The updated median PFS rate was 17.9% at 12 months, 13.9% at 18 months, and 11% at 24 months with durvalumab plus chemotherapy compared with 5.3% at 12 months, 3.4% at 18 months, and 2.9% at 24 months, with chemotherapy alone. Nearly all patient subsets were found to benefit from the durvalumab plus etoposide combination.
“Remarkably, at 2-years, nearly one-quarter of the patients were still alive,” noted Lara. “This is a [significant] achievement.”
Notably, the addition of tremelimumab to durvalumab plus chemotherapy did not significantly improve outcomes in this patient population. The median PFS was 4.9 months with the triplet versus 5.4 months with chemotherapy alone (HR, 0.84; 95% CI, 0.70-1.01), and the confirmed ORR was 58.4% versus 58.0%, respectively.
Safety data revealed that the triplet regimen had a higher rate of toxicities, at 99.2% versus 98.1% with durvalumab plus chemotherapy and 97.0% with chemotherapy alone. The results further supported durvalumab plus chemotherapy as a standard of care for patients with ES-SCLC.
In the phase 3 KEYNOTE-604 trial, investigators examined the use of pembrolizumab in combination with etoposide and carboplatin (n = 228) versus placebo plus etoposide and carboplatin (n = 225).6 To be eligible for enrollment, patients had to have stage IV SCLC, have not received previous systemic therapy, had an ECOG performance status of 0 or 1, no unstable brain metastases, adequate organ function, and a life expectancy of ≥3 months.
Results showed an ORR of 70.6% in the pembrolizumab arm versus 61.8% in the placebo arm. The pembrolizumab combination resulted in a statistically significant improvement in PFS compared with chemotherapy (HR, 0.75; 95% CI, 0.61-0.91). Although the combination led to an improvement in OS, it did not meet statistical significance per the prespecified statistical plan (HR, 0.80; 95% CI, 0.64-0.98). The OS rates with the pembrolizumab combination were 45.1% at 12 months and 22.5% at 24 months versus 39.6% and 11.2%, respectively, with the placebo.
“[The trial] showed improved PFS and a benefit from pembrolizumab, but it was not enough to make this combination a new standard of care,” Lara said.
Shifting to the maintenance setting, in the CheckMate-451 trial, investigators examined the use of single-agent nivolumab maintenance therapy versus the combination of nivolumab plus ipilimumab (Yervoy) in patients with ES-SCLC who had stable disease following first-line platinum-based therapy, an ECOG performance status of 0 to 1, no untreated CNS metastases, and no autoimmune disease.7
The trial enrolled 810 patients who were randomized 1:1:1 to receive either a nivolumab monotherapy, nivolumab plus ipilimumab, or placebo. Results showed that the OS was not significantly prolonged with nivolumab/ipilimumab versus placebo (HR, 0.92; 95% CI, 0.75-1.12; P = .3693) nor was OS improved with nivolumab monotherapy versus the control (HR, 0.84; 95% CI, 0.69-1.02).
“This was a negative trial, whether you’re looking at nivolumab/ipilimumab or nivolumab [alone], these experimental arms failed to improve outcomes versus placebo, which is very disappointing,” noted Lara.
In the CheckMate-331 trial, investigators compared nivolumab monotherapy with either topotecan or amrubicin in the second-line setting. To be eligible for enrollment, patients had to have received 1 prior line of systemic platinum-based therapy or chemoradiation, had to have an ECOG performance status of 0 to 1, no CNS metastases, and have not received prior treatment with immunotherapy.8
The trial enrolled a total of 480 patients who were randomized 1:1 into 1 of the 2 treatment arms. The primary end point of the trial was OS, and secondary end points included ORR and PFS. Results showed that single-agent nivolumab did not improve OS compared with standard topotecan or amrubicin (HR, 0.86; 95% CI, 0.72-1.04). However, OS curves showed delayed separation after month 12. The median PFS on the investigational arm was 1.4 months versus 3.8 months on the control arm (HR, 1.41; 95% CI, 1.18-1.69).
“[CheckMate-331] was also disappointingly negative [much like CheckMate-451],” Lara explained. “The hazard ratio [was] 0.86 for OS. The PFS favored chemotherapy with a hazard ratio of 1.41.”
Lastly, KEYNOTE-158, which in part lead to the recent FDA approval of pembrolizumab for patients with unresectable or metastatic solid tumors that are tumor mutational burden–high, examined the efficacy of pembrolizumab in patients with unresectable or metastatic SCLC who have progressed on or are intolerant to standard therapy, an ECOG performance score of 0 or 1, a ≥1 measurable lesion, and no autoimmune disease or noninfectious pneumonitis.9
A total of 107 patients were enrolled on the trial. Results showed an ORR of 35.7% in PD-L1–positive patients and 6.0% in PD-L1–negative patients. Moreover, an OS of 53.1% was reported in PD-L1–positive patients at 12 months versus 30.7% in PD-L1–negative patients. Patients who had PD-L1–positive disease were additionally found to have a higher median OS of 14.9 months compared with 5.9 months in patients with PD-L1–negative disease.