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Frontline IO + CT in ES-SCLC
My Take on Frontline Chemoimmunotherapy for Extensive-Stage Small-Cell Lung Cancer

Released: October 13, 2020

Expiration: October 12, 2021

Taofeek K. Owonikoko
Taofeek K. Owonikoko, MD, PhD
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Until recently, first-line treatment for extensive-stage small-cell lung cancer (ES-SCLC) has been platinum-based chemotherapy doublets with etoposide or irinotecan. In the past 2 years, phase III trials have demonstrated clinical benefit of adding an immune checkpoint inhibitor (ICI) to frontline chemotherapy for the treatment of ES-SCLC, leading to approvals of atezolizumab and durvalumab in this setting. In this commentary, I review some of the key clinical data that have defined a new way to treat ES-SCLC and share my thoughts on why it is important for us to apply ICI-based therapies in the clinical management of our newly diagnosed patients.

IMpower133
The earliest data of an ICI combination in the frontline setting for ES-SCLC came from the randomized phase III IMpower133 trial which evaluated atezolizumab plus carboplatin/etoposide followed by maintenance atezolizumab vs placebo plus chemotherapy followed by maintenance placebo in patients with previously untreated ES-SCLC (N = 403). The coprimary endpoints were OS and PFS by investigator assessment.

Although the addition of atezolizumab to chemotherapy significantly reduced the risk of disease progression by 23% (median PFS: 5.2 vs 4.3 months with chemotherapy alone: HR: 0.77; 95% CI: 0.62-0.96; P = .017), the OS benefit is really what changed practice for newly diagnosed ES-SCLC: The OS curves for the experimental arm and the control arm separated early and stayed that way throughout the duration of follow‑up, with a median OS of 12.3 months vs 10.3 months, respectively, at the most recent report of the data (HR 0.76; 95% CI: 0.60-0.95; P = .0154). Of importance, more than one half of the patients treated with atezolizumab plus chemotherapy were still alive at the 12-month landmark analysis compared with fewer than 40% of patients treated with chemotherapy alone. Furthermore, the addition of atezolizumab to chemotherapy did not significantly alter the toxicity profile of chemotherapy (eg, grade 3/4 adverse events [AEs]: 67.7% vs 63.3%, respectively). However, as expected, there were more immune‑related adverse events (irAEs) in patients treated with atezolizumab (irAEs: 41.4% vs 24.5%, respectively), but this did not compromise the delivery of chemotherapy.

Based on these data, atezolizumab in combination with carboplatin/etoposide was approved by the FDA for the treatment of newly diagnosed ES-SCLC, and we changed our practice from treating patients with chemotherapy alone to chemoimmunotherapy in all eligible patients.

CASPIAN
The second phase III trial of frontline chemoimmunotherapy in ES-SCLC was the 3-arm CASPIAN study, which compared durvalumab plus platinum/etoposide vs durvalumab plus tremelimumab and chemotherapy vs chemotherapy alone (N = 805). Durvalumab maintenance therapy was given in each of the 2 durvalumab arms. Unlike IMpower133, CASPIAN allowed both carboplatin and cisplatin to be used. The primary endpoint was OS.

The addition of durvalumab to chemotherapy resulted in a significant OS advantage over chemotherapy alone (median OS: 12.9 vs 10.5 months, respectively; HR: 0.75; 95% CI: 0.62-0.91; P = .0032). Consistent with IMpower133, the 12-month OS rate was 52.8% in patients receiving durvalumab plus chemotherapy vs 39.3% in patients receiving chemotherapy alone. At 24 months, more than 20% of patients in the durvalumab plus chemotherapy arm were still alive compared with only 14.4% in the chemotherapy arm. Again, the addition of durvalumab to chemotherapy did not significantly increase AEs overall (eg, grade 3/4 AEs: 62.3% vs 62.8% with chemotherapy alone), but there was the increase in irAEs (20.0% vs 2.6%, respectively) expected with ICI therapy. Based on these data, durvalumab in combination with platinum/etoposide was approved for the treatment of ES-SCLC, giving us another option for these patients.

Surprisingly, there was no statistically significant improvement in OS for patients receiving durvalumab plus tremelimumab and chemotherapy compared with chemotherapy alone. There was a trend toward improved OS with the addition of dual ICI to chemotherapy, but the curves did not separate until almost 12 months. At this point, the CASPIAN data support the use of durvalumab plus chemotherapy for ES-SCLC, but there is not enough evidence that adding tremelimumab will benefit patients. Furthermore, adding tremelimumab to durvalumab and chemotherapy increased the rate of grade 3/4 AEs (70.3% vs 62.8%, respectively) and treatment‑related events leading to death (4.5% vs 2.3%). With increased toxicity and no significant OS advantage, the regimen of tremelimumab plus durvalumab and chemotherapy is not recommended for our patients.

Additional Trials of Chemoimmunotherapy for Previously Untreated ES-SCLC: KEYNOTE‑604 and ECOG‑ACRIN EA5161
Two other trials evaluating chemoimmunotherapy combinations for newly diagnosed ES-SCLC were reported at the 2020 ASCO virtual meeting. First, the phase III KEYNOTE‑604 study randomized patients to pembrolizumab plus platinum and etoposide followed by maintenance pembrolizumab or placebo plus chemotherapy followed by maintenance placebo until disease progression (N = 453). The coprimary endpoints were PFS by independent review and OS.

At the time of the second interim analysis, adding pembrolizumab to chemotherapy led to a significant PFS advantage, with a 25% reduction in the risk of disease progression or death (P = .0023). However, at final analysis, OS in the intention‑to‑treat population narrowly missed the threshold of significance, with a 20% reduction in the risk of death for the combination. AEs were as expected, mostly what we would expect with the addition of immunotherapy to chemotherapy, without any significant worsening of hematologic toxicities from chemotherapy. Overall, KEYNOTE-604 is supportive of the findings from the IMpower133 and CASPIAN trials, although we do not have regulatory approval yet to use pembrolizumab plus chemotherapy as a standard of care.

The second trial presented at ASCO 2020 was the randomized phase II ECOG‑ACRIN EA5161 study that looked at the addition of nivolumab to platinum/etoposide followed by nivolumab maintenance compared with chemotherapy alone (N = 160). The primary endpoint was PFS, and secondary endpoints included OS and safety. Despite the small sample size, the addition of nivolumab to chemotherapy led to a significant PFS benefit (HR: 0.68; P = .047). Of interest, despite the fact that the study was not sufficiently powered to show OS advantage, the addition of nivolumab to chemotherapy also improved OS significantly (median: 11.3 vs 8.5 months; HR: 0.67; 95% CI: 0.46-0.98; P = .038). Most patients did well, whether or not they received nivolumab along with chemotherapy, similar to what we saw with the other chemoimmunotherapy studies. This small, non-definitive trial is also supportive of the strategy of chemoimmunotherapy for ES-SCLC but its data are not sufficient to add nivolumab-based chemoimmunotherapy as a frontline option.

Importance of Using Frontline Chemoimmunotherapy for ES-SCLC
At this point in time, combination chemoimmunotherapy with either atezolizumab or durvalumab is standard of care for the treatment of newly diagnosed ES-SCLC—unless we have a reason not to offer this option based on a patient's presentation or medical history that may make the use of ICI unsafe.

However, I have heard some clinicians express concern that the impact of adding ICI to chemotherapy for ES-SCLC appears modest and, thus, in terms of real‑world patients in a normal practice scenario, does not seem to be cost effective or worth fighting to get for these patients, in contrast to what they would do to get chemoimmunotherapy for their patients with advanced non‑small‑cell lung cancer (NSCLC). I agree that if we look at the SCLC data with the same prism we currently use when looking at NSCLC data, the data may not seem that impressive. However, we must remember where we were with NSCLC before we got to where we are now.

To clinicians with these concerns I would say: Although the impact of adding ICI to chemotherapy in SCLC might look modest—some people might look at median OS and not be impressed by a 2-month improvement—we are dealing with a very lethal and aggressive cancer, so a 25% reduction in the risk of death for this disease state is big. Furthermore, when you look at long-term survival, adding ICI to chemotherapy nearly tripled the rate of patients who are alive at 2 years from a historical rate of approximately 9% to approximately 23% with chemoimmunotherapy. In my eyes, this is not a modest benefit but a benefit worth fighting for in every eligible patient.

The impact of chemoimmunotherapy would be even greater if we could find a biomarker that predicts which patients with ES-SCLC might benefit, a lesson we can take from the advent of targeted therapy in NSCLC. The EGFR TKI erlotinib was initially given to all comers because at first, we did not know who would benefit. But we were systematic in our analyses, identified that patients with EGFR mutations were the ones who were benefiting, and look where we are now with targeted therapy in NSCLC 10-15 years later.

Your Thoughts?
How do you use frontline chemoimmunotherapy in your patients with ES-SCLC? Please share your thoughts and questions in the discussion box below.