Evaluating New Standards in Extensive-Stage Small Cell Lung Cancer

Igor I. Rybkin, MD, PhD

The addition of an immune checkpoint inhibitor––namely durvalumab (Imfinzi) or atezolizumab (Tecentriq)––to platinum-based chemotherapy has demonstrated level 1 evidence in support of its use as a frontline standard of care in patients with extensive-stage small cell lung cancer (ES-SCLC), according to Igor I. Rybkin, MD, PhD, who cautioned that the same cannot yet be said of lurbinectedin (Zepzelca) in the second-line setting.

“Any patient who is a candidate [for chemoimmunotherapy] should receive it in the frontline setting, whereas the data [with lurbinectedin] are not as robust in the second-line setting,” said Rybkin.

In March 2019, the FDA approved the combination of atezolizumab with carboplatin and etoposide for the frontline treatment of patients with ES-SCLC. In March 2020, the FDA approved durvalumab in combination with etoposide plus carboplatin or cisplatin for the first-line treatment of patients with ES-SCLC. The regulatory approvals were based on data from the phase 3 IMpower133 and CASPIAN trials, respectively, wherein both regimens led to an improvement in overall survival (OS).

In June 2020, lurbinectedin received regulatory approval for the treatment of patients with metastatic SCLC with disease progression, following platinum-based chemotherapy, based on findings from a phase 2 basket trial (NCT2454972). The results compare favorably with historical data with the current second-line standard, topotecan.

However, until the results of the phase 3 ATLANTIS trial (NCT02566993) read out, the field will not have definitive evidence of its true advantage over topotecan. Even then, it may be difficult to parse out the differences between both agents because patients will be randomized to lurbinectedin plus doxorubicin versus cyclophosphamide, adriamycin, and vincristine (CAV) or topotecan alone, explained Rybkin.

In an interview with OncLive® during the 2020 Institutional Perspectives in Cancer webinar on lung cancer, Rybkin, a medical oncologist at Henry Ford Cancer Institute, discussed the data with these frontline and second-line regimens in ES-SCLC.

OncLive®: How has the approval of durvalumab plus platinum-based chemotherapy affected the frontline setting in ES-SCLC, where atezolizumab is also approved?

Rybkin: Durvalumab is a PD-L1 checkpoint inhibitor. This class of agents already has a role in frontline therapy for [ES-SCLC]. In 2018, the IMpower133 trial with atezolizumab showed superior [OS] and progression-free survival [PFS] in combination with platinum-based chemotherapy and etoposide versus platinum and etoposide alone. In a sense, this is not completely new data. However, it is very reassuring to see a second trial with another medication in the same class with very similar data. It gives us more flexibility as far as available medications.

How does durvalumab compare with atezolizumab?

The CASPIAN study design was a little bit more complex than that of the IMpower133 trial because it had 3 arms. The first comparison between platinum, etoposide, and durvalumab and platinum and etoposide was published in October 2019. At [the 2020 ASCO Virtual Scientific Program] we saw an update on that comparison, as well as the first look at the comparison between platinum and etoposide and platinum, etoposide, durvalumab, and tremelimumab. Because of the more complex design of this trial, there are some differences in statistical analysis. [Cross-trial comparisons are always dangerous]. However, both trials do have a control arm and an anti–PD-L1 agent that allow us to have reasonable comparison of outcomes between these 2 trials.

The CASPIAN trial enrolled 805 treatment-naïve patients with [ES-SCLC], with an ECOG performance status of 0 or 1. The investigators allowed patients with symptomatic or treated and stable brain metastases to enroll. Ten percent to 14% of patients had brain metastases. Patients received 4 to 6 cycles of treatment. Prophylactic cranial irradiation [PCI] was optional, which deviates from common practice in the United States. Most of the time we use PCI in the United States after response to frontline therapy. That may reflect differences in practices between the United States and Europe. CASPIAN was mostly done in European countries.

With regard to efficacy, the median OS was 12.9 months with durvalumab versus 10.5 months with chemotherapy alone. In comparison, in the IMpower133 trial, the median OS was 12.3 months [with atezolizumab] versus 10.3 months [with chemotherapy alone]. The median OS [in the investigational and control arms] are very similar. The hazard ratio was 0.75 and the P value was .032, which was statistically significant. Additionally, the 2-year survival rate was 22% versus 14%, which is pretty remarkable.

In an exploratory analysis of patients with brain metastases, despite the fact that about 8% of patients in the control arm received PCI, the percentage of new brain metastases at the time of first progression was equal between the [3 arms], which is very interesting. It raises the question about the role of PCI in small cell lung cancer.

Moving to the second-line setting, lurbinectedin received accelerated approval in June 2020. Full approval is contingent on the results of the ATLANTIS trial. Could you elaborate on the design of the trial?

ATLANTIS is evaluating a novel agent called lurbinectedin, which is basically a cytostatic medication. The agent was approved by the FDA based on phase 2 data in the second-line setting in patients with [ES-SCLC]. Patients had progressed on platinum-based therapy. Prior immunotherapy was also allowed. [Lurbinectedin] led to a 35% overall response rate, which is quite high compared with historical data with topotecan. Additionally, the toxicity profile of lurbinectedin was favorable compared with topotecan. ATLANTIS is an ongoing global randomized phase 3 study, which is comparing lurbinectedin plus doxorubicin with topotecan alone or [CAV]. We don’t know how many patients from the United States will be accrued to the trial. However, once we have the results, we still won’t know how topotecan compares with lurbinectedin.