Evaluating Five-year Efficacy Outcomes in the EMPOWER-Lung 1 Study | Written Recap
Eric K. Singhi, M.D., is an assistant professor in the Department of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston, and Ben Creelan, M.D., is a medical oncologist and clinical researcher in the Department of Thoracic Oncology at the Moffitt Cancer Center in Tampa, Florida. In this Managed Healthcare Executive Between the Lines video series, Singhi and Creelan discuss the EMPOWER-Lung 1 study and its implications. The study compared cemiplimab, sold under the brand name Libtayo, to conventional chemotherapy as a treatment for patients with advanced non-small cell lung cancer (NSCLC) whose tumors expressed PD-L1, a common biomarker in cancer, in at least 50% of the tumor cells.
Evolution of immunotherapy
Cemiplimab is an immunotherapy that targets the PD-1/PD-L1 pathway so the immune system recognizes tumor cells and attacks them. Creelan noted that there was once a lot of angst about whether to start treatment with conventional chemotherapy or with immunotherapy, such as cemiplimab, but research has now shown that it is best to start treatment for NSCLC with both. Creelan and Singhi discussed trials that have compared other individual immunotherapies to conventional chemotherapy, and Singhi said there is a “consistent beneficial effect that patients with stage 4 disease are seeing with single-agent immunotherapy.”
The design of EMPOWER-Lung 1
Researchers enrolled patients into the EMPOWER-Lung 1 study from 2017 to 2020 in Europe, Asia and other parts of the world. Of the 712 total patients, 565 had PD-L1 tumor expression of 50% or greater. Creelan said immunotherapy was not yet the standard of care in the places where the study was done, and access to second-line treatment was limited or not available. Singhi described the trial as having a design that “seemed to fit the landscape at the time.” He said the trial had two standout features. First, patients who were randomly assigned to the conventional chemotherapy were allowed to cross over to treatment with cemiplimab. Second, patients in the cemiplimab group whose disease progressed were allowed to continue with cemiplimab when four cycles of conventional chemotherapy were added to their treatment. Creelan and Singhi said it was noteworthy that EMPOWER-Lung 1 researchers have reported five years of follow-up data.
PD-L1 as a biomarker
Creelan stressed that PD-L1 is not binary but a continuum. At the same time, he said research has shown that NSCLC tumors with 90% to 100% PD-L1 expression are “way different” than those with 50% to 60%. “I think most of us have leaned toward doing dual chemotherapy-IO [immunotherapy] for those with 50 to 60, and we are feeling more confident about IO, single agents for those in the 90s to 100,” he said. Creelan also noted that the PD-L1 expression is prognostic, regardless of treatment. Singhi said that the five-year overall survival rate improves in relation to PD-L1 expression: for patients with NSCLC tumors with zero PD-L1 expression, it’s approximately 10%; for those with 1% to
49% expression, it’s 20% and for those 50% or higher, it’s 30%.
Patient characteristics
The median age of the participants in the EMPOWER-Lung 1 trial was 63, and a large majority (88%) were men. Singhi said that a greater proportion — 43% — of the participants had squamous cell carcinoma than participants in other similar NSCLC treatment trials. Although 84% of the participants had stage 4 lung cancer, most were active per a standard performance status score. The PD-L1 expression was distributed fairly evenly, with 33% at 90% or above, 31% above 60% and less than 90%, and 34% at or above 50% or at 60% or below. Creelan described EMPOWER-Lung 1 as a “very honest study” in respect to the patients it enrolled. “These are the oil workers in Houston. These are the Rust Belt factory workers in Michigan. These are real-world patients.”
Efficacy outcomes
Singhi and Creelan discussed data from both the one- and five-year analyses of the EMPOWER-Lung 1 study and from the group with PD-L1 expression of 50% or above and the larger intention-to-treat group. Their conversation centered on the five-year analysis of the group with PD-L1 expression of 50% or above. Creelan noted that the overall survival in the patients randomly assigned to treatment with cemiplimab was 26.1% compared with 13.3% in the chemotherapy group. He also noted the favorable objective response rate (46.5% in the cemiplimab group vs. 20.6% in the conventional chemotherapy group). “This isn’t just taking the football and moving it four yards down the line. We’re actually getting into the red zone,” Creelan said. Results from studies of other immunotherapies have not been as impressive. Singhi and Creelan also discussed the five-year overall survival by PD-L1 expression. The general rule that the higher the PD-L1, the better the outcome, applied. The 99 participants in the cemiplimab group with PD-L1 expression of 90% or greater had a median overall survival of 33.8 months. “That’s pretty exciting to see,” said Singhi. Those in the middle PD-L1 range had a median overall survival of 26.2 months, and those in the lowest rate, 19.5 months, according to data presented by Singhi.
Singhi and Creelan spoke about a subgroup analysis that showed that the difference in the benefits of cemiplimab and chemotherapy among the patients with squamous cell NSCLC was greater than among those with nonsquamous cell NSCLC. Singhi said there is an unmet need for treatment of squamous cell cancer, “so it was nice to see that benefit in these patients with squamous histology.” Creelan observed that chemotherapy tends to have a modest benefit across all types of squamous cell tumors, especially those induced by smoking. “It’s certainly within the realm of expectation that squamous cell would have more of a benefit from immunotherapy compared with adenocarcinoma.”
Safety
Creelan noted a low incidence of pneumonitis in the trial compared with phase 3 trials of other immunotherapies, especially because the trial was conducted in parts of the world where severe emphysema related to smoking is common. The small number of cases and no deaths due to pneumonitis is “kind of astounding,” he said. Creelan said many clinicians are now familiar with the side effects of immune checkpoint inhibitors such as cemiplimab. “I think we’re all feeling more comfortable using steroids when we need them,” he said.
Continuing cemiplimab
Singhi said a unique aspect of EMPOWER-Lung 1 was the option of continuing to treat patients in the cemiplimab group with cemiplimab after their cancer progressed, in conjunction with four cycles of chemotherapy. Creelan cautioned that this was not a randomized trial, but the positive results were a signal and a proof of concept. He said the objective response rate of 28% in 75 patients who continued with cemiplimab was higher than expected. He said other research has suggested that there is synergy between immune checkpoint inhibitors and chemotherapy.
Takeaways
Creelan said he was struck by the positive results that cemiplimab produced in patients with squamous cell NSCLC. “When I think about squamous [disease] and when I think about a single agent, I am definitely thinking about cemiplimab,” he said. He pointed out that cemiplimab is also approved as a treatment for squamous cell skin cancer. He added that cemiplimab will be a “great option” for the treatment of people who were heavy smokers because of the apparently low risk of pneumonitis. Singhi spoke about the advantages of having options and about EMPOWER-Lung 1 providing data points that “we can use as evidence for some of our decision-making.” Of cemiplimab, Singhi said, “I think there is a place for this drug in pathways and value-based care programs.” With more options, it is key that providers discuss them with their patients and make individualized decisions about treatment.
