Op-Med is a collection of original articles contributed by Doximity members.
We have several exciting news and presentations in the lung cancer arena coming this week from the 2020 ESMO Congress. The first one was about cemiplimab, which is a human PD-1 inhibitor already approved for the treatment of patients with advanced cutaneous squamous cell carcinoma. In the phase I and II studies, cemiplimab demonstrated antitumor activity in other advanced solid tumors, including non–small cell lung cancer (NSCLC). Data presented in the 2020 ESMO virtual congress showed that cemiplimab, as a single agent, led to a significant improvement in overall survival (OS) and progression-free survival (PFS) versus platinum-doublet chemotherapy as frontline therapy in patients with advanced NSCLC with PD-L1 expression in more than 50% of their tumor cells, according to findings from the phase III EMPOWER-Lung 1 trial. In the PD-L1 ≥50% intention-to-treat (ITT) population, the median OS was not reached (17.9+ months) in the cemiplimab arm versus 14.2 months in the chemotherapy arm; we observed a 43% reduction in the risk of death with the PD-1 inhibitor. Cemiplimab is now a new first-line monotherapy option for patients with advanced NSCLC with PD-L1 expression ≥50%. Though these results are interesting the bar is high for cemiplimab. While we already have positive data for front-line therapy with pembrolizumab and atezolizumab in the same setting, it’s not easy to come to an arena that is already busy.
There is no standard TKI treatment now for patients that have failed EGFR therapy with osimertinib; these patients frequently have to go for chemotherapy or clinical trial. Amivantamab is a fully human bispecific antibody that targets EGFR and MET, and lazertinib is a potent third-generation EGFR TKI that demonstrated activity in patients with activating EGFR mutations and T790M resistance mutations. The combination of amivantamab and lazertinib was presented at the 2020 ESMO congress, demonstrated high response rates and, was well tolerated in treatment-naïve and osimertinib patients with EGFR mutations, as seen in the phase 1 CHRYSALIS study. In osimertinib-resistant, chemotherapy-naïve patients, the ORR was 36% with one complete response (CR) and 15 PRs. We are in great need of options for patients that are failing osimertinib; instead of the current standard of chemo/immunotherapy. This combination is very promissory, though there are also other studies with lazertinib as a single agent.
The third presentation at ESMO which caught my attention was about the KRAS G12C mutation that occurs in NSCLC, colon cancer, and other solid tumors. Sotorasib is a first-in-class small molecule that selectively and irreversibly targets KRAS p.G12C. David Hong from MD Anderson presented a phase I trial with 59 patients with this mutation, and they found 32.2% ORR and 88.1% disease control and good toxicity profile. Sotorasib is a first-in-class small molecule that selectively and irreversibly targets KRAS p.G12C. David Hong from MD Anderson presented a phase I trial with 59 patients with this mutation, and they found 32.2% ORR and 88.1% disease control and good toxicity profile.
A presentation by Dr. Ben Solomon of the first-line treatment with the third-generation ALK TKI lorlatinib that significantly improved PFS proved noteworthy. This was also associated with higher ORR and intracranial response rates (IC-ORR), compared with crizotinib in patients with ALK-positive NSCLC in the phase 3 CROWN trial. The median PFS by blinded independent central review (BICR) was not achieved for lorlatinib compared with 9.3 months for crizotinib, leading to a 72% reduction in the risk of disease progression or death (HR, 0.28; P <.001). The IC-ORR was 82% in patients with measurable brain metastases, with a CR rate of 71% with lorlatinib, along with a significantly prolonged time to IC progression, versus crizotinib. The median OS was not estimable in both arms and favored lorlatinib (HR, 0.72; 95% CI, 0.41-1.25). This data can bring lorlatinib as an option for front line therapy, however, there are many more caveats to consider like the fact that lorlatinib is usually the TKI that can rescue patients that fail first and second-generation ALK inhibitors, giving the strongest agent first might not be the best approach, more data is needed.
We also have some negative studies presented at 2020 ESMO that are relevant: first, the combination of osimertinib and bevacizumab that did not prolong PFS in patients with advanced adenocarcinomas who had EGFR T790M mutations compared with osimertinib alone, the median PFS in the combination arm was 9.4 months versus 13.5 months for the monotherapy arm (HR, 1.44; P = .20). However, the ORR was higher in the combination arm at 71.8% compared with the osimertinib arm 55.0%. Osimertinib is the agent of choice for T790M mutations and preclinical studies, and even a clinical trial (osimertinib + ramucirumab) has demonstrated already that there was a benefit in the combination of TKI and anti-VEGF inhibitors. Perhaps bevacizumab is the wrong anti-VEGF to combine with osimertinib, and ramucirumab needs to be considered. Another negative study showed that postoperative radiotherapy (PORT) was linked with a non-significant increase in DFS in patients with completely resected stage IIIA N2 NSCLC and thus cannot become the standard of care for this population, despite the use of PORT is currently a common practice in the US and other countries, as per the results from the phase 3 Lung ART trial. The median DFS in the control arm where patients did not receive PORT was 22.8 months versus 30.5 months in those who received PORT (HR, 0.85; 95% CI, 0.67-1.07; P = .016). The three-year DFS rates were estimated to be 43.8% in the control arm versus 47.1% in the PORT arm. OS rates at three years were 68.5% in the control arm and 66.5% in the PORT arm. This will decrease the current use of PORT for patients with N2 disease after surgery.
ESMO 2020 has been an exciting conference for lung cancer doctors, bringing a lot of hope to our patients. We have had the opportunity to see new agents like cemiplimab and AMG501 show promissory data that can bring them online and lorlatinib, lazertinib, TAK788, pembrolizumab, and others with potential new indications and survival updates.
Dr. Raez is the chair of the IASLC Latin American Group (LATAM) and is past chair of the IASLC Membership Committee. He is also the president of the Florida Society of Clinical Oncology (FLASCO). He works as chief scientific officer and medical director of Memorial Cancer Institute at the Memorial Health Care System. He is also clinical professor of Medicine at Florida International University.