Researchers Report on Efficacy of Pfizer's Xalkori in MET-mutated Lung Cancer

NEW YORK – In an expansion cohort of the Phase I PROFILE 1001 trial, 32 percent of advanced non-small cell lung cancer patients with MET exon 14 alterations saw their tumors shrink when treated with crizotinib (Pfizer's Xalkori).

Researchers led by Paul Paik from Memorial Sloan Kettering Cancer Center reported data from 65 evaluable patients in Nature Medicine on Monday, and wrote that despite the activity seen in the study, it may not be an improvement upon other existing options. "These results address an unmet need for targeted therapy in people with lung cancers with MET exon 14 alterations and adds to an expanding list of genomically driven therapies for oncogenic subsets of NSCLC," they wrote. 

The observed median duration of response was 9.1 months and the median progression-free survival was 7.3 months.  

Among evaluated patients, 5 percent had a complete response, 28 percent had a partial response, 45 percent had stable disease, and 6 percent had disease progression. 

From the early days of the crizotinib development program, Pfizer knew it to be a MET and ALK inhibitor. The drug was first approved in 2011 for late-stage, ALK-positive NSCLC. In 2016, the FDA expanded that approval to include ROS1-positive NSCLC patients. 

As a MET inhibitor, crizotinib received breakthrough therapy designation from the US Food and Drug Administration in 2018 based on initial data from PROFILE 1001 for previously treated metastatic NSCLC with MET exon 14 alterations.

These alterations — including point mutations, insertions, and deletions — occur in 3 to 4 percent of NCSLC patients and are even more rare in other cancers. In PROFILE 1001, the genetic alteration was identified by local testing, mostly using DNA or RNA-based next-generation sequencing. 

Most of the treatment-related adverse events were grade 1 or 2. However, three patients had hypophosphatemia, lymphopenia and pulmonary embolism, and one patient developed interstitial lung disease. 

Paik and colleagues wrote in the paper that while the response rates were "robust" in this study, and higher than the responses patients could hope to have with second-line chemotherapy, the efficacy to crizotinib was comparable to first-line platinum doublet-chemo. Furthermore, the efficacy seen with crizotinib in this subset doesn't improve upon first-line chemo-immunotherapy combinations, which can now be given in biomarker-unselected populations. 

The researchers probed why the responses to MET inhibition with crizotinib was lower than what has been seen with drugs targeting other molecular drivers. They considered in exploratory analysis whether different MET exon 14 alterations, other concurrent alterations, or ctDNA status impacted patients' ability to respond to crizotinib but did not find any strong associations. 

"Other factors that potentially affect crizotinib outcomes should continue to be explored," Paik and colleagues wrote. "It was recently shown, for example, that no responses were observed with crizotinib in MET exon 14-altered NSCLCs without MET protein expression." 

The researchers noted that newer, more selective investigational agents, such as Novartis' capmatinib, Merck KGaA's tepotinib, and AstraZeneca's savolitinib, are being explored and may be more efficacious in this setting. However, further follow-up studies are needed to understand whether the efficacy and toxicity profiles of these drugs improve upon crizotinib and other available drugs in MET exon 14-altered lung cancer.  

"The results of PROFILE 1001 established a clinical paradigm for the treatment of MET exon 14-altered lung cancers with MET-directed targeted therapy," the researchers wrote. The study "pav[es] the way for additional research to move forward in this space with the goal of regulatory approval of one or more MET inhibitors for this genomic indication."