NEW YORK – ALK inhibitors have shown clinical benefit in a clinical trial involving patients with ALK-rearranged gastrointestinal cancers, presenting an opportunity to expand the drug's use outside of lung cancer.
In the study published last month in JCO Precision Oncology, researchers from cancer centers in Italy, Norway, and the US collected clinical and molecular data from ALK-positive GI cancer patients treated with ALK inhibitors. Since so few patients with GI cancer have received ALK inhibitors off label, they analyzed treatment outcomes from only 13 patients with unresectable or metastatic pancreatic, colon, gastric, duodenal, rectal, and biliary tract tumors.
ALK rearrangements are rare in GI tumors, representing less than 1 percent of colorectal tumors and 0.2 percent of pancreatic tumors. However, these alterations are associated with worse survival in several GI cancers, such as colorectal, gastric, and pancreatic cancer, according to previous research.
Lead author Margherita Ambrosini and senior author Filippo Pietrantonio, both from Italy's Fondazione IRCCS Istituto Nazionale dei Tumori, said that the broader use of genomic profiling has helped researchers identify rare mutations in cancers that could not be detected in the past.
"ALK-rearranged GI cancers seem to represent a subgroup with peculiar characteristics in which the ALK fusion may be regarded as a driver genomic alteration," Ambrosini and Pietrantonio said in joint responses to questions over email. "Therefore, we think that ALK inhibitors represent a clinically significant treatment option in this setting and that it deserves to be pursued."
There are a number of ALK inhibitors on the market both in the US and Europe, but they're all approved for ALK fusion-positive non-small cell lung cancer. The present study included GI patients who received three ALK inhibitors: Pfizer's inhibitor Xalkori (crizotinib), Genentech's Alecensa (alectinib), and Genentech's Rozlytrek (entrectinib). The first two are NSCLC cancer drugs, and the third, Rozlytrek, is approved in the US to treat ROS1-positive NSCLC and NTRK-positive solid tumors.
In colorectal cancer, ALK rearrangements often occur with ROS1 and NTRK rearrangements and are associated with older age at diagnosis, right-sided primary tumor location, high microsatellite instability, and lymph node involvement. These are all characteristics that are associated with worse survival, the researchers wrote.
ALK rearrangements are also mutually exclusive with the most common drivers of colorectal cancers, RAS and BRAF mutations, which limits the targeted therapy options for these patients.
ALK-positive gastric cancers have been associated with a signet ring cell component, or disease that is associated with younger age, perineural invasion, and lymph node metastasis, and ALK-positive pancreatic tumors have been characterized by young onset diagnosis and KRAS wild-type status, according to the study.
Across tumor types included in the study, five of 13 patients (41 percent) achieved a partial response to first-line ALK inhibitor treatment, and another five patients (41 percent) reached stable disease, leading to an overall disease control rate of 82 percent.
Five patients went on to receive second-line ALK inhibitor treatment. Among those, two patients (40 percent) achieved a partial response and three (60 percent) reached stable disease. Responses were seen in patients with pancreas, biliary tract, and left and right colon tumors. Progression-free survival across all patients was five months, and the median overall survival was 9.3 months.
There are no precision oncology therapies approved specifically for ALK-rearranged GI cancers, Ambrosini and Pietrantonio said. These patients would have to receive ALK inhibitors through a clinical trial or through off-label or compassionate use programs. The researchers hope these findings spur other oncologists to look for ALK rearrangements in GI cancer patients and help biomarker-positive patients get on a ALK inhibitor through a research or compassionate use program.
There are a few platform studies, such as Genentech's MyPathway and the TAPISTRY trial, in which researchers are exploring Alecensa in ALK-rearranged solid tumors. At the American Association for Cancer Research's annual meeting last month, researchers reported promising activity for Alecensa in non-lung tumors harboring ALK rearrangements in MyPathway. One patient with ALK-positive colon cancer achieved a partial response, while a colon cancer patient and a pancreatic cancer patient achieved stable disease on Alecensa treatment.
Ambrosini and Pietrantonio believe their research points to the need to further study ALK inhibitors in tumor types other than lung cancer. They also noted that biological similarities between ALK fusions and NTRK fusions suggest that ALK inhibitors could show tissue-agnostic benefit like NTRK inhibitors have.
The researchers urged multinational collaboration to better study rare mutations, such as ALK rearrangements, and avoid "neglecting" subgroups of patients who could benefit from already approved targeted therapies.
"We certainly believe that there is a tissue-agnostic potential for ALK inhibitors, based on the results of our research that evidence remarkable responses to ALK inhibitors of ALK-rearranged GI tumors across different histologies and primary sites, and also given the proven benefit in lung cancer," Ambrosini and Pietrantonio said. "Prospective validation of this biomarker and characterization of determinants of response to ALK inhibitors in this setting are crucial to demonstrate our hypotheses."