Potentially practice-changing results from a trial evaluating larotrectinib as a tumor agnostic therapy for children and adults with solid tumors expressing tropomyosin receptor kinase (TRK) fusion proteins were presented at the 2017 ASCO Annual Meeting (Abstract LBA2501).
“I believe these data support larotrectinib as a potential new standard of care for these patients,” said lead study author David Hyman, MD, Chief of Early Drug Development at Memorial Sloan Kettering Cancer Center, New York City.
Vassiliki A. Papadimitrakopoulou, MD, Professor of Medicine in the Department of Thoracic/Head and Neck Medical Oncology at the University of Texas MD Anderson Cancer Center, Houston, described the results as possibly “practice-changing.”
Targeting TRK Fusion Proteins
Larotrectinib, which received Breakthrough Therapy Designation from the FDA in July 2016, selectively targets TRK fusion proteins, an abnormality fairly rare among common cancers yet frequent among rare cancers. TRK fusion proteins can be detected throughout the lifecycle of cancer and are a biomarker for tumor agnosticism. Gene rearrangements in NTRK genes (NTRK1, NTRK2, and NTRK3) encode TRK fusion proteins.
The perceived overall frequency of TRK fusion proteins in lung cancer is in the order of 1 in 100 or 1 in 1,000 lung cancer cases, according to Anna Farago, MD, PhD, a coauthor on the study and attending physician in the Center for Thoracic Cancers at Massachusetts General Hospital and an instructor at Harvard Medical School, Boston.
These study results come shortly after the FDA in May granted the first accelerated approval for a tumor agnostic therapy to pembrolizumab. The indication is for a group of patients with unresectable or metastatic, microsatellite instability-high or mismatch repair deficient solid tumors.
Also in May, the FDA granted Breakthrough Therapy Designation to a different TRK inhibitor, entrectinib.
The study enrolled 55 patients with TRK fusion-positive solid tumors from three ongoing phase I or II trials. TRK fusion status was not centrally-determined; instead patients were identified through 15 unique laboratories.
“This in a sense really represents the real-world identification of these patients and these results,” Hyman said in regard to the 15 laboratories.
Participants included children and adults who had a wide range of tumor types, totaling 17 unique types for this study. The more prevalent types in this patient population were salivary gland cancer (22%), infantile fibrosarcoma (13%), thyroid cancer (9%), colon cancer (7%), lung cancer (7%), and melanoma (7%). The primary endpoint was objective response rate (ORR). All were given larotrectinib as therapy.
Of the patients enrolled, 50 had confirmatory response data at the time of analysis; five had data pending. Of the 50, 76 percent of patients had a response; 64 percent were partial responses and 12 percent complete.
“This was a very positive signal for a rare subset of patients,” Papadimitrakopoulou noted.
“More than three out of every four patients responded to therapy,” Hyman said. “You'd be hard pressed to find a targeted therapy even within a single disease context that has results like this.”
These results were independent of tumor type, patient age, NTRK gene, and fusion partner, suggesting larotrectinib is an age and tumor agnostic therapy.
For the five patients with data pending, four were suspected to be partial responses and one complete. If these data are confirmed, ORR would raise to 78 percent (95% CI, 65%-88%).
“Most of these patients were not just meeting criteria for partial response, but had very deep tumor regressions. And, in fact, two of these patients had such deep regressions that they actually were able to be downstaged and then taken forward to potentially curative surgery, which previously would not have been possible, and have pathologic complete responses, meaning once they had surgery there was no microscopic cancer left in their resection specimen,” Hyman explained.
Secondary endpoints, which were duration of response and progression-free survival, have not yet been reached. Median time to response was 1.8 months, which was also the time of the first scan.
“In the clinic, patients report dramatic improvement of their symptoms within days of beginning therapy,” Hyman said.
“Their safety profile of the drug was very tolerable,” Papadimitrakopoulou added.
Only 13 percent of patients needed a dose reduction and, despite having a reduced dose, all maintained tumor regression (one complete response, five partial responses, and one stable disease). Of patients who had a confirmed response to therapy, 93 percent remain on therapy or underwent surgery with curative intent.
“As with any other agent that has achieved this level of activity, the question that will arise is development of resistance to therapy, which is possibly addressed already,” Papadimitrakopoulou said.
Six patients acquired resistance to larotrectinib, one of which was a non-small cell lung cancer (NSCLC) patient. For five of those six (including in the NSCLC patient), a resistance mutation was found. LOXO-195 has been used so far in two of the five patients (neither of which had NSCLC) and was successful.
Future Treatment Options
Farago stated that, going forward, she expects that when she finds NSCLC patients with an NTRK gene rearrangement, there is a “very high” likelihood the tumor will be sensitive to larotrectinib.
She also advised when to screen for TRK fusions in NSCLC.
Patients who have stage IV or unresectable stage III NSCLC should be screened for a gene rearrangement involving NTRK1, NTRK2, or NTRK3. Farago added that the rationale for this is there are no data for NSCLC patients who are surgical candidates.
“If we find a patient with one of those gene rearrangements, we should put them on a TRK inhibitor because there is a very high likelihood that the tumor is dependent on TRK signaling and will be highly sensitive to an oral TRK inhibitor,” she said.
On the big picture scale, these study results mark progress toward providing personalized medicine to patients.
“In the era of personalized medicine, the identification of targetable genetic alterations represents a step forward in anti-cancer therapy,” Papadimitrakopoulou stated.
“We have witnessed the paradigm change in the management of advanced non-small cell lung cancer with several approvals by the FDA of drugs in rare subsets, and [TRK fusions] is one of the alterations that we can now add to the successes,” she said, recognizing that an FDA approval has not been granted yet.
Christina Bennett is a contributing writer.