The next tumor agnostic agent could be approved this summer, now that data from several clinical trials with entrectinib (Genentech) have been filed with the US Food and Drug Administration (FDA).
Entrectinib has shown activity in various tumors that are positive for fusions in the neurotrophic tropomyosin receptor kinase (NTRK) gene.
It is the second drug to target NTRK+ tumors, and follows larotrectinib (Vitrakvi, Loxo Oncology/Bayer), which was approved by the FDA in November 2018.
However, entrectinib is also going for an additional indication: use in non-small cell lung cancer that is positive for ROS1.
One difference between the two drugs is activity in the central nervous system (CNS), Robert C. Doebele, MD, PhD, director of the University of Colorado Cancer Center Thoracic Oncology Research Initiative in Denver, told Medscape Medical News.
This means that entrectinib provides intracranial responses and larotrectinib does not, he elaborated.
This is important especially in cases like NSCLC, he explained. One third of patients with NSCLC have brain metastases at diagnosis and two thirds are likely to develop brain metastases during treatment. For the small group of NSCLC patients with NTRK+ or ROS1+ tumors, entrectinib will become a front-line option, he suggested.
"Entrectinib will be the sixth targeted agent that is likely to be available for patients with NSCLC," he said.
Clinical Data on Entrectinib
Clinical data from the pivotal phase 2 STARTRK-2 study, as well as from the phase 1 STARTRK-1 and phase 1 ALKA-372-001 trials, were presented recently at the annual meeting of the American Association of Clinical Research.
For patients with NTRK-positive (NTRK+) tumors, which included a subset of patients with non-small cell lung cancer (NSCLC), the overall response rate (ORR) was 57.4% for the pooled population and 70% for patients with NSCLC.
For patients with ROS1-positive (ROS1+) tumors, the pooled analysis showed that entrectinib provided ORR of 77.4%. For patients with no CNS metastases at baseline, ORR was 80%; for patients with CNS metastases at baseline, intracranial ORR was 74%.
Study Details for NTRK+ Tumors
Fifty-four patients with NTRK+ tumors were of a median age of 57.5 years; 59% were women; 37% were treatment naïve, and 22% had CNS metastases.
A subgroup of 10 patients had NTRK+ NSCLC (19% of the total population); these patients had a median age of 62.5 years; 50% were women; 30% were treatment naïve, and 60% had CNS metastases.
Other NTRK+ tumors included sarcomas (24%), mammary analogue secretory carcinoma (13%), and cancers of the breast (11%), thyroid (7%), colon (7%), pancreas (6%), and neuroendocrine system (6%).
All responses were based on blinded independent central review. In the total population, ORR was 57.4% (complete responses: 7.4%), median duration of response was 10.4 months, median progression-free survival (PFS) was 11.2 months, and median overall survival (OS) was 20.9 months.
In patients with NTRK+ NSCLC, ORR was 70% (complete responses: 10%), median PFS was 14.9 months, and median duration of response and median OS were not reached.
ORR was higher in patients with no CNS metastases at baseline: 59.5% vs 50% for those with CNS metastases at baseline. Intracranial responses were 54.4% for patients with NTRK+ tumors and 66.7% for patients with NTRK+ NSCLC.
Study Details for ROS1+ NSCLC
Doebele told Medscape Medical News that ORR with entrectinib in patients with ROS1+ NSCLC was similar to that seen for patients with NTRK+ NSCLC.
The 53 patients with ROS1+ tumors were of a median age of 53 years; 64% were women; 58.5% never smoked; 13.1% were treatment naïve; and 43.4% had CNS metastases at baseline.
All responses were based on blinded independent central review. In the total population, ORR was 77.4% (complete responses: 5.7%), median duration of response was 24.6 months.
For the 23 patients with CNS metastases at baseline, ORR was 73.9% (all partial responses). Median duration of response was 12.6 months. For the 30 patients without CNS metastases at baseline, ORR was 80% (complete responses, 10%). Median duration of response was 24.6 months.
PFS was 19 months, 13.6 months, and 26.3 months for the overall population, for patients with CNS metastases at baseline, and those with no CNS metastases at baseline, respectively.
Intracranial responses were also reported for patients with CNS metastases at baseline. ORR was 55% (complete responses, 20%; partial responses, 35%), and duration of response was 12.9 months.
Safety data were reported for 355 patients who received at least one dose of entrectinib across the three studies. Most adverse events were of grade 1 or 2, which were reversible. Treatment-related adverse events leading to treatment discontinuation was 3.9%. Dose reductions and interruptions were reported for 27.3% and 25.4% of patients, respectively. Rate of serious adverse events was 8.5% and no grade 5 events (deaths) were reported.
The safety profile reported for patients with ROS1+ NSCLC was consistent with the safety profile of entrectinib in the overall population.
Is Advanced NSCLC Ready for Entrectinib?
Given that there will be six targeted therapies in NSCLC, how will entrectinib, an NTRK+ and ROS1+ inhibitor, be used in this space?
Lung cancer expert Alice T. Shaw, MD, PhD, of Massachusetts General Hospital in Boston, told Medscape Medical News that entrectinib as a TRK+ and ROS1+ inhibitor is entering a crowded space.
"With its good CNS penetration, entrectinib will have an advantage over crizotinib (Xalkori, Pfizer)," she noted. "However, entrectinib cannot overcome the common resistance mutation ROS1 G2032R, which emerges to crizotinib and entrectinib. In addition, other ROS1+ inhibitors such as lorlatinib (Lorbrena, Pfizer) and repotrectinib are just as brain penetrable, if not more," said Shaw, who was not involved with the current studies.
Lorlatinib was recently granted approval for the second- and third-line treatment of ALK+ advanced NSCLC. Repotrectinib is the next-generation ROS1/TRK/ALK inhibitor, which is currently in clinical development (Drilon, A. et al. Cancer Disc. 2018;8:1227-1236).
Doebele told Medscape Medical News that most patients with NSCLC will start with a tyrosine kinase inhibitor (TKI) against the epidermal growth factor receptor (EGFR) such as osimertinib. It is conceivable to use entrectinib following resistance to EGFR inhibitors such as osimertinib, he suggested, and explained that multiple groups have reported resistance due to mutations in anaplastic lymphoma kinase (ALK) or NTRK fusions, or BRAF V600E.
Shaw indicated that when patients relapse on a third-generation EGFR-targeted therapy, it is important to know the resistance mechanism prior to treatment. "Patients should undergo biopsy at the time of relapse in order to identify the resistance mechanism," she said.
She explained that MET gene amplification drives resistance in roughly 20% of cases and combination therapy with EGFR and MET TKIs can be effective in some patients, based on results from the TATTON study (also presented at AACR 2019 and reported by Medscape Medical News).
However, rare targetable alterations are also seen in these patients, and once resistance mechanisms are identified it may be appropriate to rechallenge the tumors with the combination of the EGFR TKI and a second agent that targets the resistance mechanism, she added.
In their own practice, Shaw and colleagues identified RET mutations and rechallenged two patients with osimertinib and BLU-667 (an agent under investigation), which was associated with a rapid radiographic response in both patients. (Piotrowska, Z. et al. Cancer Disc. 2018;8:1529-1539). And Doebele indicated that a patient under his care is being treated with the combination of an EGFR TKI and entrectinib for nearly a year. "Retreating patients has to be done every cautiously," he said.
The FDA is expected to make a decision on approval of entrectinib by August 18, according to the manufacturer.
Doebele reports being a speaker or on the advisory board of Takeda, Ignyta, AstraZeneca, Bayer, Genentech, F. Hoffmann-La Roche, Trovagene, Spectrum, Pfizer, Ariad, Guardant Health, and Rain Therapeutics. He holds shares with Rain Therapeutics; has grant/research support from Ignyta; and gets royalties and/or holds IP rights/patent holder from Abbott Molecular (patent license), Rain Therapeutics (patent license), Black Diamond (licensing fee for biologic materials), Ignyta (licensing fee for biologic materials), Foundation Medicine (licensing fee for biologic materials), and Genentech (licensing fee for biologic materials). Shaw is a consultant/advisory board member for TP Therapeutics, Pfizer, Blueprint Medicines, KSQ Therapeutics, Novartis, Roche/Genentech, Loxo Oncology, Ignyta, Takeda/Ariad, Foundation Medicine, Guardant, and Natera.
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