Testing for RET Fusions in NSCLC Remains Critical as Targeted Therapy BLU-667 Evolves

Justin F. Gainor, MD

Justin F. Gainor, MD

The selective RET inhibitor BLU-667 has demonstrated durable responses in patients withRETfusion-positive lung cancer in the phase I ARROW study. The agent is also generally well-tolerated, creating a bigger need for physicians to test for this rare alteration in their patients with non—small cell lung cancer (NSCLC).

In the dose-escalation phase of the study, the recommended phase II dose was determined as 400 mg per day of BLU-667. Patients withRETfusion-positive solid tumors were enrolled, and data were presented for 120 patients with lung cancer for safety and 48 patients with lung cancer for efficacy.

According to Justin F. Gainor, MD, the objective response rate (ORR) was 58% in the overall population that was assessed for efficacy, while the ORR in patients who had received prior platinum-based chemotherapy was 60%. Safety data determined BLU-667 to be well tolerated at the recommended phase II dose, and the most common adverse events (AEs) were mostly grade 1/2. The most common AEs were constipation, hypertension, neutropenia, and alanine aminotransferase (ALT), and aspartate aminotransferase (AST) elevation.

Although these findings demonstrate a role for targeted therapy, physicians are not testing their patients for genetic alterations enough. Gainor argues that testing for molecular drivers, includingRET, should be done in 100% of patients, but next-generation sequencing (NGS) is still not being utilized to this capacity just yet.

“We know that if you have a targetable genetic alteration like anEGFRmutation or ALK, ROS1,and now RETfusion, you can derive significant clinical benefit from the use of targeted therapies,” said Gainor, director of the Center for Thoracic Cancers and Targeted Immunotherapy at Massachusetts General Hospital. “It underscores that we need to be testing all of our patients.”

In an interview withTargeted Oncology, Gainor discussed the significance of identifyingRETalterations in patients with NSCLC and the prevalence of this molecular target. He also highlighted data supporting further evaluation of BLU-667 in patients with RET-altered NSCLC.

TARGETED ONCOLOGY: Could you discuss the prevalence of RET fusions in NSCLC?

Gainor:RETrearrangements define a distinct molecular subgroup of NSCLC, and they are found in 1% to 2% of patients. This is a relatively rare genotype, and it’s on the same frequency level of ROS1rearrangements. One of the challenges is if you do 1 of the 1-off tests, such as EGFRthen ALK, many times providers won’t send forRETfusion testing because we don’t have an FDA-approved RET inhibitor right now. However, I think as the number of targetable genetic alterations continues to increase in lung cancer, it just emphasizes the need for multiplex testing or NGS where you capture most of these molecular targets. My hope is that as we move more toward this multiplex testing, we can identify more patients.

TARGETED ONCOLOGY: Does testing forRETfusions have to become more widespread now?

Gainor:I would make the argument broadly throughout the management of lung cancer that rates of testing for molecular alterations remain low, or rather they are not at 100% for patients with nonsquamous histology, which is where they need to be. We know that if you have a targetable genetic alteration like anEGFRmutation or anALK, ROS1,and now RETfusion, you can derive significant clinical benefit from the use of targeted therapies. It underscores that we need to be testing all of our patients. The hope is that for patients who have inadequate tissue to permit this testing that we can complement that with liquid biopsies.

TARGETED ONCOLOGY: What is the mechanism of action for BLU-667, and what is the hope for this agent as a treatment in this space?

Gainor:RETfusions were first identified in lung cancer around 2012. Around that time, a number of basic science papers suggested that this would define a distinct molecular subset. These genetic changes were transforming in vitro, and it looked like they were mutually exclusive with other genetic alterations like EGFRor ALK. They also occurred in patients who are never smokers, which is a typical patient cohort where they seemed like a distinct subset.

We staretd with early efforts to targetRETfusion lung cancers much like we did for ALKand ROS1, building off that success. We tried to use these multikinase inhibitors, drugs that were repurposed and not designed as RET inhibitors. They were targeting multiple things, such as cabozantinib (Cabometyx) or lenvatinib (Lenvima). The goal was to repurpose them to target RET. Unfortunately, the results were modest. There was modest activity around 20% to 30% ORRs, but those also showed significant off-target toxicity, such as hypertension. That limited the dose intensity, so it seemed like we weren’t hitting the target hard enough.

Over the last 2 years, we have developed more selective RET inhibitors. These are drugs that are purposely designed to targetRET, and the 2 selective RET inhibitors that are currently in trials are BLU-667 and LOXO-292. These are both selective inhibitors.

TARGETED ONCOLOGY: What data have we seen to support the use of BLU-667 in this patient population?

Gainor:The ARROW study was the phase I study of BLU-667. This study had 2 parts; part 1 was the dose-escalation aspect, which recruited patients withRET-altered solid tumors and enrolled 62 patients. Those results were presented at AACR 2018, where we reported that the recommended phase II dose had been determined at 400 mg once daily.

Last year at ASCO, I presented an updated analysis that focused on part 2 of the study; this is where we have initiated dose expansion. Right now, there are 7 expansion cohorts, and my presentation was focused on 2 expansion cohorts, which included theRETfusion-positive cohorts of patients previously treated with platinum-based chemotherapy, as well as patients who were platinum-based chemotherapy-naïve.

We presented 2 sets of data, and the first was the safety population. This consisted of 120 patients withRETfusion-positive lung cancer, all of whom were treated with the recommended phase II dose of 400 mg per day. We showed that, in general, BLU-667 is well-tolerated, and most AEs were predominantly grade 1 and grade 2. We also reported the most common side effects being constipation, hypertension, neutropenia, and ALT/AST elevation. These toxicities did not require the elimination of dosing in general, so only 7% of patients ultimately discontinued BLU-667 because of treatment-related AEs.

The second major aspect was focused on the efficacy. In this part, we focused on 48 patients who had an adequate amount follow-up scans. All of these patients had RECIST evaluable disease, and we showed an ORR of 58% in the overall population, and among patients who were previously treated with a platinum-based chemotherapy, there was a confirmed ORR of 60%. I think these are promising data with a high response rate that emphasizes to us thatRETfusions constitute a bonified genetic alteration It’s a real oncogenic driver in lung cancer, and as a result, BLU-667 received a Breakthrough Therapy Designations by the FDA. The ARROW study continues, and we hope to enroll more patients with treatment-naïve RETfusion-positive lung cancer.

TARGETED ONCOLOGY: What were your findings in patients with brain metastases?

Gainor:In the data that we presented, we demonstrated that the responses appeared comparable if patients had a history of brain metastases or had no history of brain metastases. This study allowed patients with asymptomatic brain metastases to enter the study, so during the presentation, we focused on 9 patients who had brain metastases that were target lesions. We were able to show that 7 out of 9 patients had tumor shrinkage of their brain metastases. That tumor shrinkage was observed in patients with multiple different fusion partners, including KIF5B and CCDC6.

It is really promising that we are seeing good responses in the central nervous system because it can be a sanctuary setting of disease for patients. We also know that in this trial, 40% of patients had brain metastases, so this a critical need for our patients to have a CNS penetrantRETinhibitor.

TARGETED ONCOLOGY: What are some of the unanswered questions you hope to address in the future?

Gainor:We need to get a better understanding of the activity of BLU-667 in the treatment-naïve setting. In this study, we had 7 patients who were treatment-naïve, and 5 of them had responded. What we have seen with the whole paradigm of using targeted therapies is that we want to use our best therapies first. We need to gain additional clinical experience of what these drugs do in the first-line setting. We also need to see not only response rates but the durability of the responses. We need longer follow-up to get a better idea of how long patients are responding to therapy.

TARGETED ONCOLOGY: What should physicians take home from this research?

Gainor:The point is that physicians should be testing forRET