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06-12-2021 | Non-small-cell lung cancer | Interview | Article

ARROW points the way for RET fusion-positive NSCLC treatment

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Speaker: Stephen Liu 

Stephen Liu outlines the ARROW study design and findings and discusses the impact of pralsetinib on the care of patients with treatment-naïve and previously treated NSCLC positive for a RET fusion (7:20).

This content is intended only for healthcare providers and was made possible by educational funding provided by F. Hoffmann-La Roche Ltd.

Transcript

Hi. This is Stephen Liu, medical oncologist and Director of Thoracic Oncology at Georgetown University in Washington, DC. RET or rearranged during transfection has become increasingly relevant in oncology. We know this gene from our training as a proto-oncogene. Mutations within RET are associated with medullary thyroid cancer and hereditary cancer syndromes.

But what's of interest now is RET gene fusions. These are also known oncogenic events. And we see these across various types of cancer, but perhaps best known in non-small-cell lung cancer, where it makes up about to 1% to 2% of all new diagnoses. Now, RET is an important event to detect because it now guides optimal therapy.

Over the past few years, we've had multikinase inhibitors that were approved for the treatment of other cancers. Cancers like thyroid cancer, renal cell carcinoma, that had activity at RET. But these were non-selective inhibitors with a lot of off-target activity. And that really limited their impact, because it limited the dose we were able to safely deliver due to an increasing tolerability issues.

These drugs had response rates around 30% to 40% with notable toxicity. We now have selective RET inhibitors. And chief among those is pralsetinib. Pralsetinib is a selective RET inhibitor that was studied in the ARROW trial, a phase 1-2, multi cohort trial for RET- altered cancers. Now, the phase 1 portion established the dose, which was 400 mg by mouth daily.

The phase 2 portion really looked at efficacy, gathered a lot of information in separate cohorts for different tumor types and different treatment settings. The eligibility criteria were pretty standard for ARROW. Age over 18 with unresectable or locally advanced tumors with a RET fusion or mutation in measurable disease. As I mentioned, that phase 2 portion had multiple cohorts. We're going to focus here on the non-small-cell lung cancer cohort.

There were different groups. One for patients who had had prior therapy-- prior platinum-based chemotherapy largely. And another cohort for patients who were treatment naive. Now note that initial version of the protocol allowed patient that were treatment naive, but those patients had to be ineligible for standard front-line therapy for various reasons, performance status, organ dysfunction.

And so the initial front-line cohort didn't necessarily reflect the front-line cohort that we would see in our clinic. In July 2019, an amendment to the ARROW protocol lifted that caveat where patients were allowed to enroll in the treatment-naive setting, even if they were eligible for first-line therapy. And this really, I think, reflects a true front-line population in our clinic.

When all is said and done, that included 233 patients with RET fusion-positive non-small-cell lung cancer in just over 3 years. Quite an achievement for a relatively rare subtype. There were many different fusion partners with RET. The most common, as expected, was KIF5B. That accounted for about three quarters. Followed by CCDC6, but there are many other fusion partners within RET.

If we look at the cohort of patients who had had prior platinum-based chemotherapy, the response rate was a very impressive 62%, with 4% complete response. These responses were deep. These responses were quick, with median time to response of 1.8 months. Most patients really responding that first or second scan. And these were durable with a median duration of response of 22 months, almost 2 years.

Median progression-free survival, 16.5 months. Important note for ARROW, we do know that for patients with RET fusion-positive lung cancer, CNS involvement is not so rare. There were patients that did have measurable CNS disease. All of those patients did have some tumor reduction.

Looking at the details here, the responses that we saw with pralsetinib of in the ARROW trial were independent of fusion partner. And also, if the fusion was detected by liquid or by tissue, those patients responded equally well. So as long as you're finding that RET fusion, pralsetinib is a very effective option. Even more so in that front-line space.

In the initial treatment-naive cohort, patients were not eligible for front-line therapy for various reasons. There, the outcomes were even more impressive with a response rate of 74%, 9% complete response. After that amendment in the summer of 2019, where patients that were treatment-naive eligible for all therapy were included, that response rate was very impressive, 88%, with a disease control rate of 96%.

Very impressive responses. Very durable at the last reported efficacy update. The median duration of response, median progression-free survival still not reached. So these are durable, quick, and very deep responses. And with a response rate of 88%, almost 90%, really quite impressive in that front-line setting.

In addition to being a very effective drug, pralsetinib is extremely well tolerated. If we look at that cohort of 233 patients, the grade 3 and higher toxicities were largely paper toxicities. We saw neutropenia in about 20% of patients, which does seem a little bit high. But the rate of interruption or reduction for neutropenia, only 15%. And only two patients out of the entire cohort stopped therapy to do neutropenia. Well less than 1%.

They also saw anemia. Again, largely a paper toxicity, about 13%. And grade 3 plus hypertension at 12% reflecting probably some spillover into VEGF. The rate of discontinuation due to adverse event overall across all cohorts was only 6% out of 471 patients. So quite impressive.

When I look at the safety profile of pralsetinib, this is a drug that is extremely well tolerated, certainly much better tolerated than something like chemotherapy. My strategy here would really be to monitor laboratory values, including a CBC. Watching that to see if any dose reduction or modification is required. But all in all, extremely well-tolerated drug.

The impact of pralsetinib, I think, is immediate. This is a highly effective front-line treatment. And when you have a front-line response rate for RET fusion positive lung cancer of almost 90%, it gives an oncologist that confidence that when we start this treatment, very quickly, patients can feel better. Symptomatic relief with, importantly, CNS efficacy.

Outside of targeted therapy, we know the field has moved towards immunotherapy. But in a lot of work done, globally, including the IMMUNOTARGET study led by Dr. Julien Mazières, we know that immunotherapy is really not effective for RET fusion-positive lung cancer with response rates in that single digit. Most patients experiencing progression as their best possible response.

So without an immunotherapy option, our standard historically would be chemotherapy, pralsetinib, and targeted therapy for RET fusion-positive lung cancer really making an immediate impact. But this can only make that impact if you detect that RET fusion. So critical to be sure we're testing for RET, we're testing for RET fusions.

And the multiplex testing panel that we are doing for all of our patients with metastatic lung cancer includes RET in that panel. Based on these overwhelmingly positive results from the ARROW trial, pralsetinib received FDA accelerated approval in September 2020, and received European Commission approval November 19, 2021. And the immediate option for our patients with RET fusion-positive lung cancer.

About the contributor

Stephen Liu

Dr. Stephen Liu, MD, is an Associate Professor of Medicine, Director of Thoracic Oncology and Director of Developmental Therapeutics at the Lombardi Comprehensive Cancer Center of Georgetown University.


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