Selpercatinib and Pralsetinib Generate Enthusiasm in RET Fusion+ NSCLC

Janakiraman Subramanian, MD

The RET inhibitors selpercatinib (Retevmo) and pralsetinib (Gavreto) demonstrated high response rates in both treatment-naïve and pretreated patients with RET fusion–positive non–small cell lung cancer (NSCLC) in the pivotal LIBRETTO-001 and ARROW trials, respectively, but ongoing phase 3 research is exploring these drugs even further up front.

Both agents are approved for patients with RET fusion–positive NSCLC. Currently, their distinguishing feature is their toxicity profile, explained Janakiraman Subramanian, MD, who emphasized the gastrointestinal adverse effects (AEs) that have been reported with selpercatinib vs the hematologic AEs that have been observed with pralsetinib. 

However, the ongoing phase 3 LIBRETTO-431 (NCT04194944) and AcceleRET Lung (NCT04222972) trials will provide much needed information regarding the differential activity of these agents up front, which is ultimately where targeted therapy should be used, he added. 

“With targeted therapies, the focus is not to wait until [patients] progress but to [give them in the first-line setting] if the drug is effective. [We want to prescribe] the most effective treatment available [up front],” said Subramanian. “Since the bulk of the patient data we have is in patients who have had been heavily pretreated––I think the median number of treatments in both studies was around 3 or 4––the real benefit from these drugs will be seen when the phase 3 trials are completed when we see the response rates and survival outcomes in treatment-naïve patients.”

In LIBRETTO-431, patients will be randomized to 1 of 3 arms: selpercatinib alone, pemetrexed plus physician’s choice of carboplatin or cisplatin with or without pembrolizumab (Keytruda), or pemetrexed plus platinum-based chemotherapy and pembrolizumab.

In AcceleRET Lung, patients will be randomized to pralsetinib alone or platinum-based chemotherapy with or without pembrolizumab.

In an interview with OncLive^® during a 2021 Institutional Perspectives in Cancer webinar on lung cancer, Subramanian, a medical oncologist and director of Thoracic Oncology in the Center for Precision Medicine at Saint Luke’s Cancer Institute, discussed the depth and durability of responses that have been reported with selpercatinib and pralsetinib, as well as ongoing research focused on improving outcomes and overcoming resistance mechanisms in RET fusion–positive NSCLC.

OncLive^®: How have the FDA approvals of selpercatinib and pralsetinib affected the paradigm? 

Subramanian: The regulatory process has been quite nimble, and they are trying to keep up with these new agents as they become available. They have kept up very well. Of course, as a clinician, I wanted these drugs [a long time ago], but that’s wishful thinking. The reality is they’ve kept up really well as these drugs are coming along, and they are making them available for our patients. 

On top of that, even before regulatory approvals, sometimes we have the breakthrough designations that come from the FDA, which gives us some guidance on how effective these drugs are. At the same time, we have drugs being made available through expanded access protocols by pharmaceutical companies, which does help our patients quite a bit. Even if they don’t have access to a clinic, they are able to get access to these medications on an expanded access protocol or compassionate basis.

The other issue is that there are still so many other patients who would benefit from getting access to clinical trials. We should, as a community work hard to open these trials and open them quickly and offer them to our patients.

It has taken a while for better drugs to become available for targeting RET fusion–positive lung cancer. Now we have selpercatinib and pralsetinib, which give us more options when it comes to treating our patients. It will be very interesting to see the upcoming phase 3 trials comparing selpercatinib and pralsetinib with standard platinum-based doublet chemotherapy plus or minus pembrolizumab. 

As we use these drugs, we are also noticing patients developing resistance to these drugs. We are just scratching the surface of resistance mechanisms. We are noticing new gatekeeper mutations, which are resistant to these kinase inhibitors. Also, in some cases, we see MET amplification. We don’t know enough about how to manage those patients when they progress. Once more studies are done, we’ll have a better understanding [of these resistance mechanisms] and better management strategies for those patients.

Do single-gene panels still have a role to play, or do you recommend broad panel testing for all patients?

We need to test our patients for molecular alterations. All of our patients with NSCLC should have molecular testing on a broad panel, not just single alterations. We should be doing a next-generation platform that looks for the key mutations and the fusion genes, as well as PD-L1 expression and tumor mutation burden. Secondly, we need to get these results quickly and then be able to connect the dots and get patients the right treatment. 

Is selpercatinib an effective and tolerable treatment for patients with RET fusion–positive NSCLC?

Selpercatinib is a specific RET tyrosine kinase inhibitor that was recently approved by the FDA. Selpercatinib has an excellent response rate of slightly over 60%. In the treatment-naïve population, [the response rate is] well over 80%. It’s quite an effective and well-tolerated drug. The median duration of response was about 17 months, so we’re getting deep [and durable] responses with this medication, which is definitely an improvement compared with some of the previous multikinase inhibitors that we were using for the treatment of patients with RET fusions.

[In terms of safety], one of the common AEs we run into is hypertension, but that’s usually well controlled. In the LIBRETTO-001 study, most of the grade 3/4 AEs [occurred at a frequency] of 1% or less, which tells us that [the drug] is relatively well tolerated. Of course, there are some other AEs, [such as] GI [effects], nausea, and even diarrhea sometimes, but those were all primarily grade 1/2 [events in the study]. 

How does pralsetinib compare with selpercatinib?

Pralsetinib is also a novel RET kinase inhibitor. It does have some multikinase effect against other kinases as well, but its effectiveness is quite high when it comes to RET kinase. The data that we have seen from the clinical trial has also shown that it is quite effective with response rates in the 50% to 60% range.

In treatment-naïve patients, we see even better response rates. The duration of response is quite durable in these patients as well, so even though it has some off-target effects, at least looking at the preclinical data, that’s what we see; compared with selpercatinib, the effectiveness seems to be quite good for pralsetinib.

In terms of the toxicity profile, we did see a slightly higher incidence of cytopenias with pralsetinib, particularly with anemia and neutropenia, but these are different studies, and we can’t compare them to say that one is better or worse in terms of efficacy or AEs. In the ARROW trial with pralsetinib, overall, patients tolerated the drug quite well. The number of patients who discontinued treatment because of AEs was quite low, at around 7% to 8%. 

Ultimately, we want to see more data. When we see [more] treatment-naïve patients getting this drug, we’ll have a much better understanding [of the drug’s activity]. 

Are there any other emerging RET inhibitors that are currently being examined in the space that you want to highlight?

There are, but they are all at a very early phase [of development] at this point. We don’t know the activity of these new RET inhibitors in some of these gatekeeper mutations that we are seeing, particularly in the V804 residue. I would be very interested to see [what that ends up being]. 

I also came across a few case reports and case series showing that patients who have MET amplification while they have been on a RET kinase inhibitor and developed resistance due to MET amplification, adding crizotinib [Xalkori] seems to be quite effective, or at least beneficial for those patients. Now with newer MET inhibitors becoming available, that is interesting to look forward to as well.