LIBRETTO-001 and ARROW Trials Show Positive Data in RET Fusion–Positive Lung Cancer

Jessica Bauman, MD, the chief, Division of Head and Neck, Medical Oncology, assistant professor, Department of Hematology/Oncology, and associate program director, Hematology/Oncology Fellowship Training Program at Fox Chase Cancer Center, reviewed data from the LIBRETTO-001 and ARROW trials which show the efficacy and safety of selpercatinib (Retevmo) and pralsetinib (Gavreto) for the treatment of patients with RET fusion-positive lung cancer.

Review of these data were part of a discussion about a 59-year-old patient during a virtual Targeted Oncology Case-Based Roundtable event.

Targeted Oncology^TM: How often are RET mutations seen in patients with cancer?

BAUMAN: RET fusions and mutations are associated with oncogenesis across multiple different malignances, the most common being papillary thyroid cancer, medullary thyroid cancer, and non–small cell lung cancer [NSCLC], though there have been RET alterations seen in other places. We also know that there is a difference between mutation and fusion, and that fusions are the predominant mechanism in lung cancer, with the KIF5B being the most common fusion that we see, in about 70% to 90% of patients with lung cancer.¹

What treatments are recommend for these patients?

Certainly, from the National Comprehensive Cancer Network [NCCN] guidelines and the FDA perspective, both selpercatinib [Retevmo] and pralsetinib [Gavreto] have been approved, and they’re both listed as preferred on the NCCN guidelines.²

Which trials back the approval and recommendation of selpercatinib?

The LIBRETTO-001 trial [NCT03157128] was a phase 1/2 trial that used selpercatinib in patients with RET fusion–positive NSCLC.³ It was a large trial that had several cohorts, and we’ll briefly discuss the data from the RET fusion–positive metastatic NSCLC cohort, which had 2 cohorts within that cohort, 1 of which was treatment naive, and the second was patients who were previously treated with platinum chemotherapy.

On the LIBRETTO-001 trial, the patients in both cohorts were similar in age, race, and ECOG status. They had adenocarcinoma, and in the [previously treated patients], they all had had platinum-based chemotherapy and some already had a multitargeted tyrosine kinase inhibitor [TKI]. There were patients who had brain metastases in both cohorts, and the KIF5B-RET fusion was the most common [fusion].

What was the efficacy of the LIBRETTO-001 trial?

What was most impressive from this study were the response rates that we saw in both the patients who had platinum chemotherapy previously and the patients who were not previously treated. The response in the prior treatment cohort was 64% to 70%, depending on which assessment, whereas in treatment-naive patients it was 85% to 90%. So these were impressive response rates.

Then I think what we are looking to more and more is the duration of response [DOR] when people do respond, and the DOR was not reached in the treatment-naive cohort and was about 18 months in the prior platinum chemotherapy [17.5 months with independent review and 20.3 months with investigator assessment]. This was a significant duration of disease control, and those responses were seen regardless of the type of prior treatment, as well as regardless of the RET fusion partner.

We also saw from this study that there was an intracranial response for patients who had measurable intracranial disease. Of the 11 patients who had intracranial disease that was measurable, 91% responded, with one-third of them having a complete response [27%] and two-thirds a partial response [64%], and the DOR intracranially was also significant, with a decent amount of 10.1 months.

Twenty-two additional patients had measurable CNS disease, with multiple different fusion partners. For these patients, there was a confirmation of this similar response, with a little more than 80% of patients responding to selpercatinib with their CNS disease. The median progression-free survival [PFS] was somewhere between 16 and 18 months—which is very impressive for a TKI—in the previous chemotherapy-treated population. In the untreated population, the median PFS was not yet reached.

Certainly, in my mind, this is very reminiscent of some of the ROS1 data with crizotinib [Xalkori], in which we saw a PFS of 18 months—what we are starting to seenow with osimertinib [Tagrisso] in the frontline for EGFR mutations. Certainly alectinib [Alecensa] eclipsed all of this with its activity in ALK. But clearly [selpercatinib] is a very effective treatment for these patients in terms of the length of time it’s able to control their disease.

Hypertension [any grade, 17%] and liver function tests [increased aspartate transaminase level: any grade, 22%; increased alanine aminotransferase level: any grade, 20%] were some of the most common treatment-related adverse events [AEs] that were seen. There were some diarrhea [any grade, 25%] and xerostomia [any grade, 36%] noted, as well as edema [any grade, 13%]. Also important to note, and not a huge instance, but there was also prolonged QT on EKG seen [any grade, 10%]. So, for patients who have prolonged QTc [interval] at baseline, [this is] also a question about the role of selpercatinib in that population. But otherwise, in general, the toxicities were all manageable and fairly low grade. With these data, the FDA approved selpercatinib for both lung and thyroid cancers for patients who had RET gene fusions or mutations.⁴

Pralsetinib is also used in this setting—what are the data for that agent?

The ARROW trial [NCT03037385] was also a phase 1/2 trial in patients with advanced RET fusion–positive NSCLC with the drug pralsetinib with a dose of 400 mg daily.⁵ They also had a prior platinum group and a treatment-naive cohort in the ARROW study, with similar characteristics as the LIBRETTO-001 study, again with the KIF5B being the most common of the fusion partners that were seen.

In the treatment-naive cohort, there was a response rate of 70% [95% CI, 50%-86%]. The response rate was 57% in the post–platinum chemotherapy cohort [95% CI, 46%-68%]. There was a median DOR in the treatment-naive cohort of about 9 months versus a duration that was not yet reached in the post–platinum chemotherapy cohort. The numbers are a bit less than with selpercatinib, though the DOR in the treatment-naive population was different. I think it leaves us to wonder—using cross-trial comparison, which we don’t love to do—the differences of these drugs.

There was CNS activity with pralsetinib as well. There were fewer patients who were enrolled with baseline CNS metastases, [with] 8 patients who [had measurable disease]. Of those, 50% of the patients had responses in the intracranial lesions, and 75% of those patients had a DOR greater than 6 months.

In terms of the AEs on the ARROW study, gastrointestinal AEs [constipation any grade, 35%] and musculoskeletal pain [any grade, 32%] were most common. We also saw hypertension [any grade, 28%; grade 3/4, 14%] and some issues with edema [any grade, 20%] and fever [any grade, 20%]. There were some issues with interstitial lung disease or pneumonitis, with about 10% any grade [and 2.7% grade 3/4], but still concerning with any of these drugs when you’re thinking about toxicities. Dose interruptions were about 60%, and dose reductions were about 36%. Then we also saw somewhat of an impact on neutrophils [any grade, 52%]. Based on the impressive data from pralsetinib, this was also approved in lung cancer with RET gene fusions.⁶

How do the LIBRETTO-001 and ARROW studies compare?

I think the numbers with selpercatinib look somewhat stronger. It is hard to completely do cross-trial comparison, but the DOR, objective response, and CNS activity were very positive. The dosing is different for each of them—selpercatinib is twice a day, pralsetinib is once a day—so [adherence] is an issue.7,8 It’s hard to take a twice-a-day medication, and that may play into the role of the patients that you’re caring for.

The QT prolongation with selpercatinib could potentially be an issue, but the issue of pneumonitis, 10% any grade…raises a concern in the current era, though, in general, I think the pneumonitis can be a concerning AE. I think that’s a really important point. We know that osimertinib, for example—when people have been previously treated with immunotherapy, there’s a much higher rate of pneumonitis. So there’s a real concern about some of these TKIs post immunotherapy and the potential toxicities. I think that may be potentially why that [AE] was seen more prominently in that arm of the trial.

In summary…both of these drugs are approved. They have slightly different toxicity profiles, though both, in general, are better tolerated than the drugs that we had been using before, with cabozantinib [Cabometyx] or vandetanib [Caprelsa] when we were trying a TKI. Clearly the response rates are beautiful and similar to some of the responses that we see in other targeted therapy populations.

_References:

_{1. Subbiah V, Cote GJ. Advances in targeting RET-dependent cancers. Cancer Discov. 2020;10(4):498-505. doi:10.1158/2159-8290.CD-19-1116}

_{2. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 2.2021. Accessed March 17, 2021. https://bit.ly/35kO18V}

_{3. Drilon A, Oxnard GR, Tan DSW, et al. Efficacy of selpercatinib in RET fusion-positive nonsmall- cell lung cancer. N Engl J Med. 2020;383(9):813-824. doi:10.1056/NEJMoa2005653}

_{4. FDA approves selpercatinib for lung and thyroid cancers with RET gene mutations or fusions. FDA. Updated May 11, 2020. Accessed March 18, 2021. https://bit.ly/3hPMahq}

_{5. Gainor JF, Curigliano G, Kim DW, et al. Registrational dataset from the phase I/II ARROW trial of pralsetinib (BLU-667) in patients (pts) with advanced RET fusion+ non-small cell lung cancer (NSCLC). J Clin Oncol. 2020;38(suppl 15):9515. doi:10.1200/JCO.2020.38.15_suppl.9515}

_{6. FDA approves pralsetinib for lung cancer with RET gene fusions. FDA. Updated September 8, 2020. Accessed March 5, 2021. https://bit.ly/3nm0C1I}

_{7. Selpercatinib. Prescribing information. Eli Lilly and Company; 2020. Accessed March 17, 2021. https://bit.ly/3s1syeq}

_{8. Gavreto. Prescribing information. Blueprint Medicines Corp; 2020. Accessed March 17, 2021. https://bit.ly/3kMI8b1}