Patient With RET-Mutated Lung Cancer Is Eligible for Therapy With Selpercatinib or Pralsetinib

Luis Raez, MD

Luis Raez, MD, Hematology & Oncology medical director and chief scientific officer, Memorial Cancer Institute, Memorial Healthcare System, discussed the case of a 59-year-old patient with RET-mutated lung cancer.

Targeted OncologyTM: What would the preferred agents be for the treatment of this patient in the frontline setting?

RAEZ: The NCCN [National Comprehensive Cancer Network] guidelines include both [selective RET inhibitor] agents [selpercatinib (Retevmo) and pralsetinib (Gavreto)] that are approved now as a frontline therapy,1 and so that’s why, when we have a RET genetic alteration, it doesn’t make too much sense to use cabozantinib [Cabometyx] or vandetanib [Caprelsa] anymore, because they are not really targeted. We know that they work, but they are not as targeted agents as we would like [them] to be.

What data support the use of these 2 selective RET inhibitors, starting with selpercatinib?

I want to present data from the LIBRETTO-001 trial NCT03157128],² the lung cancer section. This study was big, so we still are accruing for GI [gastrointestinal] malignancies and other solid tumors. I will present what is approved, but I have a lot of hope that maybe in the other tumors we can have something. I have a patient with metastatic colon cancer, who [has been] more than 1 year on selpercatinib and doing very well. But I don’t [treat] colon cancer. My GI colleagues say that it’s very rare to have responses in colon cancer, but who knows, we will see when we have the data.

From the lung cancer cohort, we have 2 cohorts: the treatment naive, and [those who have] had at least platinum-based therapy one time. In this study, we accrue patients with RET fusions or mutations [who are] in good shape. There’s very few patients [with a] performance status of 2, I think less than 5. A lot of these TKIs [tyrosine kinase inhibitors] give QT prolongations, so QT was a pain in the neck, because we had to, in the study, be doing ECGs every visit, and sometimes 2 or 3 times in the same visit, to be sure that we are not seeing QT prolongation.

The baseline characteristics—like in any other lung cancer study, despite the fact that the median age [of patients with] lung cancer is 72, we always accrue younger people, so we are always a little bit biased. It’s not a surprise for the lung cancer studies’ [median age to be in the 60s]. Most of the patients had adenocarcinoma. The interesting thing is, the [study allows for] brain metastases. So, that was great, because in most of the studies, we don’t allow brain metastases, so we don’t know if it will work. But lately, a lot of these studies with genetic aberrations are allowing brain metastases that are controlled. We can find that there is CNS activity. The type of fusions— KIF5B is the most common one, but there are other variants and other fusions. One hundred five [patients were in] the platinum-based therapy [previously treated group], and 39 in the untreated group.

The objective response rate [ORR] in the platinum group [by independent assessment was 64% (95% CI, 54%-73%)], and by investigator assessment, [the ORR was 70% (95% CI, 60%-78%)]. The ORR [in the untreated group by independent review was 85% (95% CI, 70%-94%) and 90% (95% CI, 76%-97%) by investigator assessment]. Looks like, maybe, untreated patients have a higher response, but we’re not comparing these groups, so it’s hard to make a conclusion.

The other important thing is stable disease, [found here in 29% of previously treated patients and in 10% of untreated patients by independent review]—I think our rules for response rates on chemotherapy are rules for the old times. We only cared when they shrink tumors, but with a lot of TKIs now in cancer, you don’t have to shrink tumors, what matters is the survival. Sometimes, even if you achieve stable disease, you can survive [for a long time]. That’s why stable disease is very important. [Here], if you add the ORRs plus the stable disease, that [clinical] benefit [covers] pretty much everybody. There are few patients who progressed, between 2% and 4% progress and don’t get any benefit from this agent. The other important thing I want to mention several times is that [109 of] these patients were treated with chemotherapy, but some of them were also treated with checkpoint inhibitors, and these patients still respond.

There are several patients that have had anti–PD-1/ anti–PD-L1 treatment before, and patients that didn’t have immunotherapy before, and patients that have the multitarget kinase inhibitors—[these are] very impressive responses because it looks like pretty much everybody has responded.

How did the patients with brain metastases, like this patient, fare on selpercatinib in the trial?

[Among the patients with] CNS metastases, regardless if [they had] prior anti–PD-1 therapy, anti–PD-L1 therapy, or multikinase inhibitor, these patients are having responses in the brain.3 Some of them can be impressive, 100%. [The CNS response rate in the cohort of 22 patients with baseline CNS metastases was] 81.8%. Most of them are partial responses, but then we add the stable disease in as another 18.2% of the patients, so pretty much all of them benefit in the brain. So [it is] very impressive that pretty much everybody benefits in the brain.

That’s why, nowadays, [RET] is another genetic aberration in which, if we have a new patient like [this] one with a minimum number of CNS lesions, and if they are not life-threatening, I think we can easily start [the patient on] one of these RET inhibitors, and wait 6 weeks, 8 weeks, and see the brain responses without a need to put them on stereotactic radiation therapy.

Stereotactic radiation therapy is mild, there are no adverse effects [AEs]. But now the patients are living a long time. You don’t see AEs in stereotactic radiation therapy in the brain when the patient survives 2 years. But, for example, our ALK patients have a median survival now of 7 years. So, I have patients that are ALK-positive and alive 9 years, and I have done 5 or 6 stereotactics, and now [they] have brain necrosis. I have several patients with brain necrosis, and it’s a concern with stereotactic radiation that, hopefully, can be avoided now that we have so many TKIs…or it can be delayed so we can do the stereotactic radiation therapy later.

Progression-free survival [PFS] was impressive; with this TKI it’s 16.5 to 18.4 months [in the previously treated patients], and it has not [yet] been reached in the untreated patients. We don’t know what the final number will be, but it’s [expected to be] a very impressive number. The 1-year PFS rate is also very good, from 66% to 75%, so good numbers.³

What are the toxicities of concern with selpercatinib?

In general, these agents are well tolerated, in my opinion. I see my patients, even in the study, only once a month, and I have rarely seen anybody in between visits because they have an emergency complication or AE. Dry mouth is very common [in 41%], everybody has dry mouth. Hypertension [in 31% requires] close attention because not a lot of drugs cause hypertension. We use bevacizumab [Avastin] and also ramucirumab [Cyramza], and these are the type of agents [where] we keep asking the patients, do you check your blood pressure? But now, with this agent too, we have to do that, so that’s why we always ask the patient to please check their blood pressure. [The rate of] grade 3 hypertension is 14%. Basically, we manage these by giving a blood pressure agent, amlodipine or something tough, and we don’t have to have issues. There is also increase of liver function tests. But the rest [are the same] types of AEs you get with any other TKI—diarrhea, constipation, peripheral edema. Remember, it’s dry mouth and hypertension [that are], in my opinion, the [important] ones for this drug.

The FDA approved selpercatinib, and the approval was for lung and thyroid cancers [with RET gene fusions or mutations].⁴ The approval for pralsetinib was first for lung cancer [with RET gene fusions], and recently for thyroid cancer.^5,6

How do the data compare in the pralsetinib trial?

The design from the ARROW trial [NCT03037385] for pralsetinib [was pretty] similar; basically, it was patients with RET fusion–positive, non–small cell lung cancers, more than 18 years old, with metastatic disease.⁷ The whole [point] of this study is that we didn’t need the central review, because sometimes when we do these studies, they want us to send for central review, and it takes forever to enroll patients. So, that was good, as long as we used a CLIA [Clinical Laboratory Improvement Amendments]– certified lab. The dose for this agent is 400 mg once a day. The main end point in the study was the ORR.

[In the lung cancer groups], there was a prior platinum treated and a treatment-naive cohort. There are 87 patients in the prior platinum [treated group], and 27 in the treatment-naïve group. The population is similar to the LIBRETTO-001 study because the median age is 60 to 65; there are [about 50%] females, most of the patients are White. Patients were in good shape, despite the fact that they allowed enrolling [patients with a] performance status of 2. They, again, allowed people with CNS metastases. That was great so we can see the activity of the agent. They also allowed people that had anti–PD-L1 before [and/or] a multikinase inhibitor before, so we can see the responses in [these groups].

In the treatment-naive group, the ORR was 70%, and the median [duration of response] was 9 months, and there is still a good number of patients, 58%, that had a duration of response of more than 6 months. In the platinum [pretreated] side, their ORR was 57%, and they have not yet achieved the median duration of response. Eighty percent of the patients have a duration of response of more than 6 months.

[All of the patients are] responding, pretty much, including patients that have had prior PD-1/PD-L1 checkpoint inhibitors, patients that are treatment-naive, patients that had platinum before, [and patients that] had other treatments other than platinum.

From the 87 patients, 8 had CNS metastases at baseline, and there were 4 responses, 50% response [rate], and 75% of the responders, 3 patients, had a duration of more than 6 months.8

What is the toxicity profile like for pralsetinib in comparison with that of selpercatinib?

The toxicity profile seems to be similar. The hypertension [rate was 28%]. The interesting thing is the pneumonitis— there is 10% of any grade, and this is something that the other drug doesn’t have, or it’s not reported. So that is why, maybe, this can be a factor that you can use to decide for this drug or [the other].

Then, there was decrease of the neutrophils [in 52%], cytopenias, and maybe that can be a difference in these 2 agents. We have all of the [same] laboratory abnormalities with selpercatinib too, especially liver function test alterations, so that’s why I don’t think that makes a lot of difference. Remember, with both of these agents, grade 3 and 4 events are not very common, so these agents are well tolerated in general.

What are your thoughts on the differences between the 2 agents? How do you choose between the 2?

The response rate, apparently, in the CNS seems to be higher in selpercatinib than pralsetinib.

[But these] are 2 different studies, so we can’t compare numbers from 2 different studies and say, “Oh, this drug is better than the other one.” Certainly, we would love to see more data, and more patients in the pralsetinib ARROW study. I guess, with time, we will have more data to see if they are really equivalent or not. I don’t think, in my personal opinion, we are going to base [the decision] on CNS data only presented in 2 different studies like this. [I don’t think it’s] enough information to make a decision which one is better, which one we might prefer.

_References:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 2.2021. Accessed April 8, 2021. https://bit.ly/35kO18V}

_{2. Drilon A, Oxnard GR, Tan DSW, et al. Efficacy of selpercatinib in RET fusion-positive non-small-cell lung cancer. N Engl J Med. 2020;383(9):813-824. doi:10.1056/ NEJMoa2005653}

_{3. Subbiah V, Hu MIN, Gainor JF, et al. Clinical activity of the RET inhibitor pralsetinib (BLU-667) in patients with RET fusion+ solid tumors. J Clin Oncol. 2020;38(suppl 15):109. doi:10.1200/JCO.2020.38.15_suppl.109}

_{4. FDA approves selpercatinib for lung and thyroid cancers with RET gene mutations or fusions. FDA. Updated May 11, 2020. Accessed April 8, 2021. https:// bit.ly/3hPMahq}

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

_{6. FDA approves pralsetinib for RET-altered thyroid cancers. FDA. December 1, 2020. Accessed April 8, 2021. https://bit.ly/2VqIqsi}

_{7. 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}

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