Hanna Discusses Efficacy Results of Different Treatments in RET-Positive Lung Cancer

Nasser H. Hanna, MD

Tom and Julie Wood Family Foundation Professor of Lung Cancer Clinical Research

Professor of Medicine

Indiana University School of Medicine

Targeted Oncology^TM: What do the National Comprehensive Cancer Network (NCCN) guidelines say, and what drives your selection of a RET inhibitor in the front line?

HANNA: You want to use selpercatinib [Retevmo] or pralsetinib [Gavreto] as first-line therapy if you know the patient has a RET fusion.¹ The question is: What if you started them on treatment and then found out they had a RET fusion? The NCCN says you should complete [the treatment you’re] already doing, including giving a maintenance therapy, if you see they are benefitting from the treatment. I have a low threshold to quit on it, but if somebody is responding and tolerating well, it’s not unreasonable to continue to treat them with the drugs that are tolerable and working. However, you should quickly follow that with either selpercatinib or pralsetinib at the earliest sign that you need to do something differently.

The ARROW trial [NCT03037385] with pralsetinib had a phase 1 that went into a phase 2 dose expansion looking at response rates and safety.² This trial had 2 cohorts; those who had received platinum therapy and those who were treatment naïve. With pralsetinib, [up to] 40% had central nervous system [CNS] metastases—either current or a prior history of—and you can see the KIF5B is the most common fusion partner.^2,3

The overall response rate [ORR] in the treatment-naïve group was 70%, and in the previously treated group with platinum, it was 57%. A little lower activity for pralsetinib in the previously treated group. With pralsetinib and some combined data sets, there was a 62% response rate with prior treatment and a 79% response rate in the treatment-naïve group, and the studies underwent a revision for the treatment-naive group.

Originally, you could not be eligible for chemotherapy, then they revised it and said [that], yes, even those who are eligible for chemotherapy can go on it. When they looked at the treatment-naïve group and that expanded cohort of patients who were more fit and chemo-appropriate, the response rate went up to 88%. There was a small subset of patients with brain metastases, and of these patients, 4 of the 8 with brain metastases had a response in the brain, usually durable.

There are a couple of adverse events [AEs] I want to point out: No. 1 being hypertension [and the second being] pneumonitis. You [must] pay attention to pneumonitis because 10% of patients do get pneumonitis, although it’s usually grade 1 or 2.³ Pneumonitis is associated with pralsetinib. It’s not associated with selpercatinib, but hypertension is also a class feature.^3,4 Transaminase elevations also occur, although they’re usually grade 1, and you can get a little bit of hematologic toxicity that is usually grade 1.³ You can get a little bit of lymphopenia, but [it’s] usually not clinically significant. Pralsetinib was also recently FDA approved if the patient had a RET gene fusion in their lung cancer.⁵

The LIBRETTO-001 trial [NCT03157128] data with selpercatinib [were] in [patients with] RET fusion–positive non–small cell lung cancer [NSCLC], both treatment-naïve and previously treated cohorts.^6,7 It had a phase 1 study, which led into a phase 2 dose escalation study. The important take-home messages [are] that [approximately] 70% [of these patients were] never smokers and almost all of them have adenocarcinoma. In the previously treated group, 36% had CNS metastases, and the most common fusion partners were KIF5B, once again.

Were the patients in the ARROW and LIBRETTO trials treated with radiation, or were they just started on the RET inhibitors?

Some of them were not treated. Some of them were allowed to go to the tyrosine kinase inhibitor [TKI] without treatment, [as long as they were asymptomatic].^6,7 I typically extrapolate from the data we know with EGFR and ALK, where we have huge robust data sets, and those studies show that you should consider doing gamma knife or stereotactic radiation to the brain metastases.

Of course, it can be limited to the number, size, and location, plus giving the TKI. But doing just the TKI is not as good for long-term CNS control, and you should largely avoid whole-brain radiation unless you absolutely can’t avoid it. Most of these studies do not show that you improve outcomes by giving these patients whole-brain radiation. I do quite a bit of stereotactic radiosurgery, as well as giving the TKIs. If they’re very small brain metastases, I just give the TKI and observe, but if they’re a bit larger brain metastases, I tend to use Gamma Knife for the more symptomatic larger ones. Now in the treatment-naïve group of the LIBRETTO trial, the response rate is 85% and the disease control rate overall is 94%.^6,7

The evaluation of the patients with CNS metastases had a sample size of 22 patients, so more than the 8 patients with pralsetinib. You can also see 8 of those patients had brain radiation, [whereas] the other 14 did not. The objective response rate in the brain was 82%, so again, higher than pralsetinib, but I wouldn’t read too much into that. Pretty much every patient got an objective response in the brain, and those patients did have some prior therapy.

[In terms of adverse reactions,] hypertension is a class effect, as is elevation of liver enzymes [and] transaminitis, so that is a class effect.^4,7 You do get a little bit of peripheral edema with selpercatinib, as well. You get that with other drugs; the MET inhibitors are notorious for peripheral edema. There [were] very few grade 3 or 4 adverse reactions [with selpercatinib]. There can be pyrexia, a little bit of QTc prolongation, and a little bit of rash.⁸ [Earlier in 2020], the FDA approved this treatment for patients with RET-mutated or -fused disease and for [patients with] lung and thyroid cancers, as well.⁹

As a summary, pralsetinib is [administered] once per day, and selpercatinib is [administered] twice per day ^3,4 Pneumonitis is a risk with pralsetinib, but you see hypertension in both [as well as] some transaminitis in both. The response rates were 80% to 85% in the untreated group, and [approximately] 60% in the previously treated group, with high CNS response rates.

What do the NCCN guidelines say, and what are the data for therapy in patients who have an ALK fusion in the frontline setting?

According to the NCCN guidelines, if you know the patient has an ALK fusion, they prefer alectinib [Alecensa], brigatinib [Alunbrig], or lorlatinib [Lorbrena].¹ If you are already treating them and then discover they have an ALK fusion, [then it’s the] same story as RET. [So it is] reasonable to continue what you’re already doing, including maintenance—perhaps maybe pemetrexed [Alimta]—but [if there are] any signs of toxicity or of treatment failure, [there should be a quick switch] to any one of those drugs.

[There are various] ALK inhibitors, such as crizotinib [Xalkori], ceritinib [Zykadia], alectinib, brigatinib, and lorlatinib. The latter 3 are preferred first-line drugs.¹ Both crizotinib and ceritinib have been compared head-to-head [with] platinum/pemetrexed, and both had substantially better response rates and PFS [progression-free survival].^10,11

The ALK inhibitors are superior to chemotherapy both in the first-line setting and second-line setting. Brigatinib and lorlatinib are taken once daily, [whereas] alectinib is taken twice daily. They’ve all been compared head-to-head [with] crizotinib.^12-19 All [these treatments] had higher response rates and substantially better PFS, and most importantly, incredibly high response rates in the CNS, which was much higher than what we see with crizotinib.

The ALEX trial [NCT02075840] was a head-to-head comparison of alectinib [with] crizotinib.¹⁵ The PFS favored alectinib [HR, 0.43; 95% CI, 0.32-0.58]. The CNS PFS in those patients with and without brain metastases were evaluated, and there was much better PFS at 1 year, 2 years, 3 years, and 4 years compared [with] crizotinib. In fact, crizotinib failed to maintain progression-free time in almost all patients who had brain metastases past 1 year. The overall survival [OS] showed the superiority of [long-term] alectinib [65% with alectinib vs 45.5% with crizotinib (HR, 0.67; 95% CI, 0.46-0.98; P = .038)]. Interestingly, the active smokers crossed 1.00, but it was only a sample size of 17. Otherwise, pretty much everything else favored alectinib.

Are there other trials of note for this treatment?

The ALTA-1L trial [NCT02737501] studied brigatinib vs crizotinib.¹⁸ It’s important to know that crossover was allowed and that’s going to obscure OS, but it’s also important to know because of the [potential for] pneumonitis. Brigatinib should never be started at 180 mg/day, but [it] should be started at 90 mg/day for a week before it’s escalated to 180 mg. The incidence of pneumonitis goes down substantially when you do it in that dose-escalation fashion.

The investigator and independently reviewed PFS both favored brigatinib over crizotinib, as did the subgroup analyses.¹⁸ The brain metastases PFS [had a] much better control of not developing brain metastases at all, or controlling them, if you have brain metastases at baseline. The ORR was 74%, [with a range of 66% to 81%], for brigatinib [OR, 1.73; 95% CI, 1.04-2.88; P = .034]. Two-year probability of maintaining the response was 50%, and about half the patients maintained their response there, even at the 4-year mark there was almost a flattening of the curve at around 2 years. The intracranial control, again, favored brigatinib. Remember there was crossover allowed, so you lose the OS advantage when patients are allowed to crossover and get brigatinib after they have already been on crizotinib.

The CROWN trial [NCT03052608] studied lorlatinib against crizotinib.¹⁹ No crossover was allowed, so when you look at survival, remember that. There was an impressive difference in PFS, with the largest difference compared [with] any of the other trials. Hazard ratio was 0.28, so the magnitude was greatest, and the PFS was favored in the lorlatinib arm in pretty much every subgroup [95% CI, 0.19-0.41; P < .001]. There were very high response rates in the group of patients receiving lorlatinib. The ORR was 76% [OR, 2.25; 95% CI, 1.35-3.89]. The median duration of response was not reached. Only 7% had progression as their best response.

The response rate in patients with brain metastases at baseline showed lorlatinib had a much higher CNS response and duration of response compared [with] those receiving crizotinib, 66% confirmed response vs 20% [OR, 8.41; 95% CI, 2.59-27.23], but that’s if you combine measurable and nonmeasurable. Now if you just look at measurable brain metastases, there were 82% confirmed responses and 71% complete responses. With the OS, no crossover was allowed, so you do see the separation of the curves, nonstatistically significant at [the time of publication (HR, 0.72; 95% CI, 0.41-1.25)].

_REFERENCES

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_{2. Gainor JF, Curigliano G, Kim DW, et al. Pralsetinib for RET fusion-positive non-small-cell lung cancer (ARROW): a multi-cohort, open-label, phase 1/2 study. Lancet Oncol. 2021;22(7):959-969. doi:10.1016/S1470-2045(21)00247-3}

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_{4. Retevmo. Prescribing information. Eli Lilly and Company; 2021. Accessed January 16, 2022. https://uspl.lilly.com/retevmo/retevmo.html#pi}

_{5. FDA approves pralsetinib for lung cancer with RET gene fusions. News release. FDA; Updated September 8, 2020. Accessed January 16, 2022. https://bit.ly/3nm0C1I}

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_{8. 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}

_{9. FDA approves selpercatinib for lung and thyroid cancers with RET gene mutations or fusions. News release. FDA; Updated May 11, 2020. Accessed January 17, 2022. https://bit.ly/3hPMahq}

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_{13. Camidge DR, Dziadziuszko R, Peters S, et al. Updated efficacy and safety data and impact of the EML4-ALK fusion variant on the efficacy of alectinib in untreated ALK-positive advanced non-small cell lung cancer in the global phase III ALEX study. J Thorac Oncol. 2019;14(7):1233-1243. doi:10.1016/j.jtho.2019.03.007}

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_{15. Mok T, Camidge DR, Gadgeel SM, et al. Updated overall survival and final progression-free survival data for patients with treatment-naive advanced ALK-positive non-small-cell lung cancer in the ALEX study. Ann Oncol. 2020;31(8):1056-1064. doi:10.1016/j.annonc.2020.04.478}

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_{19. Shaw AT, Bauer TM, de Marinis F, et al. First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer. N Engl J Med. 2020;383(21):2018-2029. doi:10.1056/NEJMoa2027187}