Konduri Discusses Treating Patients With RET-Mutated NSCLC

Kartik Konduri, MD

Molecular testing revealed RET-mutant non–small cell lung cancer in a 59-year-old patient. The case was a topic of discussion during a Case-Based Roundtable event led by Kartik Konduri, MD, medical director, Chest Cancer Research and Treatment Center, Baylor Charles A. Sammons Cancer Center, Medical Oncologist/Hematologist, Texas Oncology.

Targeted OncologyTM: What do the NCCN (National Comprehensive Cancer Network) guidelines recommend for treatment of NSCLC with RET rearrangements?

KONDURI: The NCCN guidelines for NSCLC [non-small cell lung cancer] with RET rearrangements [divide patients into 2 groups].¹ When the RET rearrangement is discovered prior to first-line therapy, NCCN recommends using selpercatinib [Retevmo] or pralsetinib [Gavreto]. If the RET rearrangement is discovered after or during first line systemic therapy, the recommendation is to complete the planned systemic therapy, including the maintenance therapy, or interrupt it followed by selpercatinib or pralsetinib. In other words, the preferred medicines are selpercatinib and pralsetinib followed by chemotherapy after progression.

What data support the use of selpercatinib?

The data supporting the use of selpercatinib come from the phase 1/2 LIBRETTO-001 trial [NCT03157128].² This was a large multi-center trial and it enrolled about 700 patients. A subgroup, consisting of 322 patients, had RET fusion-positive metastatic NSCLC. After screening, 39 treatment-naïve patients and 105 who received previous treatment with platinum chemotherapy were enrolled in the study. To be enrolled, patients needed to have good functioning start cells and a normal QT interval (corrected for heart rate ≤470 msec). They were also evaluated based on how many prior treatments they had received and the type of RET alteration they had. The primary end point was the ORR [objective response rate], and the secondary end points were DOR [duration of response], [PFS (progression-free survival), and drug safety]. In this trial, a good functional status [ECOG performance status score of 0 or 1] was a requirement, but there were a couple of patients [with an ECOG PS score of 2].³

Most patients had adenocarcinomas, followed by large-cell neuroendocrine carcinomas/squamous cell carcinomas, and some had not otherwise specified histology.3 For patients who received previous platinum therapy, the median number of previous regimens were 3.3 One important issue to note is that for patients who had received previous therapies, 55% received anti-PD–1 or anti-PD–L1 therapy, 36% had brain metastasis compared to 18% in the treatment naïve group, and there was more variety in terms of the RET fusion partners [KIF5B, CCDC6, NCOA4, etc] in this group than in the treatment-naive group.³

review committee, was 64% for patients with previous platinum chemotherapy [95% CI, 54-73] and 85% for the treatment naïve group [95% CI, 70-94], and the median time to response was 1.8 months.3 The DOR in the previously treated group was approximately 17.5 months [95% CI, 12.0 to NE] according to the independent review committee, and it was not reached [NE] for the treatment-naïve group. Responses were observed regardless of previous treatment with anti–PD-1 or anti–PD-L1 or with multi-target kinase inhibitors. Similarly, patients had a response despite the type of RET fusion they carried. The waterfall plots clearly suggest a significant improvement for patients who had targeted lesions. A couple of patients who were previously treated with multi-targeted kinase therapies showed a CR [complete response]. [Among the 105 patients who received prior platinum therapy, 11 had measurable CNS metastases at baseline.] The objective intracranial response rate was 91% [10 of 11] with CRs in 3 patients. The depth of the responses in the brain was significant as well.

The population of patients with measurable CNS [central nervous system] disease, 22 patients, had various RET fusion partners such as KIF5B, CCDC6, CLIP1, ERC, and others.4 About 20% of these patients had prior therapies, with 8% having received prior brain radiotherapy, which was mostly completed 2 months prior to treatment with selpercatinib. The CNS overall ORR for this group was 81.8% [95% CI, 59.7%-94.8%]. For patients without prior CNS radiation the ORR was 85.7% [95% CI, 57.2%-98.2%] and for those who had prior CNS radiation the ORR was 75% [95% CI, 34.9%-96.8%], showing that [selpercatinib] has pretty good efficacy. The overall CNS DOR was 9.4 months with 9.5- and 15.7-month median follow-up for the whole group and those [without prior CNS radiation, respectively].

The independent committee found that the median PFS, a secondary end point, was 16.5 months [95% CI, 13.7-NE] in the previously treated group and was not reached in the treatment-naive group.³ The 1-year PFS was 66% for the previously treated group, and 75% for the treatment-naïve group. It’s nice to see this.

As is the case for all similar drugs, there were some reported AEs [adverse events].^3,5 [The most common lower-grade AEs were] diarrhea and dry mouth. Hypertension and elevations in liver enzymes [AST (aspartate aminotransferase) and ALT (alanine aminotransferase)] were the most common grade 3 and 4 AEs. Some patients [5%] had to permanently discontinue treatment due to an AE, 42% had dose interruptions, and 31% had to have dose reductions. Other common grade 3 AEs were rash, abdominal pain, and dyspnea. [Another important AE to note is a] prolonged QT on electrocardiography, which is something that we are asked to look for. [Remember that] a normal QT interval [≤417 msec] is required before starting treatment.

Based on these results, the FDA approved selpercatinib for lung and thyroid cancers with RET gene [mutations or] fusions.⁶

What data support the use of pralsetinib?

The efficacy of pralsetinib for advanced RET fusion–positive NSCLC comes from the phase 1/2 ARROW trial [NCT03037385].7 Eligible patients had locally advanced or metastatic solid tumors and documented RET fusion or mutation based upon local testing. The primary end points were ORR, just like in the last trial, and safety, and the secondary end points were DOR, clinical benefit rate, and disease control rate. For this trial, the median age was 60 years, most patients had metastatic disease and 43% of patients with prior treatment and 37% of treatment naïve patients had CNS metastasis.8 The median number of prior therapies was 2, and some patients had been treated with anti–PD-1, anti–PD-L1, and kinase inhibitors. KIF5B was the most common RET fusion partner and was present in 75% of cases [with prior therapy and in 70% of the treatment-naive group].

The ORR was 70% in treatment-naive patients [95% CI, 50%-86%] and 57% in the previously treated group [95% CI, 46%-68%].⁸ The median DOR was 9 months [95% CI, 6.3-NE] in the treatment-naive group with 58% having a DOR of more than 6 months. The waterfall plot [shows that 96% of evaluable patients and 100% of treatment-naive patients had tumor reductions, and the overall CR rate was 6% for evaluable patients and 12% for treatment-naive patients].⁷ [This includes patients who had] previously been treated with anti–PD-L1 and anti–PD-1 drugs. There was a concern that we would see a toxicity signal in these patients based on previous experiences with other drugs. But that was not the case in this study.

Among the 87 patients with RET fusion–positive NSCLC, 8 had CNS metastases at baseline and 0 had received radiation to the brain within 2 months prior to therapy.⁸ [The response rate in intracranial lesions was] 50% [4 of 8], 2 patients had a CR, and 75% of responders had a DOR lasting more than 6 months. So, in general the AEs are similar, fatigue, edema, diarrhea, and dry mouth. There is one thing to note, any grade ILD [interstitial lung disease]/pneumonitis was present in 10% of patients, of which 0.5% were fatal and 2.7% were grade 3/4. One-third [36%] of patients had dose reductions and two-thirds [60%] had dose interruptions. In terms of lab abnormalities, there were increased liver enzymes and 52% of patients had decreased neutrophils, with 10% being grade 3/4. Based on these findings, the FDA approved trials for lung cancers with RET gene fusions.⁹

From your perspective, what are the similarities and differences between selpercatinib and pralsetinib in terms of efficacy, safety, and convenience?

[In terms of warnings and] precautions for these drugs, there is the QT interval prolongation for selpercatinib and ILD/pneumonitis for pralsetinib. There is also a small risk of tumor lysis syndrome in patients who have been given pralsetinib, which is something to be aware of, and of course toxicity is always an issue. Additionally, the dosage and administration for selpercatinib is dependent on the weight of the patient.3,5,7,8

If the patient has a cardiac arrythmia issue or other concerns, then I might veer away from one drug and go to the other drug and vice versa.

_REFERENCES:

1. _{NCCN. Clinical Practice Guidelines in Oncology. Non–small cell lung cancer, version 4.2021. Accessed May 19, 2021. https://bit.ly/35kO18V}
2. _{Goto K, Oxnard GR, Tan, DS, et al. Selpercatinib (LOXO-292) in patients with RET fusion-positive non–small cell lung cancer. J Clin Oncol. 2020; 38(suppl 15):3584. doi:10.1200/JCO.2020.38.15_suppl.3584}
3. _{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}
4. _{Subbiah V, Hu MIN, Gainor JF, et al. Clinical activity of the RET inhibitor pralsetinib (BLU-667) in patients with RET fusion-positive solid tumors. J Clin Oncol. 2020;38(suppl 15):109. doi:10.1200/JCO.2020.38.15_suppl.109}
5. _{Retevmo. Prescribing information. Eli Lilly and Company; 2021. Accessed May 20, 2021. https://bit.ly/3umZhLk}
6. _{FDA approves selpercatinib for lung and thyroid cancers with RET gene mutations or fusions. News release. FDA. Updated May 11, 2020. Accessed May 20, 2021. https://bit.ly/3hPMahq}
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 May 20, 2021. https://bit.ly/3kMI8b1}
9. _{FDA approves pralsetinib for lung cancer with RET gene fusions. News release. Updated September 8, 2020. Accessed May 20, 2021. https:// bit.ly/3nm0C1I}