NTRK- and RET-Targeted Agents Reshape Solid Tumor Landscape

Understanding the oncogenic drivers behind a cancer is taking on increasing importance as more effective agents targeting specific gene aberrations continue to emerge. Two classes of precision agents that have recently had drugs come onto the market include tropomyosin receptor kinase inhibitors (TRKIs) and RET inhib-itors, which have been shown to be highly effective in treating patients with tumors harboring NTRK and RET fusions and muta-tions, respectively.

During a recent OncLive Peer Exchange®, a panel of experts discussed several TRKIs and RET inhibitors that are reshaping the treatment landscape for the patients who are candidates for these treat-ments and shared their experience using these agents in their own practices. “Biomarker-driven treat-ment is here to stay, and we’re going to be continuing to evolve our treatment and involve our patients in these therapies,” Lori Wirth, MD, said.

TRKIs FOR NRTK FUSION–POSITIVE SOLID TUMORS

“The first NRTK1 gene fusion was discov-ered as an oncogene in 1982 in colon cancer. It only took 35 years to then develop a therapy, or therapies, that are NRTK directed,” Benjamin P. Levy, MD, said.

Currently, 2 TRKIs are approved for solid tumors with NTRK gene fusions: larotrectinib (Vitrakvi) and entrectinib (Rozlytrek). With these treatments available, Levy emphasized the impor-tance of testing for these fusions (SNAPSHOT^1-4). “You need to cast that wide net in the lake. Then you can identify these fusions, and these patients can go on to genotype-directed therapy with NRTK inhibition,” he said.

Larotrectinib

On November 26, 2018, larotrectinib became the first NRTK-directed therapy to receive accelerated approval from the FDA and the second agent to receive tissue-agnostic approval for the treatment of cancer.1 Approval was based on data from the first 55 patients with unresectable or metastatic solid tumors harboring an NTRK gene fusion enrolled across 1 of 3 multicenter, open-label, single-arm clinical trials: LOXO-TRK-14001 (NCT02122913), SCOUT (NCT02637687), and NAVIGATE (NCT02576431).¹

“Patients [in these trials] were 6 months all the way to 70 years of age, [so the studies] featured a wide range of patients with differ-ent ages and tumor types. These patients were highly pretreated, with about one-third having received 3 or more lines of therapy,” Levy said.

NTRK gene fusions were identified using next-generation sequencing (NGS) or fluorescence in situ hybridization (FISH). In 3 pediatric patients with infantile fibrosarcoma, NTRK fusions were inferred based on documentation of ETV6 translocation by FISH.

The objective response rate (ORR) was 75% (95% CI, 61%-85%).¹ “The drug was active regardless of fusion type, tumor type, or age,” Levy said, noting that later studies of larotrectinib also showed meaningful responses in patients with brain metastases.

Entrectinib

On August 15, 2019, the FDA granted accelerated approval to entrectinib for adults and pediatric patients 12 years and older with solid tumors harboring an NTRK gene fusion without a known acquired resistance mutation, are metastatic, or in which surgical resection is likely to result in severe morbidity who have progressed following treatment or have no satisfactory standard therapy options.² Entrectinib also received approval as a treatment for adults with metastatic ROS1-positive non–small cell lung cancer (NSCLC).

Approval in patients with NTRK gene fusions was based on data from the first 54 patients with NTRK gene fusion enrolled across 1 of 3 multicenter, open-label, single-arm clinical trials: ALKA-372-001 (NCT02097810), STARTRK-1 (NCT02097810), and STARTRK-2 (NCT02568267).² The ORR was 57% (95% CI, 43%-71%).

“These responses are durable, and there are intracranial responses as well,” Levy said, noting that this agent was designed to cross the blood-brain barrier.

Deciding between agents

In addition to the basket studies, larotrectinib and entrectinib have been evaluated in a variety of patient subsets, including those with sarcomas, thyroid cancer, and NSCLC. “We do not have any crosstrial comparisons.…I do not know if I would necessarily think there is a specific advantage of one over the other,” Levy said, explaining that both are reasonably well tolerated.

In the sarcoma setting, Jonathan Trent, MD, PhD, said he has not “really seen any marked toxicity problems” that would preclude him from prescribing either of these medications. He said that both are very well tolerated but that his clinic uses a lot of tyrosine kinase inhibitors and has become adept at aggressively managing adverse effects (AEs). Above all, he encouraged oncologists to be on the lookout for the NTRK translocations in their patients with sarcoma, noting they can be found in up to one-third of patients with spindle cell sarcoma or undifferentiated pleomorphic sarcoma and occur with varying frequencies in other subtypes, including gastrointestinal stromal tumors (GISTs), malignant peripheral nerve sheath tumors, chondrosarcomas, and angiosarcomas.

When it comes to treating patients with thyroid cancer harboring NTRK fusions, Wirth said her go-to drug is larotrectinib because the data are more robust and have been highly favorable. She explained that results of a small study presented at the European Society for Medical Oncology Virtual Congress 2020 from Cabanillas et al showed an ORR of 90% for patients with differentiated thyroid cancer (n = 21).⁵ Based on the data, she asked the other panelists “How can you not offer it?” She noted, however, that the ORR was significantly lower in the patients with anaplastic thyroid cancer (n = 7), with an ORR of only 29%.

Wirth proceeded to describe a case report in the New England Journal of Medicine that showed promise using larotrectinib as a combination treatment.⁶ In the case report, larotrectinib enabled radioactive iodine uptake in a 64-year-old woman with a 34-year history of papillary thyroid cancer with synchronous lymph node and lung metastases. “On larotrec-tinib, the patient was converted from being iodine refractory—not taking up any radioac-tive iodine—to taking up radioactive iodine. This suggests that if we block the regulated pathways with an NRTK inhibitor in these patients with NRTK fusions, we may be able to redifferentiate those patients and treat them with a combination of drugs, like larotrectinib and radioactive iodine,” she said.

Wirth anticipates more such case reports being published in the future because clinical trials are difficult to conduct in this setting. “We would need to do a trial with numer-ous centers even to get a small number of patients,” she said.

In patients with NTRK fusion–positive lung cancer, Jyoti D. Patel, MD, said she is prescribing more larotrectinib but is also using “a lot of entrec-tinib to treat patients with ROS1 fusions.” Overall, she has found both drugs to be well tolerated but noted that patients on entrec-tinib tend to have a little more fluid retention. Another issue she brought up is resistance, which has been observed with both agents. “It may be that most patients have a good duration of response, but for patients who do develop resistance, it will be interesting in the long run to see if there are any differences in the mutational profiles of patients taking larotrec-tinib and those taking entrectinib,” she said

Trent said that thus far, he has found only 1 patient with an acquired resistance. “That seemed to be the result of a mutation in the ATP [adenosine triphosphate] binding pocket of the kinase. This is what we have seen in patients with KIT mutations and patients with GISTs who become resistant to imatinib [Gleevec]…It is going to be interesting to see whether newer generations of TRKIs can overcome this type of resistance,” he said.

Targeting RET Fusions and Mutations in Solid Tumors

The RET oncogene was first discovered in an NIH3T3 cell line in 1985.⁷ One year later, after the Chernobyl accident occurred, RET fusions were identified in children from contaminated regions who developed papillary thyroid cancer; however, RET fusions did not garner clinical interest until 2012, when they were identified as being a driver of NSCLC.^8,9

“RET is a juicy target because it is a receptor tyrosine kinase,” Wirth said. She explained that RET fusions are primarily seen in papillary and other thyroid cancers and in a subset of patients with NSCLC, but that they can occasionally be found in other cancers, including pancreatic adenocarcinomas. She also noted that other alterations may be seen, such as germline or somatic RET point mutations, but that these are only thought to be cancer drivers in the setting of medullary thyroid cancer (MTC). “Because RET is not necessarily expressed in other tissues, a point mutation is not going to have any sort of oncogenic effect if it is not expressed to begin with,” she said. In patients with MTC, however, “various RET mutations do cause various degrees of aggressiveness of the cancer,” she explained.

Several drugs with RET activity have been available for some time, including sunitinib (Sutent), vandetanib (Caprelsa), and cabozantinib (Cabometyx), but these are multikinase inhibitors that also have other targets, such as VEGFR2, EGFR, and KDR. Subsequently, the panelists noted that these drugs have a lot of off-target effects that make them more difficult to tolerate and limit the ability to dose escalate. In contrast, the newer RET inhibitors have been designed to just target RET and have been shown to elicit meaningful activity while being better tolerated. Thus far, 2 RET inhibitors have been approved by the FDA: selpercatinib (Retevmo) and pralsetinib (Gavreto) (DRUG SNAPSHOT 2^9-12).

Selpercatinib

“Selpercatinib was designed to inhibit all of the RET fusions that we see in NSCLC and other cancers. It was designed to inhibit all known RET mutations seen in MTC. Then it was also designed to head off acquired gatekeeper resistance mutations at the codon V804, which was hypothesized to account for acquired resistance,” Wirth said.

Selpercatinib was granted accelerated approval by the FDA on May 8, 2020, for 3 indications.⁹ Approval was based on data from the phase 1/2 multicenter, open-label, multicohort LIBRETTO-001 trial (NCT03157128), the results of which were published in 2 separate articles.^13,14

“The primary analysis set concerned patients with RET-mutated MTC who had previously been treated with cabozantinib, vandetanib, or both,” Wirth said. In these patients (n = 55), the ORR was 69% (95% CI, 55%-81%), and the 1-year progression-free survival (PFS) was 82% (95% CI, 69%-90%).¹³ When examining the patients with RET-mutant MTC who had not previously received vandetanib or cabozantinib (n = 88), the ORR was 73% (95% CI, 62%-82%) and the 1-year PFS was 92% (95% CI, 82%-97%). In patients with previously treated RET fusionpositive thyroid cancer, the ORR was 79% (95% CI, 54%-94%) and 1-year PFS was 64% (95% CI, 37%-82%). “These responses are all durable. In the primary analysis set, the median duration of response and median PFS were not yet reached by the time of the data maturity for the publications,” Wirth said.

In patients with RET fusion–positive NSCLC (n = 105), the ORR was 64% (95% CI, 54%-73%), with a median duration of response of 17.5 months and 63% of responses ongoing after a median follow-up of 12.1 months.¹⁴ Among the patients who did not receive previous platinum-based chemotherapy (n = 39), the ORR was 85% (95% CI, 70%-94%), with 90% of the responses ongoing at 6 months. Among the patients with measurable central nervous system metastasis at enrollment (n = 11), the percentage with an objective intracranial response was 91% (95% CI, 59%-100%).

“In terms of safety, we see primarily grade 1 and 2 AEs, and these are reversible,” Wirth said. “A small number of patients had QTc [corrected QT interval] prolongation; a couple of patients had grade 3 QTc prolongation..”

Pralsetinib

On September 4, 2020, the FDA granted accelerated approval to pralsetinib for adult patients with metastatic RET fusion–positive NSCLC as detected by an FDA-approved test, and expanded the indication on December 1, 2020.¹⁰ These approvals were based on data from the multicenter, open-label, multicohort ARROW trial (NCT03037385).

“The lung cohort was reported first with the fusions, and [similar to LIBRETTO-001], patients could come on as treatment naïve,” Patel said. In those patients, the ORR was 70% (95% CI, 50%-86%), whereas in those with prior platinum treatment, it was 61% (95% CI, 50%-71%).¹⁵ Complete responses were observed in 11% and 6% of these patient cohorts, respectively. “Remarkably, 100% of patients had some tumor shrinkage. The waterfall plot went across the board,” she said.

Similar findings were observed in the patients with RET fusion–positive MTC. “The response rate was 60% [for patients previously treated with cabozantinib and/or vandetanib], with some complete responses,” Patel said. “The median duration of response, again, was not reached. For patients who were treatment naïve, their response rate was about 82%. Again, we are seeing this broad activity.”

Patel noted that in patients with NSCLC who received pralsetinib or selpercatinib, the toxicity was higher among the patients who received some immunotherapy as part of their previous platinum treatments. “Patients who received platinum alone seemed to tolerate treatment really well. I think we are seeing how that evolves as more patients are treated,” she said.

When asked to compare agents, Levy said they look fairly similar, despite the response rates being slightly higher with selpercatinib. “It is a win to have this embarrassment of riches compared to what we had before,” he said. “I think both are extremely well tolerated and elicit meaningful responses below the neck and above the neck, intracranially.”

References

1. FDA approves larotrectinib for solid tumors with NTRK gene fusions. FDA. Updated December 14, 2018. Accessed July 10, 2021. bit.ly/3hwVnML
2. FDA approves entrectinib for NTRK solid tumors and ROS-1 NSCLC. FDA. Updated August 16, 2019. Accessed July 10, 2021. bit.ly/3xNn3mB
3. Vitrakvi. Prescribing information. Bayer HealthCare Pharmaceuticals Inc; 2021. Accessed July 14, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/210861s006lbl.pdf
4. Rozlytrek. Prescribing information. Genentech USA Inc; 2019. Accessed July 14, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212725s000lbl.pdf
5. Cabanillas ME, Drilon A, Farago AF, et al. Larotrectinib treatment of advanced TRK fusion thyroid cancer. Ann Oncol. 2020;31(suppl 4):S1086. doi:10.1016/j.annonc.2020.08.1404
6. Groussin L, Clerc J, Huillard O. Larotrectinib-enhanced radioactive iodine uptake in advanced thyroid cancer. N Engl J Med. 2020;383(17):1686-1687. doi:10.1056/NEJMc2023094
7. Takahashi M, Kawai K, Asai N. Roles of the RET proto-oncogene in cancer and development. JMA J. 2020;3(3):175-181. doi:10.31662/jmaj.2020-0021
8. Ferrara R, Auger N, Auclin E, Besse B. Clinical and translational implications of RET rearrangements in non-small cell lung cancer. J Thorac Oncol. 2018;13(1):27-45. doi:10.1016/j.jtho.2017.10.021
9. FDA approves selpercatinib for lung and thyroid cancers with RET gene mutations or fusions. FDA. Updated May 11, 2020. Accessed July 12, 2021. bit.ly/36tbUv4
10. FDA approves pralsetinib for RET-altered thyroid cancers. FDA. Updated December 1, 2020. Accessed July 12, 2021. bit.ly/3e9Lp1Q
11. Retevmo. Prescribing information. Eli Lilly and Company; 2021. Accessed July 14, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/213246s002lbl.pdf
12. Gavreto. Prescribing information. Blueprint Medicines Corporation; 2020. Accessed July 14, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/214701s000lbl.pdf
13. Wirth LJ, Sherman E, Robinson B, et al. Efficacy of selpercatinib in RET-altered thyroid cancers. N Engl J Med. 2020;383(9):825-835. doi:10.1056/NEJMoa2005651
14. 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
15. 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
16. Hu M, Subbiah V, Wirth LJ, et al. Results from the registrational phase I/II ARROW trial of pralsetinib (BLU-667) in patients (pts) with advanced RET mutation-positive medullary thyroid cancer (RET+ MTC). Ann Oncol. 2020;31(suppl 4):S1084. doi:10.1016/j.annonc.2020.08.1401