Targeted Agents Show Promise Against Emerging Oncogenic Drivers in NSCLC

Liza C. Villaruz, MD

Data on many new treatment options have come forward over the past year highlighting the potential to treat more emerging oncogenic drivers impacting smaller subsets of patients with non—small cell lung cancer (NSCLC), such as RET, HER2, and MET.

“I have to ask a question: ‘Are these indeed emerging oncogenic drivers?’” Liza C. Villaruz, MD, said, explaining that several options have truly emerged already for patients with RET- and MET-altered NSCLC.

RET Inhibitors

In a presentation at the 16th Annual Winter Lung Cancer Conference^TM, Villaruz, an assistant professor of medicine at the University of Pittsburgh Medical Center Hillman Cancer Center, discussed treatment options in development for these oncogenic drivers.RET alterations can occur in a number of different ways, Villaruz explained; however, in NSCLC, the most predominant alterations are fusions—most commonly KIF5B fusions. RET fusions can be found in up to 2% of patients with NSCLC, most typically in younger and never or light smokers with adenocarcinoma or a poorly differentiated histology.

Recent data with potent, selective RET inhibitors have surpassed the modest activity that has historically been seen with multikinase inhibitors that also target RET, such as cabozantinib (Cabometyx), vandetanib (Caprelsa), and sunitinib (Sutent). Additionally, these agents were associated with high rates of toxicity due to off-target effects. Newer agents have shown more promising activity.

LOXO-292 is a highly selective RET inhibitor that has demonstrated activity in treating patients with RET fusions across a variety of tumor types in a phase I dose-escalation study. Among 38 patients with RET fusion—positive NSCLC treated in the study, the confirmed overall response rate (ORR) was 68% (95% CI, 50%-82%), with confirmed intracranial responses seen in all 4 patients with measurable intracranial lesions.¹

Interestingly, activity with LOXO-292 was seen independently of the RET fusion partner and prior treatment with a TKI. Activity was also seen in a patient with a V804M gatekeeper mutation, which Villaruz mentioned typically denotes resistance to RET TKIs. Common adverse events (AEs) seen with the RET inhibitor were diarrhea, fatigue, constipation, dry mouth, and nausea. LOXO-292 was granted a breakthrough therapy designation from the FDA in September 2018 for the treatment of patients with RET fusion—positive NSCLC.

In the RET fusion—positive NSCLC cohort of the phase I dose-escalation trial studying the RET inhibitor BLU-667, 50% of patients achieved a partial response to therapy and an additional 36% achieved stable disease. The median duration of treatment was 3.9 months (range, 0.4-11.4) and 68% of patients were still on treatment as of data cutoff.²

Villaruz noted that activity was also seen from treatment with BLU-667 in patients with brain metastases. Similar to LOXO-292, activity was also seen independently of the RET fusion partner and prior TKI treatment. The most common AEs observed included constipation, edema, fatigue, and headache. Grade 3 AEs were recorded in 16% of patients, and there were no observed grade 4/5 toxicities.

HER2 Inhibitors

She mentioned that activity with these 2 agents are “truly what we think about when we think about an actionable oncogenic driver.” She also mentioned that a newer potent RET inhibitor is also in development, RXDX-105, which has shown activity in a variety of preclinical models and both systemic and central nervous system responses in treatment-naïve patients in a phase I/Ib trial.Villaruz said that HER2-targeted therapy is much more complicated as HER2 can be altered in several different ways in NSCLC. HER2 overexpression by immunohistochemistry (IHC), which is found in 15% to 30% of lung cancer cases, is associated with a poor prognosis, as is HER2 amplification, which is seen in 2% to 6% of patients. However, they do not always co-occur. HER2 amplifications and mutations, on the other hand, are generally mutually exclusive, with HER2 insertion mutations at exon 20 frequently found in female never-smoker patients and is also associated with a poor prognosis.

Ado-trastuzumab emtansine (T-DM1; Kadcyla) has been investigated in patients with both HER2-overexpressing and -mutant NSCLC. In a phase II study looking at HER2 overexpression, responses were only seen in patients with a higher level (IHC 3+) of overexpression with an ORR of 20% (95% CI, 5.7%-43.7%) compared with 0% for those with lower levels of overexpression. The median duration of response (DOR) was 7.3 months (95% CI, 2.9-8.3).³

In a phase II basket trial, T-DM1 induced an ORR of 44% (95% CI, 22%-69%) in a cohort of 18 patients with HER2-mutant NSCLC. The median progression-free survival (PFS) was 4 months (95% CI, 3.0-not reached [NR]) and the median DOR was 5 months (95% CI, 3.0-NR).⁴

Villaruz noted that patients with HER2-mutant NSCLC who responded to T-DM1 did not have high levels of the HER2 protein. Only 1 patient had HER2 amplification, suggesting that “HER2 alterations, whether on the basis of mutation, amplification, or overexpression, are likely to define distinct populations with distinct responses to targeted therapies,” she said. The HER2 TKIs, including neratinib (Nerlynx), lapatinib (Tykerb), and afatinib (Gilotrif) have all shown only moderate activity in patients with HER2-altered NSCLC.

More encouraging efficacy has instead been seen with newer agents, such as with poziotinib which demonstrated promising activity in treating patients with NSCLC harboring EGFR and HER2 exon 20 mutations. Overall the confirmed ORR was 43%, yet half of the 12 patients with HER2 exon 20 mutations responded to treatment with poziotinib and had a median PFS of 5.1 months.⁵ Toxicities were somewhat significant with this agent, Villaruz said. The most common AEs observed with poziotinib included rash, diarrhea, and paronychia; grade 3/4 treatment-related AEs were seen in 56% of patients, and 60% required a dose reduction, though only 3% discontinued treatment.

TAK-788 was similarly studied in a phase I/II trial of patients with EGFR/HER2 exon 20—mutant NSCLC, and in results from the phase I dose-escalation portion of the study, responses were seen in 1 of 4 patients with a HER2 exon mutation, although the response was unconfirmed.⁶

MET Inhibitors

Common grade 3 toxicities included diarrhea and mucositis, and 50% required a dose reduction. “It truly remains to be seen whether this will be a better-tolerated drug,” Villaruz commented.Similarly to HER2, MET can be altered in a number of different ways, including high MET expression, which is found in about 35% to 72% of NSCLCs, de novo MET amplification found in 1% to 5% of patients, and specifically in about 20% of patients with acquired resistance to an EGFR TKI. Additionally, MET exon 14 mutations are very actionable and diverse and are found in approximately 23% of patients with NSCLC with a sarcomatoid histology and 1% to 4% of adenocarcinomas. Amplifications can overlap with MET exon 14 mutations, Villaruz explained, in approximately 20% of patients.

An anti-MET antibody—drug conjugate (ADC) demonstrated modest benefit in patients with MET-overexpressing NSCLC. Telisotuzumab vedotin was studied in a phase I trial in 48 patients with various solid tumors, which included a subset of 16 patients with heavily pretreated MET-positive NSCLC. The ORR in this patient population was 19%. Patients with NSCLC treated with the ADC demonstrated a median PFS of 5.7 months and DOR of 4.8 months.⁷

The most common grade ≥3 AEs observed at the recommended phase II dose included fatigue, neutropenia, and anemia. In MET-amplified NSCLC, responses are more likely to occur in patients with higher degrees of amplification, Villaruz said. In updated results from a phase I trial of crizotinib (Xalkori), a type Ia MET inhibitor, in patients with MET-amplified NSCLC, responses were mostly limited to patients with high (≥4.0) amplification levels with an ORR of 40.0% in this patient population versus 14.3% in patients with medium (>2.2-<4.0) amplification.⁸

Villaruz commented that some patients in the study had co-occurring MET exon 14 mutations and responses were seen irrespective of the co-occurring mutation.

Among patients with MET exon 14—mutant NSCLC treated with crizotinib in the phase I PROFILE 1001 trial, the ORR was 32%, with a median PFS of 7.3 months and a duration of response of 9.1 months. Responses were seen in this patient population regardless of the mutation type and presence of MET amplification.⁹

More recent encouraging data have been seen with 2 type Ib MET inhibitors, capmatinib and tepotinib. Villaruz explained that type Ib agents tend to be ATP competitive and highly MET specific with fewer off-target effects than with type Ia agents.

In a phase II trial of patients with advanced NSCLC harboring MET exon 14 skipping mutations, tepotinib showed an ORR of 58% by investigator assessment and 35% by independent review committee assessment across all lines of therapy. When viewed in treatment-naïve patients, the ORR was 54% by investigator assessment and 23% by independent assessment. The duration of response was 14.3 months.¹⁰

Tepotinib was generally well tolerated, with reports of mild to moderate edema and diarrhea related to treatment. Dose reductions were required in 22% of patients.

Capmatinib, on the other hand, showed a confirmed ORR by a blinded independent review committee of 39.1% in the pretreated cohort of the phase II GEOMETRY mono-1 trial of patients with advanced NSCLC and MET exon 14 skipping mutations. Notably, a majority of patients showed deep responses, and the agent also demonstrated preliminary evidence of activity in untreated brain metastases.¹¹ “One of the most significant things to be reported within this space recently is the response rate of capmatinib in previously untreated patients with MET exon 14 lung cancer,” Villaruz commented. In this cohort of patients, the confirmed ORR was 72% and these patients also achieved deep responses.

This agent was also generally well tolerated with the most common toxicities including peripheral edema, nausea and vomiting, and fatigue. Grade 3/4 AEs seen in 33% of patients and treatment discontinued by 10% of patients.

References

1. Oxnard G, Subbiah V, Park K, et al. Clinical activity of Loxo-292, a highly selective RET inhibitor, in patients with RET fusion+ non-small cell lung cancer. In: Proceedings from the 2018 World Lung Cancer Conference; September 24-28, 2018; Toronto, Canada. Abstract OA12.07.
2. Subbiah V, Taylor M, Lin J, et al. Highly potent and selective RET inhibitor, BLU-667, achieves proof of concept in a phase I study of advanced, RET-altered solid tumors. In: Proceedings from the 2018 AACR Annual Meeting; April 14-18, 2018; Chicago, IL. Abstract CT043.
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6. Doebele RC, Riely GJ, Spira AI, et al. First report of safety, PK, and preliminary antitumor activity of the oral EGFR/HER2 exon 20 inhibitor TAK-788 (AP32788) in non—small cell lung cancer (NSCLC). J Clin Oncol. 2018;36(suppl; abstr 9015).
7. Strickler JH, Weekes CD, Nemunaitis J, et al. First-in-human phase I, dose-escalation and -expansion study of telisotuzumab vedotin, an antibody-drug conjugate targeting c-Met, in patients with advanced solid tumors. J Clin Oncol. 2018;36(33):3298-3306. doi: 10.1200/JCO.2018.78.7697.
8. Camidge DR, Otterson GA, Clark JW, et al. Crizotinib in patients (pts) with MET-amplified non-small cell lung cancer (NSCLC): Updated safety and efficacy findings from a phase 1 trial. J Clin Oncol. 2018;36(suppl; abstr 9062).
9. Drilon A, Clark JW, Weiss J, et al. Updated antitumor activity of crizotinib in patients with MET exon 14-altered advanced non-small cell lung cancer. In: Proceedings from the IASLC 19th World Conference on Lung Cancer; September 23-26, 2018; Toronto, Canada. Abstract OA12.02.
10. Felip E, Sakai H, Patel J, et al. Phase II data for the MET inhibitor tepotinib in patients with advanced NSCLC and MET exon 14-skipping mutations. In: Proceedings from the IASLC 19th World Conference on Lung Cancer; September 23-26, 2018; Toronto, Canada. Abstract OA12.01.
11. Wolf J, Seto T, Han J, et al. Results of the GEOMETRY mono-1 phase II study for evaluation of the MET inhibitor capmatinib (INC280) in patients (pts) with MET ex14 mutated advanced non-small cell lung cancer (NSCLC). In: Proceedings from the 2018 ESMO Annual Congress; October 19-23, 2018; Munich, Germany. Abstract LBA52.

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