New Agents Emerge for Elusive NSCLC Targets

Christine M. Lovly, MD, PhD

Although immunotherapy has become an important modality for treating non—small cell lung cancer (NSCLC), the development of new strategies for targeting oncogenic drivers of disease in subgroups of patients is moving forward at a brisk pace.

The 2019 American Society of Clinical Oncology Annual Meeting (ASCO 2019) featured early findings for several promising novel therapies aimed at challenging less common targets in slices of the lung cancer mutation pie.

These emerging therapies and the aberrations they target include AMG 510, KRAS G12C mutations; BLU-667, RET fusions; capmatinib and tepotinib, MET exon 14 skipping mutations (METex14); and TAK-788, EGFR exon 20 insertion mutations.

The latest findings underscore the focus on expanding targeted therapy options in NSCLC, which have been moving forward since the early 2000s.¹ Those efforts led to the development of 3 generations of FDA-approved tyrosine kinase inhibitors (TKIs) in NSCLC for both EGFR mutations and ALK rearrangements as well as targeted agents for other molecular aberrations.

Nevertheless, there are no effective targeted therapies for more than half of patients with NSCLC whose tumors harbor a molecular driver, and the emergence of resistance mutations poses another challenge for the field.¹

The research presented at ASCO 2019 offers potential for treating patients with particularly problematic alterations, Christine M. Lovly, MD, PhD, said in discussing novel targeted therapies during the conference.²

“I think what ASCO has brought us is hope for some of these elusive targets,” said Lovly, a professor of medicine at Vanderbilt University Medical Center in Nashville, Tennessee. “They are complex targets. I think that is the takehome message here. These are targets that are not necessarily easy to design drugs against.”

Fred R. Hirsch, MD, PhD, whose research has helped identify and validate predictive markers for personalized lung cancer therapies, is heartened by the pace of new developments, particularly those involving patients with KRAS mutations, which have been difficult to target.

The field “is progressing quite rapidly,” Hirsch said in an interview with OncologyLive^®. “New targets are being developed. We’ve learned more about resistance mechanisms to targeted therapies, and, with that, new drugs are being developed that target resistance mechanisms. We are starting to see several generations of effective targeted therapies against specific abnormalities.

“We will learn more about resistance mechanisms, which gives us the opportunity to develop better sequential therapy for a particular subgroup of patients,” added Hirsch, executive director of the Center for Thoracic Oncology at The Tisch Cancer Institute at Mount Sinai in New York, New York.

Hirsch, who formerly served as chief executive officer of the International Association for the Study of Lung Cancer (IASLC), noted that the optimal sequencing of targeted therapies and immunotherapies remains unresolved.

As of now, the standard of care for frontline therapy in patients with advanced or metastatic NSCLC harboring an actionable molecular aberration is targeted therapy. The National Comprehensive Cancer Network recommends that patients be tested for aberrations in EGFR, ALK, ROS1, and BRAF V600E.³ MET and NTRK abnormalities also are relevant, Hirsch noted.

Looking forward, Hirsch identified several research priorities, including expanding knowledge about co-mutations. “We know that, for certain molecular drivers, there are effective therapies but not for everyone even with [that] molecular driver,” he said. “We are starting to learn about co-occurrence of other molecular abnormalities, cointeraction with other molecular pathways, and, in the future, we need to take that into account.”

In her presentation, Lovly said the findings for hard-to-target mutations highlight the need for molecular testing in NSCLC, regardless of the patient’s smoking history. “None of these advances will transmit unless every patient is tested,” Lovly said. “We need to expand the reach of precision medicine by increased utilization of biomarker testing. It’s great to have the test, but if we are not acting on those tests appropriately in clinic, that is a problem, as well.”

Click on the following for OncLive’s in-depth reporting on novel NSCLC targeted therapies presented at ASCO 2019 (Figure, Table).^4-8

AMG 510 Active in KRAS+ NSCLC

New Therapies Intriguing for Elusive Targets in NSCLC

New Targeted Therapies Show Promise for METex14-Altered NSCLC

References

1. Yoda S, Dagogo-Jack I, Hata AN. Targeting oncogenic drivers in lung cancer: recent progress, current challenges and future opportunities. Pharmacol Ther. 2019;193:20-30. doi: 10.1016/j. pharmthera.2018.08.007.
2. Lovly CM. Emerging therapies for new targets. Presented at: 2019 ASCO Annual Meeting; May 31-June 4, 2019; Chicago, IL. meetinglibrary. asco.org/record/174864/video.
3. NCCN clinical practice guidelines in oncology: non—small cell lung cancer version 5.2019. National Comprehensive Cancer Network. nccn.org/professionals/physician_gls/pdf/nscl.pdf. Updated June 7, 2019. Accessed July 9, 2019.
4. Fakih MG, O’Neil BH, Price TJ, et al. Phase 1 study evaluating the safety, tolerability, pharmacokinetics (PK) and efficacy of AMG 510, a novel small molecule KRASG12C inhibitor, in advanced solid tumors. Presented at: 2019 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2019; Chicago, IL. Abstract 3003. meetinglibrary.asco.org/record/172411/abstract.
5. Gainor JF, Lee DH, Curigliano G, et al. Clinical activity and tolerability of BLU-667, a highly potent and selective RET inhibitor, in patients with advanced RET-fusion+ non-small cell lung cancer. Presented at: 2019 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2019; Chicago, IL. Abstract 9008. meetinglibrary. asco.org/record/174550/abstract.
6. Wolf J, Seto T, Han J-Y, et al. Capmatinib in METΔex14-mutated advanced non-small cell lung cancer (NSCLC): efficacy data from the phase II GEOMETRY mono-1 study. Presented at: 2019 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2019; Chicago, IL. Abstract 9004. meetinglibrary.asco.org/record/173357/abstract.
7. Pain PK, Veillon R, Cortot AB, et al. Phase II study of tepotinib in NSCLC patients with METex14 mutations. Presented at: 2019 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2019; Chicago, IL. Abstract 9005. meetinglibrary.asco.org/record/174241/abstract.
8. Jänne PA, Neal JW, Camidge DR, et al. Antitumor activity of TAK-788 in NSCLC with EGFR exon 20 insertions. Presented at: 2019 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2019; Chicago, IL. Abstract 9007. meetinglibrary.asco. org/record/174631/abstract.
9. National Cancer Institute. Researchers discover potential way to hit elusive target in pancreatic cancer. NCI website. cancer.gov/ news-events/cancer-currents-blog/2019/pancreatic-cancer-targeting- kras-indirectly. Published April 4, 2019. Accessed July 9, 2019.
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