Drugs in the Pipeline: Non-Small-Cell Lung Cancer

Pie chart of NSCLCs

Several promising drugs for the treatment of lung cancer have been garnering attention over recent years. These new treatments have been highlighted at conferences and are sure to impact the standard of care. Some of these new treatments are detailed below.

LOXO-292

Various multikinase inhibitors (MKI) with some activity against RET have been studied, usually demonstrating low response rates and substantial toxicities. Consequently, efforts are being made to create safer, more potent agents, such as the selective RET inhibitor LOXO-292.[1] In preclinical studies, LOXO-2 demonstrated activity against activating RET fusions/mutations, potential resistance mutations, and brain metastases.[2]

Results of a global phase 1 study of LOXO-292 involving patients with RET-altered cancers were presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting.[2]

Patients studied had advanced solid tumors, including RET fusion+ non-small cell lung cancer (NSCLC), papillary thyroid cancer (PTC), RET-mutant medullary thyroid cancer (MTC), and other cancers. Patients received oral doses in 28-day cycles, and dose escalation adhered to a 3+3 design. Determination of maximum tolerated dose (MTD) was the primary endpoint; secondary endpoints included safety, overall response rate (ORR, RECIST 1.1) and duration of response (DoR).

In the study population (n=57), there were 35 RET fusion+ tumors (27 NSCLC, 7 PTC, 1 pancreatic) and 20 RET-mutant MTCs. Additionally, 67% of patients were pre-treated with MKIs. Patients received LOXO-292 at 7 doses (20 mg daily escalated to 160 mg twice daily).

The ORR in RET fusion+ patients who could be evaluated was 69% (95% confidence interval [CI], 50%-84%, n = 22/32, 11 pending confirmation, 9/13 MKI-naïve, 13/19 MKI pretreated). ORR in NSCLC was 65% (n = 17/26) and 83% (n = 5/6) in PTC. Radiographic tumor reduction occurred in 84% (27/32) (range -19% to -67%). Of note, NSCLC responses occurred independently of the upstream partner when known and included three patients with brain metastases at baseline.

No dose-limiting toxicities were noted, and neither the MTD nor DoR were reached. Over 90% of patients continued with treatment. Adverse events included fatigue (16%), diarrhea (16%) and dyspnea (12%). Most adverse events were grade 1-2, and no higher-grade adverse events were ascribed to the drug.[2]

At the International Association for the Study of Lung Cancer (IASLC) 19th World Conference on Lung Cancer in September 2018, investigators refreshed their data and announced that unconfirmed responses in the trial had been confirmed. Furthermore, 92% of responses were ongoing, with most lasting for ≥ 6 months. The drug exhibited safety and tolerability in line with highly selective drug design and showed antitumor activity in the central nervous system.[3]

In September 2018, LOXO-292 was granted Breakthrough Therapy Designation by the Food and Drug Administration (FDA). Phase 2 cohorts are currently being recruited for LIBRETTO-001, a study evaluating LOXO-292 in solid tumors, RET fusion+ solid tumors, and MTC.[3]

Capmatinib

The receptor tyrosine kinase (RTK) MET (c-Met, cMET, or c-MET) has been established as an enviable therapeutic target in cancer treatment. MET alterations hypothesized to be oncogenic include activating mutations, overexpression, gene amplification, and translocations. However, clinical development of MET inhibitors has been difficult, potentially due to the use of nonselective agents and failure to utilize a firm biomarker-based patient selection strategy during drug development.[4]

Capmatinib is a potent, highly selective MET inhibitor with activity limited to a small number of genomic parameters. It has been studied as monotherapy and in combination trials for lung and other types of cancer.[4]

Presented at the 2019 ASCO Annual Meeting, a primary analysis of capmatinib in the GEOMETRY mono-1 study indicated promising efficacy associated with capmatinib in patients with locally advanced or metastatic NSCLC with the MET exon-14 skipping (METex14) mutation. GEOMETRY mono-1 is a non-randomized, open-label phase II study evaluating capmatinib monotherapy in patients with EGFR wildtype, ALK-negative, advanced NSCLC harboring MET amplification and/or mutations. The ORR in patients receiving capmatinib was 68% for treatment-naive vs 41% for previously treated patients; median DoR was also clinically important regardless of the prior line of therapy.[5,6]

Capmatinib was given Breakthrough Therapy Designation by the FDA for the treatment of patients with metastatic NSCLC harboring METex14 mutation with disease progression before or after platinum-based chemotherapy.[6]

Tepotinib

Between 3-4% of NSCLCs harbor METex14 mutations, which appear to be sensitive to c-Met inhibition. A single-arm phase II trial presented at the 2018 ASCO Annual Meeting assessed the efficacy and safety of the potent, selective c-Met inhibitor tepotinib in patients with stage IIIB/IV EGFR/ALK negative NSCLC with METex14 mutations. Study participants, who had previously received 0-2 lines of therapy, received tepotinib 500 mg daily until disease progression, intolerable toxicity, or for other reason.

In total, 9 of 15 evaluable patients (60%) had a confirmed partial response (PR) and 3 (20%) had stable disease (SD). All responders remained in response during the investigation. According to independent review, 6 patients had confirmed PR (46.2%) and 1 patient exhibited SD (7.7%). Thirteen of 22 patients with evaluable data had grades 1-2 treatment-related adverse events (TRAEs), 3 patients had grade 3 TRAEs, and 1 patient had a serious TRAE.

TAK-788

TAK-788 is an investigational potent, selective tyrosine kinase inhibitor with activity against EGFR and HER2 mutations being evaluated in NSCLC with EGFR exon 20 insertions.

At the 2019 ASCO Annual Meeting, updated results from a phase 1/2 first-in-human, open-label, multicenter study demonstrated that TAK-788 exhibits antitumor activity with adverse effects comparable to other EGFR TKIs.[8]

TAK-788 was associated with a median progression-free survival of 7.3 months and a confirmed ORR of 43% in patients diagnosed with either locally advanced or metastatic NSCLC with EGFR exon 20 insertions.[9]

In an interview with Cancer Network in June 2018, Robert C. Doebele, MD, PhD, University of Colorado, Denver said the following about TAK-788[10]:

“It was specifically designed to meet an unmet need in non–small-cell lung cancer, which is that patients currently with certain types of EGFR and HER2 mutations do not have effective FDA-approved therapies. Specifically, these are patients who have EGFR exon 20 insertion mutations or patients with HER2 mutations. So, although we’ve had a plethora of EGFR inhibitors for non–small-cell lung cancer, drugs like erlotinib, gefitinib, alectinib, and osimertinib have not been shown to be efficacious in patients with EGFR exon 20 insertions or HER2 insertion mutations.”

On a final note, in the same interview, Dr. Doebele mentioned a challenge experienced during the trial:

“The difficulty that has occurred in this setting is that EGFR exon 20 binding molecules are very similar in appearance and drug binding to wild-type EGFR binding molecules, and that has made getting appropriate doses into patients difficult.”

Financial Disclosure:The author and reviewer have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

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