Poziotinib Shows Promise in Hard-to-Treat NSCLC Exon 20 Mutations

Nishan Tchekmedyian, MD

Poziotinib, a novel drug that targets relatively uncommon EGFR and HER2 exon 20 insertion mutations, is being tested in a biomarker-driven trial of patients with non—small cell lung cancer (NSCLC) in both second-line and treatment-naïve settings.

The phase II ZENITH20 trial (NCT03318939) is evaluating poziotinib monotherapy, an orally available agent, across 7 cohorts based on the participants’ molecular and treatment status (Figure). Two cohorts are fully enrolled, prompting investigators to expand the study in July.¹

The impetus for the study derives from a substantial unmet need for effective treatment options for patients with NSCLC with exon 20 insertion mutations, according to Nishan Tchekmedyian, MD, principal investigator on the ZENITH20 trial.

“Most of the available tyrosine kinase inhibitors [TKIs] have very low response rates in this space, and this disease tends to be resistant to both chemotherapy and immunotherapy options,” Tchekmedyian, medical director of Orange County Pod at Pacific Shores Medical Group in Huntington Beach, California, said in an interview with OncologyLive^®.

Overall, EGFR activating mutations are found in approximately 10% to 15% of patients with NSCLC. In the United States, 3.6% of patients with NSCLC harbor exon 20 mutations in EGFR (2.1%) or HER2 (1.5%), affecting approximately 7700 patients annually. The alterations also are observed in other malignancies; exon 20 alterations account for 0.6% of EGFR and HER2 mutations in cancer types other than lung cancer, affecting 8400 annually.^2,3

Although most activating mutations of EGFR-mutant NSCLCs are sensitive to available EGFR-targeting TKIs, the exon 20 insertion mutation is intrinsically resistant to these therapies, according to investigators at The University of Texas MD Anderson Cancer Center in Houston whose work has facilitated the development of poziotinib.²

Response rates for patients with this aberration were approximately 3% to 8% after first-line therapy with erlotinib (Tarceva), gefitinib (Iressa), or afatinib (Gilotrif), John V. Heymatch, MD, PhD, chair of the Department of Thoracic/Head and Neck Medical Oncology at MD Anderson and a key investigator into poziotinib, said during a presentation at the 19th International Association for the Study of Lung Cancer World Conference on Lung Cancer (IASLC 2018).³ Osimertinib (Tagrisso), which targets EGFR exon 19 deletions and exon 21 L858R mutations as well as the T790M resistance mutation, also has limited activity.²

Similarly, patients with NSCLC with HER2 mutations also fare poorly with TKIs, with findings from one analysis reporting an ORR of 11.9%.³

“Osimertinib, erlotinib, gefitinib, and afatinib are commonly used to treat patients with EGFR- and HER2- mutated lung cancers, but we use chemotherapy as a first-line option in patients with exon 20 insertion—mutated lung cancer because we know those TKIs have low response rates,” Tchekmedyian explained.

Findings from prior studies of exon 20 insertion mutations have demonstrated that these alterations restrict the size of the drug-binding pocket of exon 20 due to steric hindrance, a molecular process that obstructs TKIs’ ability to bind at the site of the drug pocket to prevent the growth and diffusion of tumor cells.²

Poziotinib’s molecular structure is smaller than those of approved TKIs. In addition, the agent is also more flexible and more halogenated. Investigators hypothesize that these characteristics allow poziotinib to fit into the exon 20 drug-binding pocket, to subvert the steric change induced by the exon 20 insertion mutations and subsequently catalyze anticancer activity.²

Figure. Poziotinib in NSCLC With EGFR or HER2 Exon 20 Insertion Mutation

“Poziotinib is one of the first molecules that we’ve realized as capable of overcoming steric hindrance, which essentially blocks all other TKIs’ ability to bind effectively,” Tchekmedyian said. “By virtue of the fact that it’s microscopically smaller and less rigid than other TKIs, poziotinib can fit into the drug-binding pocket that usually shuts out all of the other TKIs that we have available. We need an agent that gets into the drug binding pocket and binds consistently to provide the inhibition that will then cause tumors to shrink.”

Promising Early Findings

Poziotinib demonstrated potency against EGFR or HER2 exon 20 insertion mutations in genetically engineered mouse models in experiments conducted at MD Anderson, prompting investigators to initiate an open label trial at the center (NCT03066206). Patients with metastatic NSCLC exhibiting EGFR or HER2 insertion or point mutations excluding acquired T790M mutation were eligible to enroll.

Investigators administered 16 mg of oral poziotinib to 2 cohorts of patients with the exon 20 alterations, EGFR (n = 50) and HER2 (n = 13), until disease progression, death, or withdrawal, according to findings presented at IASLC 2018. Most of the participants in both the EGFR and HER2 cohorts had received prior treatment, respectively, with platinum therapy (86% and 77%), a TKI (34% and 15%), or a PD-1/PD-L1 inhibitor (54% and 62%). The study’s primary endpoint was objective response rate (ORR).³

In the EGFR group, the ORR was 55% for best response and 43% for confirmed response among 44 evaluable patients. The median progression-free survival in the intention-to-treat population was 5.5 months; 19 patients were still receiving treatment at the time of data cutoff, including 6 who were on therapy for more than 1 year.

In the HER2 cohort, 12 patients were evaluable. The best response ORR was 50% and the confirmed ORR was 42%. The median PFS among all enrolled patients was 5.1 months and 5 patients remained on treatment.

The response rates for the EGFR group compare favorably with historical ORRs in this population, Heymach said in presenting the data at IASLC 2018.

“These results add to a growing body of evidence supporting the role of poziotinib in patients with EGFR and HER2 exon 20 mutations, and are a real advance for these patients for whom no targeted therapies have been effective so far,” Heymach said in a press release.⁴ “I am highly encouraged by these results and the evolution of poziotinib data. Our study is the single largest data set in this high unmet need patient population.”

In terms of adverse events (AEs), Heymach said that “EGFR-related toxicities (including rash, diarrhea, and paronychia) were manageable and required dose reductions in 60%. Discontinuation due to poor tolerance was rare (3%).”

In the safety population of 63 patients, the most common all-grade treatment-related AEs included diarrhea (69.8%), oral mucositis (69.8%), paronychia (60.3%), and dry skin (58.7%). The most frequently observed grade 3 or 4 AEs included diarrhea (17.5%), skin rash (34.9%), paronychia (9.5%), and nausea (7.9%). No grade 5 AEs were reported.

Expanding ZENITH20

The ZENITH20 study is rapidly recruiting participants, prompting Spectrum Pharmaceuticals, the company developing the drug, to expand the trial’s scope in July with 3 new cohorts.¹

Cohorts 1 and 2, which are now closed to enrollment, have each recruited 87 previously treated patients with EGFR and HER2 exon 20 insertion—mutated NSCLC, respectively. Cohort 3 is assessing poziotinib in treatment-naïve patients with EGFR exon 20 insertion—mutated disease, while cohort 4 is evaluating the agent in treatment-naïve patients with HER2 exon 20 insertion—mutated NSCLC.

Cohort 5 is accruing previously treated and treatment-naïve patients with NSCLC who have EGFR or HER2 exon 20 insertion mutations. This fifth cohort will function as an “overflow cohort” for cohorts 1 through 4, according to Tchekmedyian.

Cohort 6 encompasses patients with NSCLC with classical EGFR mutations who have experienced disease progression while receiving first-line osimertinib. Finally, cohort 7 is accepting those with previously treated locally advanced or metastatic NSCLC with less common mutations in EGFR or HER2 exons 18 to 21 or the extracellular or transmembrane domains.

A potential role for poziotinib in the resistance setting is an “exciting development,” Jeffrey Clarke, MD, said in a press release. “With increased use of osimertinib as the treatment of first-line NSCLC patients with classical EGFR mutations, the emergence of osimertinib resistance is a growing occurrence in this setting,” said Clarke, assistant professor of medicine at Duke University Hospital/Duke Cancer Institute.

“One resistance pattern that is emerging is through the development of an additional EGFR mutation and recent preclinical publications suggest that poziotinib may be active against EGFR-dependent resistance mechanisms,” he said.

ZENITH20’s primary endpoint is objective response rate; secondary endpoints include disease control rate and duration of response. Topline results from cohort 1 are expected later this year, the company said.

Tchekmedyian said that poziotinib’s mechanism of action may cause the agent to be effective in other malignancies in which patients harbor EGFR or HER2 exon 20 insertion mutations.

“There may be a subset of lung cancer that is driven by these mutations that is the same as a subset of colon cancer or of pancreatic cancer, for instance,” Tchekmedyian said. “We might have the opportunity to identify patients with EGFR and HER2 exon 20 insertion—mutated cancers in general to impact those small subsets in a meaningful way.”

References

1. Spectrum announces expansion of the poziotinib clinical program [press release]. Henderson, Nevada: Spectrum Pharmaceuticals, Inc.; July 22, 2019. investor.sppirx.com/news-releases/news-release-details/spectrum-announces-expansion-poziotinib-clinical-program. Accessed August 27, 2019.
2. Robichaux JP, Elamin YY, Tan Z, et al. Mechanisms and clinical activity of an EGFR and HER2 exon 20-selective kinase inhibitor in non-small cell lung cancer. Nat Med. 2018;24(5):638-646. doi: 10.1038/s41591-018-0007-9.
3. Heymach J, Negrao M, Robichaux J, et al. A phase II trial of poziotinib in EGFR and HER2 exon 20 mutant non-small cell lung cancer (NSCLC). Presented at: The IASLC 19th World Conference on Lung Cancer; September 23-26, 2018; Toronto, Canada. investor.sppirx.com/static-files/d6e05c4b-2c55-4b8c-8d7f-15b6c484f1c9. Accessed August 30, 2019.
4. Spectrum Pharmaceuticals announces release of poziotinib abstract as part of the IASLC 19th World Conference on Lung Cancer [press release]. Henderson, NV: Spectrum Pharmaceuticals, Inc; September 5, 2018. investor.sppirx.com/news-releases/news-release-details/spectrum-pharmaceuticals-announces-release-poziotinib-abstract. Accessed August 30, 2019.