NEW YORK – Last December, Spectrum Pharmaceuticals said that its drug candidate poziotinib failed to meet the pre-specified primary endpoint of overall response rate in the first cohort of participants in a Phase II clinical trial investigating the therapy in EGFR exon 20-mutated non-small cell lung cancer (NSCLC).
At the American Association for Cancer Research's Virtual Annual Meeting on Monday, Xiuning Le, a study investigator from MD Anderson Cancer Center, presented more details on the efficacy of poziotinib from cohort 1 in the Phase II ZENITH20 trial, and explored the various reasons for why it demonstrated lower efficacy in terms response rate compared to another study involving the same drug.
Meanwhile, drugmaker Spectrum focused instead on the impact of the drug on progression-free survival and duration of response. In a call with market analysts, Spectrum executives remained convinced that the drug is active in this difficult- to-treat subset of lung cancer patients but said they would make some changes to the trial design so the therapy would have a better shot at demonstrating efficacy.
EGFR mutations have been established as oncogenic drivers in NSCLC since 2004, with the most prevalent being exon 19 deletions and exon 21 L858R substitutions. There are multiple small molecule inhibitors approved by the US Food and Drug Administration to target those mutations. However, there are no currently approved therapies targeting EGFR exon 20 alterations, which are mostly insertions, that account for about 10 percent of all EGFR alterations.
EGFR exon 20-altered lung cancers tend to not be sensitive to approved EGFR inhibitors, Le said. When treated with an EGFR tyrosine kinase inhibitor in other studies, progression-free survival was about two months for EGFR exon 20-altered patients compared to 14 months in patients with classic EGFR mutations.
Poziotinib's shape and size allows it to fit into the exon 20 ATP binding pocket, according to Le. In preclinical cell line studies, the molecule was found to be more selective for EGFR exon 20 insertions over EGFR wild type.
The Phase II ZENITH20 study was a multi-center, multi-cohort study of poziotinib in NSCLC patients harboring EGFR or HER2 exon 20 insertions. In order to be eligible for the study, the mutations had to be detected in patients' tissue samples at baseline.
Cohort 1 contained previously treated patients with EGFR exon 20 insertions. Cohort 2 had previously treated patients with HER2 exon 20 insertions. Cohort 3 and 4 included treatment naïve patients with EGFR and HER2 exon 20 insertions, respectively.
All patients received 16 mg poziotinib once daily in a 20-day cycle. The primary endpoint of the study was objective response rate determined by an independent review committee. Secondary endpoints included other efficacy parameters, as well as safety and toxicity.
In cohort 1, a total of 115 patients received at least one dose of poziotinib. The overall response rate was 14.8 percent, and the disease control rate was 68.6 percent. The median duration of response was 7.4 months, and the progression-free survival was 4.2 months. Even heavily pretreated patients who had three or more lines of therapy, including an EGFR tyrosine kinase inhibitor, responded to poziotinib.
Out of the 115 patients, 17 recorded partial responses and saw their tumors shrink more than 50 percent. Although the primary endpoint of response was not met, Le noted that they observed some tumor shrinkage in the target lesions for 65 percent of patients, who were categorized as having stable disease but not included in the overall response rate calculation.
During the study, 10 percent of patients discontinued treatment due to adverse effects, which Le pointed out is similar to what has been seen in other large trials of second-generation EGFR TKIs. Moving forward, Le said that the team will use an 8 mg twice-daily regimen on the more recently added cohorts in the hopes that it will reduce toxicity and improve compliance and efficacy.
In a call Spectrum hosted with investors on Tuesday, Mark Socinski from AdventHealth Cancer Institute and  chairman of the steering committee on the ZENITH20 study, said that even though the drug did not meet the primary endpoint of response, poziotinib's impact on progression-free survival and duration of response demonstrated "clear evidence of efficacy."
Additionally, during her presentation at AACR, Le delved into further detail about poziotinib's ability to shrink tumors. She cited a separate, single-center trial of poziotinib conducted at MD Anderson involving 44 patients, which has yielded a response rate of 43 percent to date. Â
She ascribes the discrepancies between that trial and the ZENITH20 trial to three possible factors. Le noted that unlike the ZENITH20 trial, the single-center MD Anderson trial allowed patients with exon 20 point mutations. "Mutation groups in general are more sensitive to TKI," Le said. Other influencing factors impacting the data readout could be that in the MD Anderson study toxicities were managed more aggressively and more patients were motivated to stay on the drug trial longer, according to Le.
The data from the MD Anderson study is currently undergoing independent review and will be reporting updated results soon.
Additionally, the location of specific EGFR exon 20 insertions may impact patients' level of response to poziotinib, Le suggested. At the molecular level, the exon 20 insertions are located between amino acids 762 to 773. In the study, the highest frequencies of insertions occurred at amino acid 770 and 771.
"We have some evidence showing maybe those insertions also have different oncogenic potential and the response to different EGFR TKI. That part of the data is still under analysis," Le said.
In discussing the data Le presented at the meeting, Taofeek Kunle Owonikoko from Emory University School of Medicine generally agreed with her rationale with regard to why the response rates in the two trials are different. Â "The reason for the significant drop in response rate could be ascribed to patient selection factors," Owonikoko said. "However, that could also be ascribed to relevant biological differences, especially with respect to the type of exon 20 insertion mutation between the two populations."
He noted that it is currently unclear what the differences are between the spectrum of mutations present in the ZENITH20 trial versus those from the MD Anderson single-center trial. He said that depending on where the alteration is located in the hotspot, it may influence sensitivity to different types of TKIs.
Spectrum Chief Medical Officer Francois Lebel said during the call that the company has recently implemented new recommendations for side effect management, such as earlier use of steroids for treating rashes, a common side effect of the drug, and will encourage patients to stay on the trial for longer.
"There's no question that poziotinib is an active drug, and our current priority is to expand the therapeutics window," said Lebel. "We believe that the 16 mg once daily dose led to too many dose reductions or interruptions that prevented the drug from demonstrating its full potential."
Lebel said that Spectrum expects to present data on cohort 2 from the ZENITH20 trial by mid-year and from the fully enrolled cohort 3 in the second half of this year.