Targeted therapies for HER2m NSCLC actively developed

Various companies have started developing drugs for HER2-mutant non-small-cell lung cancer

Boehringer Ingelheim’s candidate drug shows effect in trial…Yuhan Corp starts clinical trial

Hanmi Pharmaceutical reattempts anticancer drug development after failing with poziotinib

The domestic and foreign pharmaceutical industry has taken up the challenge of developing a new drug for HER2-positive NSCLC.

 

After Enhertu opened the door by obtaining the first marketing authorization as an anticancer drug targeting the HER2 mutation in Korea, many later entrants such as Yuhan Corp, Boehringer Ingelheim, and Hanmi Pharmaceutical have also started clinical trials.

 

Until now, there have been a number of drugs targeting various gene mutations such as EGFR, ALK, ROS1, BRAF, MET, and RET in NSCLC, but none has targeted HER2.

 

Approximately 2-4% of patients with NSCLC have a HER2 mutation.

 

Due to its low prevalence, the companies had difficulty developing targeted therapies.

 

This is why the clinical results of the latecomers are gaining interest.

 

Boehringer Ingelheim disclosed early phase clinical trial results confirming the efficacy of its HER2-targeted antitumor candidate, and Yuhan Corp secured multinational IND approval for its HER2-mutation targeted antitumor drug candidate after Leclaza.

 

Hanmi Pharmaceuticals also launched a new HER2-targeted NSCLC drug after failing with poziotinib.

 

According to industry sources on the 18th, Boehringer Ingelheim's zongertinib (Development code name: BI-1810631) showed an effect in HER2-positive NSCLC.

 

Zongertinib is a tyrosine kinase inhibitor (TKI) that binds to the HER2 mutation without inhibiting the wild-type EGFR.

 

The Phase 1 trial, named BEAMION-Lung01, evaluated the efficacy of zongertinib in 36 patients with metastatic/advanced NSCLC who were refractory to standard of care and had HER2 mutations.

 

The study was designed to determine if zongertinib can slow the progression of advanced NSCLC compared to the current standard of care, Keytruda plus platinum-based chemotherapy.

 

The primary endpoint was set as an investigator-assessed overall response rate (ORR).

 

Trial results as of July 31, 2023, showed that the ORR was 58% with zongertinib with a disease control rate (DCR) of 97%.

 

In terms of safety, the most common treatment-related adverse events (TRAEs) were diarrhea and rash.

 

Based on the tolerability and safety of the drug demonstrated in the Phase 1 trial, Boehringer Ingelheim plans to conduct a full efficacy evaluation of zongertinib through the Phase 2 trial.

 

Korean companies including Hanmi and Yuhan also start developing treatments for HER2 NSCLC

Yanghwa has also jumped into the development of HER2-targeted anticancer drugs.

 

The company plans to develop a new drug for NSCLC to add on to its EGFR (HER1)-targeting anticancer drug Leclaza.

 

The company’s candidate, YH42946, targets NSCLC patients with EGFR exon 20 mutations along with HER2 positivity.

 

YH42946 was approved by the U.S.

 

Food and Drug Administration (FDA) last month and was then granted to start a multinational Phase I/II clinical trial in Korea in the middle of this month.

 

The company acquired the new anticancer drug candidate and its pipeline last year from a local biotech J Ints Bio.

 

The Phase I/II trial initiated this time is the first trial evaluating the tolerability and safety of YH4294 in humans.

 

In preclinical studies, YH42946 has shown anti-tumor effects against HER2 mutations and EGFR exon 20.

 

It has also shown an effect on solid tumors such as breast and colorectal cancers.

 

Hanmi Pharmaceutical is also out to develop new treatments after the failure of poziotinib.

 

Its new anticancer pipeline, the ‘selective HER2 Exon20 insertion mutation inhibitor', which had not been disclosed until now, was found to have an anti-cancer effect based on its strong activity against HER2 exon20 insertion mutation and high selectivity for EGFR and has been confirmed to be a viable treatment for NSCLC.

 

The company has a history of developing an oral treatment for HER2-mutant NSCLC.

 

Hanmi Pharmaceutical and its U.S.

 

partner Spectrum (now Assertio) developed poziotinib for locally advanced or metastatic NSCLC with HER2 exon 20 insertion mutations but ultimately failed to gain FDA approval.

 

In 2022, the U.S.

 

Oncologic Drugs Advisory Committee (ODAC) voted (9:4) that the benefits of poziotinib did not outweigh the risks, prior to the FDA's decision on whether to grant it marketing authorization.  At the time, the ODAC noted that poziotinib lacks efficacy compared to Enhertu, which also targets HER2.

 

Currently, the only targeted therapy option available for HER2-mutant NSCLC is Enhertu, developed by Daiichi Sankyo and AstraZeneca.

 

On March 20, Enhertu’s indication was extended to the treatment of patients with unresectable or metastatic NSCLC whose tumors harbor an activating HER2 (ERBB2) mutation and who have received prior systemic therapy, including platinum-based chemotherapy.

 

In the DESTINY-Lung02 study, Enhertu achieved a confirmed objective response rate (ORR) of 49%, complete response (CR) of 1%, and partial response (PR) of 48% as assessed by an independent centralized blinded review (BICR).

 

Poziotinib achieved an ORR of 28% in the ZENITH20 cohort 2 study.

 

Following the failure to receive approval, Spectrum deprioritized the development of poziotinib and reduced its R&D workforce by 75%.

 

Therefore, it will be interesting to see if Hanmi Pharmaceutical’s newly developed HER2-targeted cancer drug will be able to go on further and receive approval.