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Emerging HER2 Selective TKIs
Emerging HER2-Selective TKIs for HER2-Mutated NSCLC

Released: November 12, 2024

Expiration: November 11, 2025

Misako Nagasaka
Misako Nagasaka, MD, PhD
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Key Takeaways
  • HER2 mutations are a distinct oncogenic driver in NSCLC and are associated with a poor prognosis and common occurrence of brain metastases.
  • Two selective HER2-targeted TKIs, zongertinib and BAY 2927088, have shown promising efficacy and safety for HER2-mutated NSCLC in early-stage trials.
  • Zongertinib and BAY 2927088 are now in phase III trials for patients with previously untreated advanced HER2-mutated NSCLC.

HER2-mutated non-small-cell lung cancer (NSCLC) represents a unique subset of lung cancer cases with distinct biological behavior. This subtype accounts for approximately 2% to 4% of all NSCLC diagnoses, occurring more frequently in people with no smoking history and females. HER2 mutations, many affecting exon 20, drive tumor growth and have been linked to a poor prognosis with the frequent development of brain metastases. Therapeutic options are limited for these patients, with only 1 targeted therapy currently approved specifically for HER2-mutated NSCLC. However, treatment paradigms may be changing with the advent of new HER2-selective tyrosine kinase inhibitors (TKIs).

The current standard of care in HER2-mutated NSCLC includes first-line platinum-based chemotherapy, with or without immune checkpoint inhibitors. For those patients with progressive disease, trastuzumab deruxtecan (T-DXd) has emerged as a potent treatment option. In the phase II DESTINY-Lung01 trial, T-DXd demonstrated an overall response rate (ORR) of 55% and median progression-free survival of 8.2 months in previously treated patients with advanced NSCLC and HER2 mutations​​. The drug's efficacy in this setting led to its FDA approval and it is now being investigated as a potential first-line therapy in the ongoing DESTINY-Lung04 study (NCT05048797). However, despite the promise of T-DXd, many patients continue to require additional effective treatment options after relapse, particularly those that can target HER2 mutations while minimizing toxicity. This is where emerging HER2-selective TKIs may come into play.

The Promise of HER2-Selective TKIs
HER2-selective TKIs offer a targeted approach with a significantly improved therapeutic index compared with previously tested pan-HER TKIs like poziotinib, which was limited by severe toxicities such as rash and diarrhea due to wild-type EGFR inhibition. Two promising new HER2-selective TKIs currently in clinical trials are zongertinib (previously BI 1810631) and BAY 2927088, both of which are showing encouraging results in terms of efficacy and safety. 

Zongertinib, a highly selective HER2 TKI, has shown significant promise in treating HER2-mutated NSCLC. In the ongoing Beamion-1 phase IA/IB trial (NCT04886804), which includes both dose-escalation and expansion cohorts, zongertinib has demonstrated an ORR of 66.7% in previously treated patients​. Notably, the drug has also exhibited intracranial activity, with an intracranial ORR of approximately 35% across the different doses in patients with measurable brain metastases. These results are particularly significant given the high incidence of brain metastases in HER2-mutated NSCLC and the limited options for controlling central nervous system disease. 

The safety profile of zongertinib is another highlight. In the Beamion-1 trial, adverse events leading to dose reductions have been reported in only 11% of patients, and the rate of treatment discontinuation has been low at 3%. Of importance, there have been no treatment-related adverse events (TRAEs) leading to death, marking a notable improvement over earlier, less-selective TKIs​. Having treated several patients with zongertinib, I have found it to be generally well tolerated, especially compared with other agents that have come and gone in the past. The favorable balance between efficacy and tolerability with zongertinib could make it a game changer for patients with HER2-mutated NSCLC.

Another exciting development in the field is BAY 2927088, a reversible HER2-selective TKI that also selectively inhibits mutated EGFR vs wild-type EGFR. BAY 2927088 is being evaluated in the ongoing phase I SOHO-01 trial (NCT04874178). The drug has demonstrated an ORR of 72.1% in patients with HER2 mutations who had not received prior targeted therapy​. 

The safety profile of BAY 2927088 also appears promising, with the most common TRAEs being mild to moderate diarrhea and rash. In the SOHO-01 trial, TRAEs leading to discontinuation have occurred in 6.8% of patients, while 31.8% of patients have required dose reductions​. Serious TRAEs have been observed in 11.4% of patients, including 1 case of fatal dyspnea. Of importance is that there have been no reports of interstitial lung disease or pneumonitis, which are concerns with other HER2-targeted therapies such as T-DXd.

Ongoing Phase III Trials of Selective HER2 TKIs in NSCLC
Both zongertinib and BAY 2927088 are continuing to be evaluated in clinical trials. Of note, zongertinib is being evaluated as first-line therapy in the phase III Beamion LUNG-2 trial (NCT06151574) vs standard-of-care treatment in patients with advanced HER2-mutated NSCLC. Similarly, BAY 2927088 is being evaluated as first-line therapy in the phase III SOHO-02 trial (NCT06452277) vs standard-of-care treatment in patients with advanced HER2-mutated NSCLC. These trials will provide critical data on the drugs’ efficacy and safety in a larger number of patients with advanced NSCLC and its potential for use in earlier lines of treatment.

The continued development of these selective HER2 TKIs, along with a growing understanding of HER2 mutations, promises to reshape and hopefully improve the treatment landscape for patients with HER2-mutated NSCLC.

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