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Daiichi Sankyo's HER3-Targeted Drug May Be New Option in Treatment-Resistant EGFR-Mutated NSCLC


NEW YORK – Patients with EGFR-mutated non-small cell lung cancer who progressed on an EGFR inhibitor and platinum-based chemotherapy experienced meaningful and durable clinical benefits with Daiichi Sankyo's investigational HER3-targeted antibody-drug conjugate patritumab deruxtecan.

At the International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer this week, Helena Yu, a medical oncologist from Memorial Sloan Kettering, reported that data from the Phase II HERTHENA-Lung01 trial support patritumab deruxtecan as a potential treatment for patients with EGFR-mutated NSCLC who have failed EGFR-targeted therapy. Daiichi Sankyo believes the data are good enough to submit to regulatory authorities and seek approval in the US for patritumab deruxtecan in this setting.

EGFR-activating mutations are present in 14 percent to 38 percent of NSCLC patients, who often develop resistance to EGFR inhibitors and go on to receive platinum-based chemotherapy followed by salvage therapies that tend to have limited and transient efficacy. For example, in a 2017 study, median progression-free survival was around three months for patients with advanced EGFR-mutated lung cancer who had received Roche's EGFR inhibitor Tarceva (erlotinib) or chemotherapy as third-line treatment after becoming resistant to AstraZeneca's EGFR inhibitor Iressa (gefitinib) in the first-line setting and receiving second-line chemotherapy.

Daiichi Sankyo has high hopes that a HER3-directed antibody-drug conjugate like patritumab deruxtecan will overcome common resistance mechanisms in EGFR-mutated NSCLC. The drug comprises three parts — an anti-HER3 fully human monoclonal antibody that directs the drug to cancer cells expressing HER3, a tetrapeptide-based linker, and a topoisomerase inhibitor as the chemotherapy payload.

HER3 is commonly overexpressed in NSCLC and is upregulated in EGFR-mutant lung tumors, but it has not been linked to resistance to EGFR inhibitors. However, prior trials support investigating a HER3-targeted antibody-drug conjugate in this setting.

In an earlier Phase I study conducted by Daiichi Sankyo, for example, treatment with patritumab deruxtecan yielded an objective response rate of 39 percent and median progression-free survival of 8.2 months among 57 patients with advanced EGFR-mutated, EGFR inhibitor-resistant NSCLC. The outcomes seen in this study led Daiichi Sankyo to conduct the 225-patient HERTHENA-Lung01 trial.

Yu and her collaborators found that among patients with locally advanced, EGFR-mutated NSCLC who had failed on a third-generation EGFR inhibitor, the overall response rate on patritumab deruxtecan was 29.8 percent, though Yu said the "vast majority" of patients experienced tumor shrinkage. The median duration of response was 6.4 months with median progression-free survival of 5.5 months and median overall survival of 11.9 months.

"The results from HERTHENA-Lung01, coupled with early trial results, show that patritumab deruxtecan demonstrates clinically meaningful and durable responses, illustrating the potential of this HER3-directed antibody-drug conjugate to become a new standard of care for this patient population with high unmet medical need," Ken Takeshita, Daiichi Sankyo's global head of R&D, said in a statement. "These data will support our ongoing discussions with health authorities including our planned submission in the US."

Yu's group explored whether another biomarker, other than an EGFR mutation, could further distinguish best responders to patritumab deruxtecan. However, in patients with available pre-treatment tissue samples, the researchers found no biomarker that could further differentiate those who responded from those with stable and progressive disease.

The researchers observed clinical activity across a broad range of pre-treatment HER3 expression levels and various mechanisms of EGFR tyrosine kinase inhibitor resistance. Yu noted that the mechanisms of resistance observed in the study were very diverse and included patients with EGFR-dependent resistance mechanisms such as an acquired C797S mutation, as well as EGFR-independent mechanisms like acquired MET amplifications and fusions. Some patients' cancers transformed to small cell or squamous cell lung cancer, and half the patients "had an unidentified mechanism of resistance," Yu said.

Among 30 patients with non-irradiated brain metastases prior to treatment, the central nervous system overall response rate was 36.7 percent. Ten out of the 30 patients in this subset had a complete response, and one had a partial response. 

The safety profile of patritumab deruxtecan was consistent with what researchers had seen in previous studies. Drug-related adverse events led to discontinuation of therapy in 10 patients, and one death.

Helena Linardou, a medical oncologist at Metropolitan Hospital in Athens, Greece, emphasized the large size of the patient group in a discussion of the HERTHENA-Lung01 at the meeting. "In my opinion, the data are very valid," she said, and noted that "for the first time with this agent, we saw today meaningful intracranial responses."

Linardou, who wasn't involved in HERTHENA-Lung01, acknowledged the lack of predictive biomarkers identified in the study and suggested that researchers may need to look for alternative measures of HER3 expression or other related biomarkers. "Still, … HER3 is now a clinically actionable therapeutic target," she said, adding that HER3-targeted antibody-drug conjugates may have broader applications in other types of HER3-overexpressing tumors or even a range of drug-resistant tumors.

In addition to the HERTHENA-Lung01 trial, two other studies are exploring the use of patritumab deruxtecan in lung cancer patients who have progressed on EGFR inhibitors and platinum-based chemotherapy. Daiichi Sankyo has begun a Phase I dose escalation and expansion study to assess its drug with AstraZeneca's EGFR inhibitor Tagrisso (osimertinib) in patients who have progressed on Tagrisso but haven't received platinum-based chemotherapy. The company is also comparing the activity of patritumab deruxtecan against platinum-based chemo in EGFR-mutated advanced NSCLC patients who have failed a third-generation EGFR inhibitor in the HERTHENA-Lung02 Phase III trial.