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NCI-MATCH Analysis Suggests Dual HER2 Therapy Activity Beyond Breast, Gastric Cancer

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NEW YORK – Researchers explored the tissue-agnostic activity of HER2-targeted therapies in a cohort of the National Cancer Institute's Molecular Analysis for Therapy Choice (NCI-MATCH) platform trial and found signals of efficacy for the combination of two Genentech HER2 inhibitors, Herceptin (trastuzumab) and Perjeta (pertuzumab), in non-breast and non-gastric tumors.

The cohort analysis, published this month in Clinical Cancer Research, fell short of its prespecified primary endpoint, but nonetheless suggests that dual anti-HER2 therapy may be potentially efficacious in biomarker-defined subsets of patients with urothelial cancer and cholangiocarcinoma.

Herceptin is already available on the market as a treatment for HER2-overexpressing breast and gastric cancers, and Perjeta combined with chemotherapy and Herceptin is approved in the US for HER2-positive breast cancer in the adjuvant, neoadjuvant, and metastatic settings.

In the NCI-MATCH cohort, researchers enrolled 35 patients with HER2-amplified tumors other than breast and gastric cancer that could not be treated with other standard therapies that can improve survival. Patients enrolled in the study had gynecologic, gastrointestinal, genitourinary, and head and neck cancers. Researchers focused specifically on tumors with high levels of HER2 amplification, marked by abnormally high numbers of HER2/ERBB2 gene copies, because such amplifications in tumors can indicate a heavier biological dependence on this receptor and pathway than in tumors without amplification. The researchers defined HER2 amplification as copy number seven or greater, which was chosen as a conservative estimate because the use of next-generation sequencing to determine copy number variation was new at the time the study began.

Researchers capped the enrollment of colorectal cancer patients with HER2 amplification due to emerging evidence at the time the study was going on that this subset of tumors benefited from anti-HER2 therapies. In that vein, Seagen's Tukysa (tucatinib) plus Herceptin was approved in the US last year for metastatic colorectal cancer whose tumors are RAS wild type and HER2-positive.

In recent years, several drugmakers have begun to explore the activity of HER2-targeted therapies in tumor types other than breast cancer. Jazz Pharmaceuticals' zanidatamab and the Tukysa-Herceptin combo have shown activity in HER2-positive biliary tract cancers. AstraZeneca and Daiichi Sankyo's Enhertu (trastuzumab deruxtecan) also demonstrated responses across several HER2-positive tumor types in the Phase II DESTINY-PanTumor02 trial.

Roisin Connolly, lead author of the NCI-MATCH Herceptin-Perjeta study and a professor at University College Cork and Cork University Hospital, noted that the latest findings provided a signal of activity for the Herceptin-Perjeta combination in certain tumors, but the study did not meet its prespecified endpoint since a proportion of patients did not undergo central testing for HER2 amplification.

In the study, Connolly and colleagues observed partial responses with the Herceptin-Perjeta combo in three patients (12 percent) with cholangiocarcinoma and colorectal and urothelial cancers, out of 25 patients who had centrally established HER2-amplified tumors.

There was one additional partial response in another urothelial cancer patient who did not have a centrally confirmed increased ERBB2 copy number, an indicator of HER2 amplification. If that patient's outcome had been centrally confirmed, the trial would have met its prespecified efficacy benchmark of a 16 percent partial response rate. The Herceptin-Perjeta combo also led to stable disease in patients with colorectal cancer, cholangiocarcinoma, endocervical papillary adenocarcinoma, and gallbladder cancer.

"There's [known] breast cancer benefit from HER2 treatments, and gastroesophageal cancers do well with HER2 treatments, so they were excluded from the study because we were looking for those unknowns [that may benefit from the treatment]," Connolly said. "The fact that we have identified another two or three types of cancer that might benefit, it absolutely suggests that there could be a more tissue-agnostic role for this [anti-HER2] treatment."

The researchers also explored potential biomarkers of response or resistance and the role of co-occurring mutations in this NCI-MATCH cohort, though the sample sizes were small. They found no associations between greater HER2 copy number and treatment response, and patients most readily had TP53 mutations alongside HER2 amplification. In line with previous research flagging PIK3CA mutations with resistance to HER2-targeted therapy, they noted that four patients with co-occurring PIK3CA mutations in the NCI-MATCH cohort did not respond to treatment.

However, two patients who responded to dual HER2 treatment had a SMAD4 co-mutation. The researchers plan to conduct further genomic analysis on tumor tissue and cell-free circulating tumor DNA from these patients to evaluate potential mechanisms of response and resistance.

"There may be other pathways that are important, that might limit the impact of HER2 therapies," Connolly explained. "We can't guarantee that anyone coming in with HER2 application is definitely going to benefit [from this treatment]."

She added that further evidence generated on these co-mutations may also inform other combination treatment strategies with anti-HER2 drugs against these tumors. Because the Herceptin-Perjeta combination is well tolerated, there is a potential for other therapeutic combinations to better treat these rare tumors, though any novel drug combinations would need to be evaluated for safety and tolerability in preclinical studies, she said.

Because this NCI-MATCH analysis did not meet its prespecified endpoint, the Herceptin-Perjeta combination will not be further investigated by Connolly's group or by NCI. However, the researchers noted in the paper that the signal they identified may inform the design of future studies exploring anti-HER2 treatment in rare tumors with HER2 amplification.

"Additional strategies targeting HER2 and potential resistance pathways are warranted in cancers that may not respond to dual HER2-directed therapy," they wrote. "Based on our results, it may be most pertinent to focus on rare cancer subtypes, which is an area of unmet medical need."

For example, Connolly noted that the data from this study may inspire researchers to design trials that home in on HER2-amplified tumor types, in which the efficacy signal was strongest, such as urothelial cancer or cholangiocarcinoma.

The NCI-MATCH trial has officially ended, but in the next phase, called ComboMATCH, researchers will test biomarker-informed combination treatment approaches. Although the Herceptin-Perjeta combination is not being explored in ComboMATCH, there is an arm testing combination approaches with HER2-targeted treatment, specifically, Puma Biotechnology's HER2, HER3, and EGFR inhibitor Nerlynx (neratinib) and Pfizer's CDK4/6 inhibitor Ibrance (palbociclib) in recurrent or persistent HER2-positive solid tumors.

While the market for HER2-targeted therapy is a crowded one, there's still much room for improvement in Connolly's view. In NCI-MATCH, the Herceptin-Perjeta cohort enrolled advanced cancer patients who had an average of three prior treatments and were out of options.

"There's rarely a situation with stage IV disease where we have a cure, and it is good to always have more options to offer patients," she said, adding that there is a particular need for less toxic treatments for patients who may be less fit after many rounds of therapy.

"The purpose of the [NCI-MATCH] study overall was to identify more rare groups of patients who might benefit from targeted treatment approaches with HER2 therapies," Connolly said. "The suggestion from our results is that if we could have a larger cohort of those patients [with HER2 amplification], we might find larger groups of patients who would benefit. The question now is: What would happen if you brought this treatment earlier in the disease course? Could you do better?"