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Dual Anti-HER2 Tx Shows Benefit in Advanced CRC

The targeted therapy combination of pertuzumab (Perjeta) plus trastuzumab (Herceptin) yielded responses in heavily pretreated colorectal cancer patients with HER2-amplified disease, a cohort of the MyPathway study found.

Among 57 patients who met criteria for inclusion, the overall response rate (ORR) was 32%, which included one complete response, Funda Meric-Bernstam, MD, of MD Anderson Cancer Center in Houston, and colleagues reported.

“Our data suggest promising activity and durable responses in heavily pretreated patients (median of four previous lines of therapy) with HER2-amplified metastatic colorectal cancer,” the authors wrote in the Lancet Oncology.

Median treatment duration was 2.1 months and median duration of response was 5.9 months (95% CI 2.8-11.1), with responses in four patients lasting beyond a year. The disease control rate was 44%.

A post-hoc exploratory analyses revealed an ORR of 40% in the KRAS wild-type group (17 of 43 patients) and 8% in the KRAS-mutated group (1 of 13 patients).

“Patients with HER2-amplified, KRAS wild-type metastatic colorectal cancer derive a greater benefit from pertuzumab plus trastuzumab than those with KRAS-mutated metastatic colorectal cancer,” Meric-Bernstam’s group wrote.

“I would respectfully suggest that this interpretation, although accurate, is an understatement,” Leonard B. Saltz, MD, of Memorial Sloan Kettering Cancer Center in New York City, wrote in a linked comment. “My interpretation is that clinically meaningful activity was shown exclusively in the KRAS wild-type population.”

Saltz added that “an isolated trial of a regimen that showed response in one of 13 patients with a median progression-free survival of less than 3 months would not be considered as positive, or even encouraging.”

At data cutoff, most of the patients had progressive disease (88%). Median progression-free and overall survival were 2.9 and 11.5 months, respectively. Progression-free survival was 1.4 months in KRAS-mutated patients versus 5.3 months in the KRAS wild-type group, and overall survival was 8.5 versus 14.0 months, respectively.

“It is well established that to properly treat a patient with metastatic colorectal cancer we must know their KRAS, NRAS, BRAF, and mismatch-repair (or microsatellite-instability) status,” Saltz said. “Arguably, HER2 amplification status can now also be considered clinically relevant in metastatic colorectal cancer.”

The current study confirms findings from HERACLES, a trial of the anti-HER2 combination of trastuzumab and lapatinib (Tykerb), where 10 of 33 patients had objective responses and 13 patients had stable disease, for a clinical benefit rate of 70%.

“How and when to sequence these regimens, and what to offer to patients whose molecular profile indicates that they will not benefit, or to those who have progressed after receiving these treatments, remains the focus of intense investigation,” Saltz wrote. “The work in HER2-amplified colorectal cancer represents progress, but this progress is more modest than we would have hoped for from precision oncology, has high financial costs, and is not sufficient.”

From 2014 to 2017, the MyPathway study enrolled 57 HER2-amplified colorectal cancer patients (mean age 55) with metastatic disease. Eight of the patients had HER2-amplified disease with no overexpression — none of these patients responded to treatment. Responses were similar among those with fewer than four lines of prior therapy (32%), and those with four or more (31%).

PIK3CA mutational status also appeared to predict response, with an ORR of 43% in PIK3CA wild-type patients versus 13% in those with a PIK3CA mutation. The best ORR was seen in patients without BRAF, PIK3CA, or KRAS mutations, where 48% (16 of 33 such patients) responded and disease was controlled in two-thirds.

Most patients (93%) had a treatment-emergent adverse event (TEAE). Common events of any grade (≥20%) included diarrhea (33%), fatigue (32%), nausea (30%), anemia (25%), abdominal pain (23%), chills (23%), and dyspnea (20%). Grade 3/4 TEAEs occurred in 37% of patients, with abdominal pain (5%) and hypokalemia (5%) being the most common. Serious TEAEs occurred in 18% of patients, but no deaths were attributable to treatment.

The study was funded by F. Hoffmann-La Roche/Genentech.

Meric-Bernstam reported research funding from AbbVie, Aileron Therapeutics, AstraZeneca, Bayer, Calithera Biosciences, Curis, CytomX Therapeutics, the Debiopharm Group, eFFECTOR, Genentech, Jounce, Novartis, PUMA Biotechnology, Pfizer, Taiho Pharmaceutical, and Zymeworks; and consultant or advisory board relationships with DarwinHealth, Dialectica, Inflection Biosciences, Pieris, and Sumitomo Dainippon.

Several co-authors work for Roche/Genentech, and others reported various relevant industry relationships.

Saltz disclosed grants from Taiho Pharmaceuticals.