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Genentech Basket Trial Identifies Impact of Co-Mutations in Dual HER2-Targeted Treatment Response

NEW YORK – A new analysis within Genentech's MyPathway basket trial has shed further light on the range of HER2-overexpressed or -amplified tumors that respond to combination HER2-targeted treatment and shown that the presence of KRAS co-mutations can limit treatment benefit.

At the American Society of Clinical Oncology's virtual annual meeting on Friday, Funda Meric-Bernstam, chair of the department of investigational cancer therapeutics at the MD Anderson Cancer Center, presented data from the MyPathway non-randomized, Phase IIa basket trial, a study launched in 2014 by Genentech to identify new populations of patients who might benefit from its marketed treatments. Across multiple cohorts in the trial, researchers are exploring the activity of trastuzumab (Herceptin) plus pertuzumab (Perjeta); vemurafenib (Zelboraf) plus cobimetinib (Cotellic); vismodegib (Erivedge); erlotinib (Tarceva); alectinib (Alecensa); and atezolizumab (Tecentriq).

Basket trials have proven useful as a vehicle for drug companies and researchers to discover new molecularly defined indications. At the meeting, Meric-Bernstam and her colleagues presented data from a large cohort of MyPathway patients who had a variety of HER2-positive advanced solid tumors and received dual HER2-targeted therapy (pertuzumab plus trastuzumab), and showed that basket trials can also provide insights into co-mutations that may be impacting treatment efficacy.

Between 2 percent and 3 percent of patients with solid tumors have HER2 amplification or overexpression, which is often associated with more aggressive disease. To date, the US Food and Drug Administration has approved HER2-targeted therapies for breast, gastric, and gastroesophageal cancers.

For this analysis, the researchers enrolled patients with cancers for which pertuzumab or trastuzumab are not yet FDA approved, and who had no satisfactory alternate treatments. A total of 258 patients were enrolled in the trial with colorectal, biliary, non-small cell lung, uterine, urothelial, salivary, ovarian, pancreatic, or other cancers.

All tumors had HER2 amplification or overexpression. The majority of the patients had HER2 amplification, but 20 patients also had HER2 mutations, Meric-Bernstam noted.

Of the 258 patients, 60 (23.3 percent) had a confirmed objective response to the pertuzumab-trastuzumab combination. Among responding patients, five experienced a complete response and 55 had a partial response. Further, 115 patients (44.6 percent) had controlled disease. The median duration of response was 7.9 months, median progression-free survival was 2.8 months, and median overall survival was 10.9 months.

As part of an exploratory biomarker analysis, researchers analyzed patients' clinical outcomes by their KRAS status. Of the 258 patients in the study, 199 had wild-type KRAS. Of these, 51 (25.6 percent) had an objective response and 99 (49.7 percent) had controlled disease. The median duration of response in this subgroup was 8.3 months, median progression-free survival was 3.9 months, and median overall survival was 12.6 months.

In contrast, of the 26 patients with mutated KRAS, only one patient (3.8 percent) had an objective response on pertuzumab-trastuzumab. The patient responded to the regimen for 2.7 months, was progression free for 1.4 months, and lived an additional 5.7 months.

"You can see that the progression-free survival was significantly longer in the KRAS wild-type patients versus KRAS-mutated patients," Meric-Bernstam said in a presentation at the meeting. "Looking at the curves for overall survival, you can see again that there was a significant difference in overall survival of KRAS wild-type patients versus KRAS-mutated patients."

Next, in patients with HER2 amplification or overexpression, researchers were interested to see whether their HER2 mutation status impacted disease progression. They found that the median progression-free survival in the 20 HER2-mutated patients was 5.5 months compared to 2.8 months in the non-mutated patients, while the objective response rate in the HER2-mutated patients was 30 percent compared to 20.8 percent in the non-mutated patients. Therefore, Meric-Bernstam said, "HER2 mutation[-status] did not significantly alter progression-free survival or objective response rate."

Finally, researchers explored the possible impact PI3K pathway mutations could have on progression-free survival in patients with HER2 amplification or overexpression treated with pertuzumab-trastuzumab, but they found that those mutations had no significant impact.

In an analysis of how specific tumor types in this MyPathway cohort responded to the combination treatment, the researchers found that every tumor type they studied showed some tumor regression with treatment, but that responses were most notable in the colorectal and salivary tumors.

The objective response rate by tumor type in KRAS wild-type tumors was 30.9 percent in colorectal tumors, 25.7 percent in biliary tumors, 23.6 percent in NSCLC tumors, 6.3 percent in uterine tumors, 15.8 percent in urothelial tumors, 63.6 percent in salivary tumors, 10 percent in ovarian tumors, 33.3 percent in pancreatic tumors, and 18.8 percent in the other types.

Overall, Meric-Bernstam said that her group's analysis showed that the pertuzumab-trastuzumab combination was active in a wide variety of KRAS wild-type, HER2-amplified or -overexpressed advanced solid tumors, with especially high response rates in colorectal and salivary cancers. "Our data suggests that HER2-targeted therapy may have utility in a wide variety of HER2-positive, KRAS wild-type tumors," she said. "MyPathway also demonstrates the value of biomarker-driven basket trials for assessing efficacy across tumor types, while enhancing the ability to determine the impact of co-alterations on anti-tumor efficacy."