HER2-Targeted Therapy Shows Activity In HER2-Positive, KRAS Wild-Type Tumours

Author: By Lynda Williams, Senior medwireNews Reporter 

medwireNews: Many HER2-positive tumours that are wild-type for KRAS may respond to combination therapy with pertuzumab and trastuzumab, suggest findings from the MyPathway HER2 basket study. 

The phase IIa research was presented to the 2021 ASCO Annual Meeting by Funda Meric-Bernstam, from the University of Texas MD Anderson Cancer Center in Houston, USA, who explained that the study looked at the use of HER2-targeted therapies in tumour types without US FDA indications for these treatments. 

Patients with solid tumours with HER2 amplification and/or overexpression who had previously received a median two prior therapies were given a pertuzumab 840 mg loading dose followed by 420 mg every 3 weeks alongside a trastuzumab loading dose of 8 mg/kg and 6 mg/kg every 3 weeks thereafter until disease progression or unacceptable toxicity. 

In all, there were 258 patients with colorectal cancer (n=84), biliary cancer (n=40), non-small-cell lung cancer (NSCLC; n=27), and uterine (n=23), urothelial (n=22), salivary (n=18), ovarian (n=12), pancreatic (n=10) or other (n=22) types of tumours. 

Of note, most patients (n=191) had HER2 amplification, 30 patients had HER2 amplification and overexpression, 17 patients had HER2 amplification and mutations, and 17 patients showed HER2 overexpression only, while three patients exhibited all three HER2 factors. 

After a median 9.4 months of follow-up, the investigator-assessed objective response rate (ORR) was 23.3%, including five complete and 55 partial responses that lasted for a median 7.9 months. The disease control rate was 44.6%. 

The median progression-free survival (PFS) and overall survival (OS) durations were 2.8 and 10.9 months, respectively. 

However, response to combination HER2-targeted therapy differed by KRAS mutation status, reported Funda Meric-Bernstam. 

The ORR was 25.6% for the 199 KRAS wild-type patients, 3.8% for the 26 patients with a KRAS mutation and 24.2% for the 33 patients with unknown KRAS status. 

The disease control rates were 49.7%, 3.8% and 45.5%, respectively, and the median durations of response were a corresponding 8.3, 2.7 and 6.7 months.  

Median PFS for KRAS wild-type, mutated and unknown status groups was 3.9, 1.4 and 2.7 months, respectively, with KRAS wild-type and unknown status patients having significantly better PFS, with hazard ratios versus KRAS mutated patients of 0.25 and 0.34, respectively. 

Median OS durations for the KRAS wild-type, mutated and unknown status groups were 12.6, 5.7 and 8.3 months, respectively, with wild-type and unknown status patients having significantly longer OS than their mutated counterparts, with hazard ratios of 0.44 and 0.51, respectively. 

When the ORR among the KRAS wild-type patients was examined by tumour type, the highest rate of 63.6% was found among 11 patients with salivary gland disease. An ORR was also recorded in one of three patients with pancreatic tumours, 30.9% of the 68 colorectal cancer patients, 25.7% of the 35 biliary cancer patients and 23.8% of the 21 NSCLC patients. 

Lower ORRs were found for patients with nonspecified tumours (18.8%), and those with urothelial (15.8%), ovarian (10.0%) and uterine (6.3%) cancer. 

Of note, there was no evidence that the presence or absence of HER2 mutations affected HER2-targeted therapy efficacy, nor was it impacted by the presence or absence of a PI3K pathway alteration. 

Funda Meric-Bernstam said that there were “no new safety signals” in the study. Treatment-emergent adverse events (AEs) led to study drug discontinuation, dose reduction or interruption in 4.7%, 1.6% and 21.3% of patients, respectively. Treatment-related AEs occurred in 72.1% of participants, of which 11.2% were grade 3–4 and 4.7% were classified as serious.  

The presenter concluded that the pertuzumab plus trastuzumab is an “active” combination achieving a “durable” response in many advanced KRAS wild-type tumours with HER2 amplification or overexpression, whereas there was “limited activity” in patients with KRAS mutations. 

“Our data suggest HER2-targeted therapy may have utility in a variety of HER2-positive KRAS wild-type tumours”, she concluded. 

“MyPathway also demonstrates the value of biomarker-driven basket trials for assessing efficacy across tumour types while enhancing the ability to determine the impact of co-alterations on antitumour efficacy.” 

Reference 

Meric-Bernstam F, Hainsworth J, Bose R, et al. MyPathway HER2 basket study: Pertuzumab (P) + trastuzumab (H) treatment of a large, tissue-agnostic cohort of patients with HER2-positive advanced solid tumors. J Clin Oncol 2021;39(suppl 15; abstr 3004). DOI:10.1200/JCO.2021.39.15_suppl.3004