Investigators are exploring a dual HER2-targeting strategy that incorporates tucatinib into a novel combination as second-line therapy for patients with HER2-positive gastric and esophageal cancers.
Investigators are exploring a dual HER2-targeting strategy that incorporates tucatinib (Tukysa) into a novel combination as second-line therapy for patients with HER2-positive gastric and esophageal cancers. The MOUNTAINEER-02 trial (NCT04499924) is a phase 2/3 study evaluating the addition of tucatinib plus trastuzumab (Herceptin), both HER2-directed agents, to standard-of-care ramucirumab (Cyramza) and paclitaxel in previously treated patients.1
The combination, if approved, would provide a new therapeutic option for patients with gastric cancer, according to John H. Strickler, MD, an associate professor of medicine at Duke University School of Medicine and a member of Duke Cancer Institute, in Durham, North Carolina, and a leading investigator on the MOUNTAINEER-02 trial.
“It could be practice-changing in that current thinking and current clinical research have told us that there is not a lot of evidence for carrying forward an anti-HER2 strategy after patients have disease progression on an anti-HER2 first-line therapy,” Strickler said in an interview with OncologyLive®.
First-line therapy for patients in this population typically consists of trastuzumab plus fluoropyrimidine and platinum-based chemotherapy, according to Strickler. “For a long time, there have been efforts to look at continuing an anti-HER2 strategy in the second line after progression on a first-line regimen,” he said. “Our current standard of care for these patients in most cases is paclitaxel and ramucirumab in the second-line setting.”
In pairing the HER2-targeting agents, investigators are seeking to replicate the benefits shown in the phase 2 HER2CLIMB trial (NCT02614794). The trial results led to the FDA approval in April 2020 of tucatinib in combination with trastuzumab and capecitabine for adults with HER2-positive metastatic breast cancer, including patients with brain metastases, who have received 1 or more prior anti-HER2-based regimens in the metastatic setting.2,3
Median overall survival (OS) with the tucatinib regimen was 21.9 months (95% CI, 18.3-31.0) compared with 17.4 months (95% CI, 13.6-19.9) for patients who received placebo plus trastuzumab and capecitabine (HR, 0.66; 95% CI, 0.50-0.87; P = .00480).2
“The thinking is that this is a therapy that might have other applications outside of breast cancer in HER2-positive malignancies, particularly where there’s an unmet need for additional therapies,” Strickler said.
For MOUNTAINEER-02, investigators are recruiting patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma (GEJ) with disease progression who have received first-line therapy and a HER2-directed antibody. In total, they plan to recruit approximately 566 patients, starting with sites in the United States and expanding into Asia and Europe (Figure).1,3
Patients are eligible to participate if they test positive for HER2 amplification by next-generation sequencing (NGS) on a blood-based circulating tumor DNA (ctDNA) assay. They are also eligible if they have HER2 overexpression or amplification by immunohistochemistry (IHC3+) and in situ hybridization (IHC2+/ISH+) analysis on fresh or archival tumor biopsy samples.
The study is being conducted in multiple steps, starting with a phase 2 paclitaxel dose optimization stage involving 6 to 12 patients who will receive the chemotherapy at either 60 mg/m2 or 80 mg/m2 on days 1, 8, and 15 of each 28-day cycle. Participants will also receive tucatinib at 300 mg orally twice daily, trastuzumab at a 6 mg/kg loading dose followed by doses of 4 mg/kg on days 1 and 15 of each subsequent cycle, and ramucirumab at 8 mg/kg on days 1 and 15 of each cycle.
Once the recommended dose of paclitaxel has been established, patients will be assigned to 1 of 2 cohorts of 24 to 30 patients each in which they will receive the 4-drug experimental regimen. Cohort 2A will comprise patients who are HER2-positive by blood-based NGS testing whereas cohort 2B will be an exploratory group of patients who are HER2-negative on blood-based NGS and HER2-positive by tissue testing. The primary end point of the phase 2 portion is the safety and tolerability of the regimen.
In the phase 3 part of the trial, patients who are HER2-positive by ctDNA testing will be randomized to 1 of 3 arms: arm 3A (n = 235), in which participants will receive the experimental 4-drug regimen; arm 3B (n = 235), in which patients will be treated with ramucirumab plus paclitaxel with tucatinib and trastuzumab placebos; and arm 3C (n = 30), in which participants will receive tucatinib plus ramucirumab and paclitaxel with a trastuzumab placebo.
The primary objective of this part of the trial will be to evaluate OS and progression-free survival per investigator assessment for arm 3A vs arm 3B. Antitumor activity in arm 3C is among the secondary end points.1,3
Investigators anticipate that the 4 therapies will function well in combination, Strickler said. Tucatinib, a small molecule tyrosine kinase inhibitor, has “very potent,” selective activity against HER2 with minimal off-target effects. “For that very reason, it’s very well tolerated,” he noted. “As a result, it combines well with other treatments whether it be trastuzumab or cytotoxic chemotherapy.”
In the HER2CLIMB breast cancer trial, the most common adverse events (AEs), mostly of grade 1 and 2 severity, were diarrhea, palmar-plantar erythrodysesthesia, nausea, fatigue, hepatotoxicity, vomiting, stomatitis, decreased appetite, abdominal pain, headache, anemia, and rash. Tucatinib can also cause severe diarrhea and hepatotoxicity. Six percent of patients who received tucatinib during the study discontinued therapy due to AEs.4
In terms of the combination being tested in MOUNTAINEER-02, there is very little overlapping toxicity between the cytotoxic chemotherapy paclitaxel and trastuzumab and tucatinib, according to Strickler. Ramucirumab, a monoclonal antibody directed at VEGFR, also has an AE profile that is predictable.
“The toxicity of trastuzumab has been well defined for many years. For most patients, it is exceptionally well tolerated. All of us as GI [gastrointestinal] medical oncologists are fairly comfortable with giving trastuzumab front line with chemotherapy,” Strickler said.
For the average patient, tucatinib also is well tolerated with occasional instances of mild elevation of liver enzymes or loose bowel movements, he added. “In my own experience, dose adjustments are rarely needed for tucatinib when it’s given in combination with trastuzumab.”
An important facet of MOUNTAINEER-02 will be analyzing the trajectory of HER2 expression among participants. Investigators theorize that prior attempts to demonstrate an OS benefit with HER2-targeting approaches vs chemotherapy as second-line therapy in this setting have faltered because of the loss of HER2 expression following trastuzumab-based therapy.3
“There will be intensive analysis of ctDNA at the time the patient is enrolled to get a better sense for whether HER2 positivity in ctDNA is a potential predictive biomarker benefit from this regimen,” Strickler said. “We may find that the patients who remain ctDNA positive for HER2 amplification are the ones who capture the benefit and that could potentially inform future practice.”
Seagen Inc, the company developing tucatinib, has launched several trials evaluating the agent in various clinical settings involving GI malignancies.
In the phase 1b/2 MOUNTAINEER trial (NCT03043313), tucatinib is being evaluated as monotherapy and in combination with trastuzumab in patients with HER2-positive metastatic colorectal cancer (mCRC). In the phase 1b SGNTUC-024 study (NCT04430738), investigators are testing tucatinib plus trastuzumab and FOLFOX (leucovorin, fluorouracil, oxaliplatin) in patients with unresectable or metastatic HER2-positive GI cancers, including mCRC, cholangiocarcinoma, gallbladder carcinoma, or gastric/GEJ cancers.
Additionally, investigators are exploring tucatinib in the phase 3 HER2CLIMB-02 trial (NCT03975647) in combination with ado-trastuzumab emtansine (T-DM1, Kadcyla) vs T-DM1 alone in patients with previously treated advanced or metastatic HER2-positive breast cancer.