Pembrolizumab/Trastuzumab Induction Highly Active in HER2+ Gastric, GEJ Cancer

Yelena Y. Janjigian, MD

Two-thirds of patients with untreated metastatic HER2-positive esophagogastric adenocarcinoma remained free of disease progression at 6 months with a combination of pembrolizumab (Keytruda), trastuzumab (Herceptin), and chemotherapy, a small clinical trial showed.

Among 35 evaluable patients, 67% remained progression-free at 6 months. The trial had an accrual goal of 37 patients and a target 6-month progression-free survival (PFS) of 70% (26 of 37), Yelena Y. Janjigian, MD, of Memorial Sloan Kettering Cancer Center, reported at the 2019 Gastrointestinal Cancers Symposium.¹ The analysis occurred after a median follow-up of 6.6 months.

The combination therapy led to an overall response rate (ORR) of 87% in 32 evaluable patients, as compared with a historical rate of 47% in patients who received frontline trastuzumab plus 5-FU/platinum chemotherapy.²

“I hope that we were clear that there is some synergy and benefit for this combination in metastatic gastric and G-junction tumors,” said Janjigian. “Pembrolizumab and trastuzumab with chemotherapy is well tolerated. There was an encouraging overall response rate that compares favorably with what we see with historical controls.”

An ongoing phase III trial of the combination in the frontline setting (KEYNOTE-811; NCT03615326) “will definitively show what this combination will do with respect to the survival benefit in this population.”

Trastuzumab’s approved indications include first-line treatment of metastatic HER2-positive gastric and gastroesophageal junction (GEJ) cancer, in combination with chemotherapy. In addition to the 47% response rate, the regimen was associated with a median overall survival (OS) of 13.8 months, said Janjigian.

Pembrolizumab has approval for the treatment of patients with PD-L1—positive recurrent or advanced gastric or GEJ adenocarcinoma who have received 2 or more lines of chemotherapy, including fluoropyrimidine- and platinum-containing chemotherapy, and, if appropriate, HER2/neu-targeted therapy.

On the basis of preclinical evidence, investigators hypothesized that combining anti—PD-1 and anti-HER2 therapy would induce T-cell activation, augment antibody-dependent cellular cytosis, and potentiate antitumor immune response in patients with HER2-positive disease.

Clinicians at Memorial Sloan Kettering enrolled patients with untreated stage IV HER2-positive esophagogastric cancer, unselected for PD-L1 expression status. The patients received induction treatment with trastuzumab and pembrolizumab with oxaliplatin and capecitabine. The trial had a primary endpoint of 6-month PFS, assuming enrollment of 37 patients and 26 or more progression-free at 6 months. Secondary endpoints included OS, ORR, and disease control rate.

The 35 patients included in the analysis had a median age of 61, and 27 (77%) were men. The primary disease site was the esophagus in 14 patients, GEJ in 12, and gastric in 9. Confirmation of HER2 status was not required, and 6 patients were subsequently found to be HER2 negative. PD-L1 expression status was negative (CPS <1) in 12 patients, positive in 14, and unavailable in 9.

No unexpected adverse events/toxicities occurred during the trial. Grade 3/4 adverse events were infrequent, the most common being decreased lymphocyte count (12%).

CT scans of 23 patients after pembrolizumab/trastuzumab induction therapy but before the start of chemotherapy showed reduction in tumor volume in 12 (52%) patients. In 32 patients evaluable for best response, 28 (87%) had objective responses, including complete responses in 3 (9%) patients. Reductions in tumor volume ranged from 9% to 100%. Four other patients had stable disease, resulting in a disease control rate of 100%.

With follow-up ranging from 0.03 to 23.5 months, median PFS in the 35 patients was 11.4 months. Median OS had yet to be reached, but the 12-month OS was 76%.

Biomarker analyses that included 29 patients revealed no tumors with microsatellite instability. Patients with PD-L1—positive or –negative tumors had similar PFS and OS. Nonamplification of ERBB2 by next-generation sequencing was associated with a short duration of response. A third of the patients had co-occurring RTK, RAS, and/or PIK3CA alterations.

“HER2 status remains important, but PD-L1 status is not a predictor of progression-free survival,” Janjigian said.

References

1. Janjigian YY, Chou JF, Simmons M, et al. First-line pembrolizumab (P), trastuzumab (T), capecitabine (C) and oxaliplatin (O) in HER2-positive metastatic esophagogastric adenocarcinoma (mEGA). J Clin Incol. 2019;37 (suppl 4; abstr 62).
2. Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376(9742):687-697. doi: 10.1016/S0140-6736(10)61121-X.

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