Ilson Explains Evolving Role of PD-1 Inhibitors, HER2 Combinations in Gastric Cancer

Howard S. Hochster, MD

David H. Ilson, MD, PhD

Treatment options are limited for gastric cancer, which impacts approximately 26,000 people each year and has an average 5-year survival rate of about 29%, according to the American Society of Clinical Oncology (ASCO). Newer agents, including immunotherapies and HER2 and VEGF-targeted therapies, are being investigated, but the jury is still out on if these therapies will be beneficial, said David H. Ilson, MD, PhD, a medical oncologist at Memorial Sloan Kettering Cancer Center.

“There is a lot of interest in immunotherapy agents,” said Ilson in an interview withTargeted Oncology. “We haven’t yet identified clearly which patients are likely to benefit from these drugs but there is a signal of activity, and clinical trials including phase III trials are ongoing. Hopefully they will identify activity for these drugs in various lines of treatment, either alone or in combination with chemotherapy, and hopefully better identify if biomarkers like PD-L1 can identify patients that are more likely to benefit.”

Pembrolizumab (Keytruda) is one agent that is being evaluated in gastric cancer. The PD-1 inhibitor is currently being investigated in an ongoing multicenter open-label phase Ib trial in patients with PD-L1-positive recurrent or metastatic adenocarcinoma of the stomach or gastroesophageal junction (GEJ) at 13 cancer research centers in the U.S., Israel, Japan, South Korea, and Taiwan. Patients in the study received intravenous pembrolizumab at 10 mg/kg once every 2 weeks for 24 months or until progression or unacceptable toxic effects occurred. Response was assessed every 8 weeks.¹

From Oct 23, 2013, to May 5, 2014, 39 patients were enrolled and 36 were evaluable for response by central assessment. Twenty-two percent of patients experienced a partial response (95% CI 10-39). In terms of safety, 13% of patients had a total of six grade 3 or 4 treatment-related adverse events, consisting of two cases of grade III fatigue, one case each of grade III pemphigoid, grade III hypothyroidism, and grade II peripheral sensory neuropathy, and one case of grade IV pneumonitis. No treatment-related deaths occurred.

The PD-1 inhibitor nivolumab (Opdivo) is also being investigated in gastric cancer as part of the the phase I/II Checkmate-032 trial, an open-label, multi-tumor cohort study that accrued patients with lung, breast, bladder, pancreatic, and ovarian cancer, and treated them with nivolumab as a single-agent or in combination with ipilimumab (Yervoy).²

Overall, 163 patients with gastric cancer were enrolled in the study. Fifty-nine patients with locoregionally advanced or metastatic gastric cancer or GEJ were assigned to single-agent nivolumab at 3 mg/kg IV every 2 weeks. The remaining 104 patients were assigned to 1 of 3 nivolumab/ipilimumab combination regimens. Thus far only the preliminary results for patients who received nivolumab monotherapy have been presented, which demonstrated a median overall response rate (ORR) of 14% (n = 8; 95% CI, 6%-25%), including 1 (2%) complete response (CR) and 7 (12%) partial responses (PR). The rates of stable disease (SD) and progressive disease were 19% (n = 11) and 58% (n = 34), respectively. Responses were not determined for 6 (10%) patients. The disease control rate (CR + PR + SD) was 32% (n = 19).

“These agents are now being explored in larger randomized trials either comparing treatment to chemotherapies in first and second line or with supportive care versus immunotherapy,” said Ilson. “They are modestly effective drugs; they are not hugely effective drugs like they are in melanoma. It still seems that for the vast majority of patients that these drugs don’t have a benefit, but there may be a small subset that benefits.”

To better determine which subset will benefit, more effective biomarkers are needed, said Ilson. PD-1 has some potential in gastric cancer, as does tumor mutational burden. While gastric cancer is not extremely immunogenic, it is more so than some other cancers where immunotherapies have been investigated, said Ilson.

“In terms of the mutational spectrum, esophageal gastric cancer is on the higher end compared to other solid tumors, but certainty we are not seeing the activity in this space with immunotherapy that we are seeing with melanoma patients,” he said.

Potential for HER2, VEGF-Targeted Agents

HER2

Since the approval of trastuzumab (Herceptin) for the treatment of patients with-positive metastatic gastric cancer in 2010, the interest in other HER2-targeted agents and novel combinations has only grown.

 

While numerous trials have been conducted, not much success has been seen, said Ilson.

HER2-targeted therapies lapatinib (Tykerb) and T-DM1 failed randomized phase III trials in gastric cancer.

However, pertuzumab (Perjeta) may offer some potential.

The results of the phase III JACOB trial, which is evaluating the efficacy and safety of pertuzumab in combination with trastuzumab (Herceptin), fluoropyrimidine and cisplatin as first-line treatment in patients with HER2-positive metastatic GEJ or gastric cancer, are eagerly anticipated, said Ilson.³

The combination of pertuzumab and trastuzumab is also being investigated in the neoadjuvant setting. The ongoing INNOVATION study aims to determine if trastuzumab or the combination of trastuzumab and pertuzumab with standard chemotherapy shows more activity against gastric cancer than standard chemotherapy given before and after surgery, and if the combination can be safely administered.

Novel VEGF targeted agents also offer some potential in gastric cancer. One agent that may be interesting is apatinib, a tyrosine kinase inhibitor (TKI) approved in China that selectively inhibits the VEGFR2, said Ilson. In findings recently published in theJournal of Clinical Oncology, apatinib demonstrated a mean overall survival (OS) rate of 6.5 months (95% CI, 4.8 to 7.6) compared to 4.7 months (95% CI, 3.6 to 5.4) for patients who received placebo (P = .0149). The mean progression-free survival (PFS) rate was 2.6 months (95% CI, 2.0 to 2.9) for patients treated with apatinib and 1.8 months (95% CI, 1.4 to 1.9) for patients that received the placebo treatment (HR, 0.455; 95% CI, 0.332 to 0.624; P < .001)⁴

Genomic profiling may shed light on even more actionable targets, but the role for this technology is still being established, said Ilson.

&ldquo;HER2 and VEGF-targeted agents are being actively investigated and we are getting emerging databases about genomic profiles of esophageal gastric cancer indicating more defined molecular subsets,&rdquo; he said. &ldquo;Unfortunately, those data haven&rsquo;t really given us a clear indication of new therapies. Even though we are seeing mutations and abnormalities, it has not yet clearly provided a sign-post about how we can design trials to make sense of these markers.&rdquo;

The challenge with genomic profiling is that it often identifies mutations where there are not currently available therapies. Genomic tests have also identified targets with available drugs, but when investigated in clinical trials, those drugs have not demonstrated a benefit.

&ldquo;Some of the more common amplified pathways studies have already shown that drugs identified by genomic profiling have not had an impact, like EGFR and MET,&rdquo; said Ilson. &ldquo;I think it is a work in progress, at the end of the day it is important to amass these data to get a better understanding of the biology of this disease and whether we can apply it clinically.&rdquo; &nbsp;

1. Muro K, Chung HC, Shankaran V, &ldquo;Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial.&rdquo; The Lancet Oncology. 2016 Jun;17(6):717-26. doi: 10.1016/S1470-2045(16)00175-3. Epub 2016 May 3.

2. Antonia S, L&oacute;pez-Martin J, Bendell J. &ldquo;Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial.&rdquo;The Lancet OncologyPublished Online: 04 June 2016

3. Tabernero, J, Hoff PM, Shen L &ldquo;Pertuzumab (P) with trastuzumab (T) and chemotherapy (CTX) in patients (pts) with HER2-positive metastatic gastric or gastroesophageal junction (GEJ) cancer: An international phase III study (JACOB)&rdquo; Journal of Clinical Oncology. 31, 2013 (suppl; abstr TPS4150) 2013 ASCO Annual Meeting, Abstract: TPS4150

4. Li J, Qin S, Xu J, et al. Randomized, double-blind, placebo-controlled phase III trial of apatinib in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction. J Clin Oncol. 2016:1448-1454; DOI:10.1200/JCO.2015.63.5995.