Designated as a “breakthrough therapy” by the FDA for both advanced and unresectable malignant melanoma and advanced non-small cell lung cancer (NSCLC), and approved by the U.S. Food and Drug Administration (FDA) in September 2014 for advanced pretreated metastatic melanoma, the immune checkpoint inhibitor Keytruda® (pembrolizumab, Merck) has also shown promise for several other indications including (but not limited to) head and neck cancer, Hodgkin’s lymphoma and triple-negative breast cancer (TNBC).
Given Keytruda’s remarkable performance as an antitumor agent in several advanced/metastatic diseases, the therapeutic potential of this promising new drug is now being explored in the context of advanced gastric cancer. In a keynote address on Thursday, Jan. 15 at the 2015 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, an updated cohort analysis of 39 patients with either recurrent or metastatic adenocarcinoma of the stomach or gastroesophageal junction from the Phase 1b KEYNOTE-012 study1 was presented. For this specific analysis, only patients with distinctive stromal or ≥1% tumor nest cell PD-L1 staining were included. Patients were heavily pretreated; 67% of the patients had received two or more prior therapies. Patients were given 10 mg/kg Keytruda every two weeks for up to 24 months or until complete response, progression or unacceptable toxicity. The primary efficacy endpoint was objective response rate (ORR), and secondary endpoints were duration of response, progression-free survival (PFS) and overall survival (OS).
Keytruda achieved a favorable ORR of 22% by central review and 33% by investigator review. This differs only slightly from that presented at the European Society for Medical Oncology (ESMO) 2014 Congress (30.8% ORR by investigator review).2 Responses were similar between Asian and non-Asian patients. The median time to response was eight weeks, and the median response duration was 24 weeks. The six-month PFS rate was 24%, and the median PFS was 1.9 months. The six-month OS rate was an impressive 69%, and the median OS was not yet reached. Patients had a median follow-up duration of 8.8 months, and 33% remained on therapy as of November 2014. Although the data were very preliminary, a trend toward an association between higher levels of PD-L1 expression and ORR (p=0.102), PFS (p=0.162) and OS (p=0.124) was observed. Only four patients experienced Grade 3 or higher drug-related adverse events: peripheral sensory neuropathy, fatigue, decreased appetite, hypoxia and pneumonitis (2.6% each); one of these adverse events (hypoxia) resulted in patient death.
To date, the treatment landscape for advanced or relapsed gastric cancer has proven to be relatively bleak. Prior to the approval of the VEGFR-2-targeted therapy Cyramza® (ramucirumab, Eli Lilly), there were no approved targeted agents for the treatment of relapsed gastric cancer, and physicians relied on fluoropyrimidine- or taxane-based chemotherapy. Cyramza was approved in the U.S. and Europe based on results from the REGARD and RAINBOW trials. In REGARD, Cyramza was associated with an OS of 5.2 months versus 3.8 months for placebo (HR 0.776, p=0.0473) in patients previously treated with first-line platinum- or fluoropyrimidine-based therapy. In addition, the six-month OS rates were 41.8% in patients treated with Cyramza versus 31.6% in the placebo group.3 RAINBOW compared paclitaxel ± Cyramza as a second-line therapy; the addition of Cyramza to paclitaxel significantly extended median OS (9.6 months versus 7.4 months, HR 0.81, p=0.017). The six-month and 12-month OS rates for Cyramza plus paclitaxel were 72% and 40%, respectively, compared with 57% and 30% for paclitaxel alone.4
The results of the KEYNOTE-012 gastric cancer cohort analysis highlight the promising antitumor activity and manageable toxicity of Keytruda in advanced gastric cancer. While there are caveats to comparing trials directly, patients treated with Keytruda monotherapy had a similar six-month OS (69%), as did patients treated with Cyramza + paclitaxel (72%); however, recall that the patients on Keytruda were more heavily pretreated. Building on this signal, Merck has announced plans to initiate a Phase II trial (KEYNOTE-059; NCT02335411) to evaluate Keytruda or Keytruda plus cisplatin and 5-FU in 270 patients with recurrent or metastatic gastric and gastroesophageal junction adenocarcinoma. The primary outcomes will be safety and response. This study will provide some important insights on the activity and safety of Keytruda, including its use in combination with chemotherapy, the importance of PD-L1 as a biomarker, and the role of Keytruda in both first-line and relapsed settings. Findings from KEYNOTE-012 should provide valuable to inform future Phase III trial design.
However, as with other tumor types, other manufacturers of PD-1 inhibitors have announced plans to compete in this space. A new Phase III trial (NCT02267343) was initiated in October 2014 to compare Opdivo® (nivolumab, ONO-4538/BMS-936558, Bristol-Myers Squibb/Ono Pharmaceuticals) versus placebo in 480 previously treated Japanese patients with unresectable advanced or recurrent gastric and gastroesophageal junction cancer. This trial will not limit patient enrollment by PD-L1 biomarker status. The primary endpoint will be OS, and secondary endpoints will include PFS, ORR and safety. To date, there are no known late-stage trials of Opdivo in Western gastric cancer patients, but it can be assumed that trials may be initiated in the near future. As in melanoma, Opdivo may ultimately have a first-to-market advantage over Keytruda in gastric cancer in Japan, but Keytruda may have a leg up in the Western markets for this indication.
Along with immunotherapy, other targeted therapies are planning Phase II trials, including Stivarga® (regorafenib, Bayer, NCT01913639) and AMG 337 (Amgen, NCT02016534). Eli Lilly has also announced plans for another Phase III trial for Cyramza (RAINFALL, NCT02314117), which will compare capecitabine plus cisplatin with or without Cyramza in 616 newly diagnosed gastric or gastroesophageal junction cancer patients.
As with other tumors, the competitive landscape for gastric could dramatically change within the next several years given the data presented. These data are certainly at an early stage, but the high response rates and preliminary OS data justify the excitement associated with the PD-1 inhibitors and add gastric cancer to the growing list of tumors in which immuno-oncology may play a significant role.
By: Stephanie Hawthorne, Ph.D., Senior Director, Clinical and Scientific Assessment, Kantar Health and Elizabeth Clarke, Ph.D., Analyst, Clinical and Scientific Assessment, Kantar Health
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