ASCO 2019: The future of Keytruda plus chemo combination therapy

Checkpoint inhibitor combination strategies remains a focus of development, but chemo combos are not a slam dunk for every indication.

As the 40,000 attendees of this year’s ASCO conference relinquish their hold of the windy city, oncology experts worldwide begin contemplating the wealth of new or expanded data which was presented, and how it might affect their everyday practice. While ASCO 2019 was noticeably focused on preliminary and early phase research, Merck & Co.’s immunotherapy Keytruda in combination with chemotherapy, also managed to cause a stir.

To date, Keytruda has received regulatory approval as a monotherapy across ten specific oncology indications; melanoma, non-small cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck (SCCHN), classical Hodgkin’s lymphoma, primary mediastinal large B-cell lymphoma, urothelial carcinoma, gastric and gastroesophageal junction adenocarcinoma, cervical cancer, hepatocellular carcinoma, and Merkel cell carcinoma, and has a broad label for microsatellite high cancer. However, it was Keytruda’s 2017 label expansion in combination with chemotherapy for first-line treatment of metastatic non-squamous NSCLC that cemented the agent’s success. Fast forward two years and Keytruda plus chemotherapy was pegged as a potential “game changing” regimen for chemosensitive solid tumours such as SCCHN and gastric cancer.

Late last year, even the largest skeptics voiced optimism for the combination when initial findings from the KEYNOTE-048 trial reported significant overall survival (OS) benefit for treatment naïve SCCHN patients compared to the current standard of care, the EXTREME regimen. At ASCO, the protocol specified final analysis from KEYNOTE-048 was one of the first oral abstracts presented.  Keytruda plus chemotherapy (platinum + 5-FU) again demonstrated superior OS benefit over EXTREME in patients with CPS≥20, CPS≥1 and the total population, as well as a longer duration of response in the CPS≥20 ad CPS≥1 cohorts respectively (CPS≥20: 7.1 months vs. 4.2 months and CPS≥1: 6.7 months vs 4.3 months). In addition, Keytruda monotherapy demonstrated superior OS in the CPS≥20 and CPS≥1 cohorts and was shown to be non-inferior to the EXTREME regimen in the total population. While this is potentially practice changing for SCCHN, the news for gastric cancer was not as good.

In April, two months after the estimated primary completion date of the KEYNOTE-062 trial, Merck & Co. released a concise press release stating the trial investigating Keytruda and Keytruda plus chemotherapy (cisplatin plus 5-FU or capecitabine) as first line treatments for gastric and gastroesophageal adenocarcinoma patients, had failed to meet its primary endpoints of OS and progression free survival (PFS) benefit. The initial results were presented for the first time in a brief poster discussion on Sunday at ACSO. Monotherapy Keytruda was found to be non-inferior to chemotherapy for OS in patients with CPS≥1 and displayed an improved safety profile over chemotherapy. However, the Keytruda plus chemotherapy arm failed to demonstrate superior OS benefit in patients with either CPS≥1 or CPS≥10 (HR=0.85; P= 0.046 and HR= 0.85; P=0.158, respectively) compared to standard chemotherapy treatment.

So, what will these results mean in practice? Regardless of the promising preliminary results across indications, is there still potential for Keytruda plus chemotherapy to be a “one size fits all” regimen for PD-L1 positive patients? Is the KEYNOTE-062 failure a sign of things to come for the other Keytruda plus chemotherapy combinations, or is it simply another regimen to fall at the feet of the beast that is gastric cancer?

The positive results from the KEYNOTE-048 trial will be practice changing, with a panel of experts as ASCO supporting its use in the first line setting. However, physicians seem weary of using Keytruda monotherapy as a first-line option. Time will tell which regimen garners physician preference in the clinical setting, as the FDA announced their approval of both Keytruda monotherapy and in combination with chemotherapy for patients whose tumours express PD-L1 (CPS≥1) on June 10th. Although some may argue Keytruda monotherapy may be useful for patients who are frail and deemed ineligible for chemotherapy, data from the KEYNOTE-062 trial does not accurately reflect these patients as they likely would not have been eligible per study criteria. Ideally, a proof of concept trial would be carried out to support this use.

As for the larger picture, per the latest update of DRG’s Oncology Clinical Trial Monitor, over 150 trials in Phase II or III investigating Keytruda plus chemotherapy have been registered to-date.  While results from NSCLC and SCCHN are encouraging and support use in both squamous and non-squamous cell carcinomas, gastric and gastroesophageal junction adenocarcinoma results have highlighted how the unique characterises of each indication will determine their response to immunotherapy and chemotherapy alone or combined. Nevertheless, this will be an interesting space to watch over the coming years.