Merck & Co’s Keytruda becomes the first PD-1 inhibitor to gain FDA approval.
By Colin White, Lead Analyst
8 September 2014
I am the Lead Analyst for Oncology at Datamonitor Healthcare. I joined Datamonitor in 2009, having previously worked as ...
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Keytruda has gained US approval for the treatment of advanced melanoma patients who are no longer responding to other drugs
On 4 September 2014, Merck & Co announced the earlier-than-expected approval of Keytruda (pembrolizumab) for the treatment of metastatic or BRAF V600 mutation-positive melanoma that no longer responds to Yervoy (ipilimumab; Bristol-Myers Squibb) or BRAF inhibitors. Keytruda has already demonstrated its efficacy in previously untreated patients, and extensive off-label use of Keytruda is anticipated for melanoma patients. Merck has gained a significant advantage by reaching the US market ahead of its rivals and rapid uptake of Keytruda is anticipated after launch.
The approval was based on data from an open-label randomized dose-comparative study cohort of the ongoing KEYNOTE-001 Phase 1b trial in 411 patients with unresectable or metastatic melanoma and disease progression. Patients in this trial had received prior treatment with Yervoy and a BRAF or MEK inhibitor, if BRAF V600 mutation-positive. All participants were treated with Keytruda, either at the recommended dose of two milligrams per kilogram (mg/kg) or at a higher dose of 10mg/kg. The major efficacy outcome measures of the trial were confirmed overall response and duration of response.
Keytruda’s efficacy was established in 173 patients with advanced melanoma whose disease progressed after prior treatment. In half of the patients who received the 2mg/kg dose approximately 24% had their tumors shrink and the effect lasted for 1.4 to 8.5 months. A similar percentage of patients that received the 10mg/kg dose also experienced tumor shrinkage. Keytruda was discontinued for adverse reactions in 6% of 89 patients who received the recommended dose of 2mg/kg and 9% of 411 patients across all doses studied. Serious adverse reactions occurred in 36% of patients receiving Keytruda. The most frequent serious adverse reactions reported in 2% or more of patients were renal failure, dyspnea, pneumonia, and cellulitis.
Keytruda is a fully humanized monoclonal antibody that inhibits the programmed death-1 co-inhibitory receptor (PD-1). The drug was designed to block the negative immune regulatory signaling of the PD-1 receptor expressed by T cells. It has been postulated that antibodies that block the interaction between PD-1 and PD-L1 in tumors may preferentially release the cytotoxic function of tumor-specific T cells with fewer systemic toxic effects than those that are seen with other immune checkpoint inhibitors.
Keytruda has also demonstrated efficacy in previously untreated patients and extensive off-label use is anticipated. Results from the KEYNOTE-001 trial were presented at the 50th American Society of Clinical Oncology Annual Meeting in June 2014 (Abstract LBA9000). The overall response rate to pembrolizumab across the total patient population (n=411) was found to be 34%, with 40% of Yervoy-naïve patients (n=190) and 28% of Yervoy-pretreated patients (n=221) responding to treatment. Patient responses were durable, and 74% of Yervoy-naïve patients and 65% of Yervoy-pretreated patients were still alive after 12 months. Pembrolizumab was also very well tolerated in both arms of the trial, with only 12% of patients experiencing grade 3/4 adverse events. Although these data come from a Phase 1b trial, the high rate of response in Yervoy-naïve patients is likely to catch the attention of physicians and, as soon as Keytruda is launched, it is likely to be used extensively off-label.
The potential for PD-1 inhibitors is huge and Merck has gained a significant advantage by getting the first PD-1 inhibitor approved in the US market. In addition to melanoma, PD-1 inhibitors have demonstrated efficacy in non-small cell lung cancer, renal cell carcinoma, bladder cancer, and head and neck cancer. This drug class is likely to generate billions of dollars a year once PD-1 inhibitors are approved across multiple indications and competition for this revenue is likely to be intense. Roche and AstraZeneca have PD-1 inhibitors in late-phase development, and Bristol-Myers Squibb’s Opdivo (nivolumab) was approved for the treatment of melanoma in Japan in July 2014. The US market will be the most lucrative for PD-1 inhibitors and Merck will now have time to establish Keytruda as the PD-1 inhibitor of choice for melanoma. Bristol-Myers Squibb has already announced its plans to seek US approval for Opdiva in Q3 2014 but will still be behind Merck in this crucial market.
Keytruda will be an expensive treatment option but Datamonitor Healthcare still anticipates uptake to be rapid after launch. Merck has disclosed that its new PD-1 inhibitor will cost payers $12,500 per month or about $150,000 per year. This does not compare favorably with the cost of treatment with Zelboraf (vemurafenib; Roche/Daiichi Sankyo), which is approximately $64,000 per year, or Yervoy which is approximately $120,000 per year. It is even slightly more expensive than Opdivo’s price in Japan which is approximately $143,000 per year. Keytruda will be an extremely expensive drug but is still likely to be reimbursed due to the unprecedented response rates it has achieved in heavily pretreated patients. Keytruda now looks set to become a blockbuster drug for Merck and a leading drug within the PD-1 inhibitor class.
Posted in Oncology.