Though it is touting the potential of its anti-PD-1 antibody lambrolizumab (MK-3475) to be a “pipeline in a product,” Merck & Co. Inc. is also looking to expand beyond the checkpoint inhibitor as it transforms into a biopharmaceutical firm more focused on oncology and particularly immunological approaches to fighting various types of cancer.

The New Jersey pharma is moving an agonistic GITR antibody into Phase I in colon cancer and has an LAG3 inhibitor in preclinical models of renal cortical adenocarcinoma, Senior VP-Global Clinical Development Roy Baynes told an R&D day audience May 6 in Boston.

But Merck also has completed a rolling BLA for ‘3475 in malignant melanoma and announced that FDA accepted the filing for priority review, establishing a PDUFA date of Oct. 28 ([A#00140127010]). An EU filing is expected before year-end.

Melanoma will be just the starting point for Merck’s checkpoint inhibitor cancer immunotherapy, predicts Roger Perlmutter, president of Merck Research Laboratories. The company has begun or is planning clinical trials of ‘3475 in 10 different tumor types comprising roughly 4,000 patients and is performing signal-identification work in 20 other forms of cancer in an effort to identify as many potential uses for the antibody as possible, he said.

Global Oncology President Frank Clyburn told the audience that Merck is investigating ‘3475 in multiple tumor types that have significant unmet need. “The way in which we think about that, we think MK-3475 can almost be a pipeline in and of itself with multiple tumor types and potentially multiple opportunities for product launches,” he said.

That’s a tried-and-true approach in oncology, as Genentech Inc.has proven with its angiogenesis inhibitor Avastin (bevacizumab) Also see "Roche Sees Avastin As Oncology Backbone, Will Focus On Combinations" - Pink Sheet, 10 July, 2006..

Pursuing BLA For Lung Cancer As Well

Melanoma has emerged as the conventional starting point for cancer immunotherapies ([A#14140205003]). Merck has four completed or ongoing monotherapy trials of ‘3475 in metastatic melanoma as well as two combination trials in progress and a third one planned; it is also planning a Phase III study in the adjuvant setting. Merck’s enthusiasm for ‘3475 was bolstered in August when FDA designated it as a “breakthrough therapy” candidate in melanoma.

Other indications are also advancing toward registration. Merck is undertaking a pivotal trial program for ‘3475 in non-small cell lung cancer, Baynes noted, and plans additional registrational trials for the antibody in squamous-cell head and neck cancer and bladder cancer. Lung cancer is expected to be the larger commercial opportunity for cancer immunotherapy.

Other clinical trials in monotherapy are focused on melanoma brain metastasis, triple-negative breast cancer, gastric cancer, hematologic malignancies and colorectal cancer, along with biomarker research in 20 solid-tumor types, according to slides presented by Merck during the R&D briefing. In addition, it has combination trials of ‘3475 underway in renal cell carcinoma and multiple myeloma, with six other trials planned to test combinations in melanoma, NSCLC, RCC, solid tumors and HER2-positive breast cancer.

Merck is placing a big bet on cancer immunotherapy, and specifically the promise of checkpoint inhibitors. Last October, it announced plans to cut expenses by $2.5 billion but at the same time increase R&D and commercial emphasis on ‘3475 Also see "Merck Bets Big On Oncology In New R&D Strategy" - Pink Sheet, 7 October, 2013.. The pharma, previously not an oncology leader, established an integrated oncology business unit that has aligned personnel from Global Human Health, R&D and manufacturing to oversee development and commercialization of the anti-PD-1 candidate.

“We think MK-3475 can almost be a pipeline in and of itself with multiple tumor types and potentially multiple opportunities for product launches.” – Merck Global Oncology President Frank Clyburn

The cancer immunotherapy wave first caught hold with approval of Bristol-Myers Squibb Co.’s CTLA-4 inhibitor Yervoy (ipilimumab). That was the vanguard agent for checkpoint inhibition, drugs that fight cancer by working on immune resistance mechanisms. The next generation, including ‘3475, has consisted of inhibitors of PD-1, which regulates the activity of T-cells, and PD-L1, one of two proteins (along with PD-L2) that bind to PD-1.

Competing with Merck in this area, Bristol is testing its anti-PD-1 antibody nivolumab in NSCLC, B-cell lymphoma, follicular lymphoma and head and neck cancer, while Roche has been quickly advancing toward registration and has been aggressively expanding its trial program for anti-PD-L1 candidate MPDL3280A (RG7446), moving into Phase III in lung and Phase II in bladder cancer ([A#14140130004]). AstraZeneca PLC, with anti-PD-L1 candidate MEDI4736 in Phase II in lung cancer, is also working in the space, while GlaxoSmithKline PLC hopes to bring two cancer immunotherapies into the clinic by 2015 ([A#00140505007]).

Bristol has begun a rolling BLA for nivolumab in lung cancer, the first immunotherapy submission in that indication, although ‘3475 was the first anti-PD-1 candidate to start a rolling submission, with the advanced melanoma filing announced in January.

Frequent Response In Melanoma

Perlmutter overviewed Phase I data in malignant melanoma presented at the Society for Melanoma Research last fall. Nearly three-quarters of patients given ‘3475 monotherapy showed evidence of tumor response, he said, and using a criteria of 30% decline for partial response, a majority of responders had a meaningful response.

“Some of them have a complete response. That is a dramatic result,” he said. “Our view of MK-3475 is that we believe that this is foundational for a new approach to cancer therapy in which our aspiration is to change the shape of the survival curve. In conventional chemotherapy, one has a survival curve for patients with advanced malignancy and you administer the chemotherapy, [and] the tumor does shrink. In the best cases, there is some improvement in survival but frankly the survival curve doesn’t really change its shape at all.”

Immunotherapy has the potential to actually prolong survival, as Yervoy, Roche’s Zelboraf (vemurafenib) and Dendreon Corp.’s Provenge (sipuleucel-T) have shown.

Merck has seen indications that ‘3475 monotherapy can increase survival for cancer population subsets, he added, and hopes that combinations of immunomodulatory agents will improve upon those findings.

“Perhaps in combination with conventional chemotherapy, all of that can help us to achieve an aspirational goal of really bending the shape of the survival curve,” Perlmutter said. “When you look at immune cells, there is no shortage of immunoregulatory molecules that could be important in this process. … We have talked about PD-1, but there is also a set of other molecules on the inhibitory side and in addition, there are a set of immune activators. It may not be enough to just inhibit the anergic signal that comes from things like PD-1. We may need to stimulate cells still further, being careful not to stimulate an autoimmune response that could be very, very vigorous.”

This research is changing basic assumptions about how to fight cancer, he added. Previously, the foundation was to kill tumor cells in any way possible. Now, Merck is asking how to invoke a tumor-directed immune response that will be enduring and “maintain a state of immune surveillance” that will work to eradicate tumors over the long term, the exec explained.

Baynes noted that Merck had obtained data with ‘3475 in metastatic melanoma showing a one-year survival rate of 81%, which he called a “remarkable finding.” In that study, 88% of responders are still in response, but median overall survival data are not available yet.

For the BLA in advanced melanoma, Merck is conducting two trials – one will compare the efficacy of ‘3475 against Yervoy in a treatment-naïve population and the other will test ‘3475 against standard of care in patients who are refractory or resistant to Yervoy treatment.

Merck also has obtained promising results testing ‘3475 monotherapy in third-line-plus NSCLC, Baynes said. Such patients generally have very short survival and do not respond to salvage therapies, but the trial saw a response rate of around 20%, with some responses on ongoing therapy lasting longer than one year. Response has been somewhat more common in patients who express PD-L1 and Merck is continuing to study the role of biomarkers in its pivotal trials, he added.

The company’s latest research showed a connection between levels of PD-L1 expression and the best response rates in lung cancer, but its role in melanoma is still uncertain and there are concerns that tying use to a biomarker could limit the market ([A#06140401020]).

Baynes promised a productive year for Merck in immuno-oncology.

“We anticipate approval in advanced melanoma in the U.S. [and] filing for advanced melanoma in the EU,” he said. “We have four additional registrational trials to begin, two in new tumor types, namely squamous cell cancer of the head and neck and bladder cancer; additional registrational trials in front-line non-small cell lung cancer and adjuvant melanoma; seven additional combination studies in melanoma, non-small cell lung cancer and renal cell cancer as well as HER2+ breast cancer. These will be combinations with standard of care, targeted therapies and other immunologic therapies.”

Analyst Reviews Mixed

But despite the progress in immuno-oncology, Wall Street assessments of Merck’s presentation were mixed.

On the negative side, analyst Alex Arfaei of BMO Capital Markets downgraded Merck’s stock from “outperform” to “market perform” following the event. “Following the company’s R&D day, which [it] is probably fair to say underwhelmed most investors, it became clearer to us that the reasons we had for staying the course are no longer as compelling,” he wrote May 8.

Going into the American Society of Clinical Oncology meeting May 31-June 2, expectations for ‘3475 remain high, Arfaei said, but focus likely will be on immuno-oncology combinations, an area in which he says the pharma trails its competitors. Merck announced a trio of deals in February to test ‘3475 in combination with other cancer drugs from Pfizer Inc., Amgen Inc. and Incyte Corp.

Analyst Vamil Divan of Credit Suisse Equity Research pointed out in a May 7 note that Merck’s share price had risen 17% year-to-date going into the R&D presentation, but dropped by 5% in the two trading days afterward. Still, Divan thinks the long-term strength of Merck in both immuno-oncology and hepatitis C is underappreciated, with plenty of catalysts in place to reassure investors over the next 12 months.

In a May 6 note, analyst Seamus Fernandez of Leerink Partners said Merck’s presentation had met but not exceeded his expectations. He maintained a “market perform” rating for the company’s shares. He predicts approval for ‘3475 in advanced melanoma on or before the FDA action date, but said conversations with key opinion leaders raised questions about initial response to the drug by payers. “The strictness of payer management may be critical to determining early uptake and usage in earlier lines of therapy,” beyond second-line therapy in patients who failed Yervoy, he wrote.

Fernandez is bullish on Merck’s plans to extend ‘3475’s potential label beyond melanoma and lung cancer. “As the number of targeted [immuno-oncology] tumors expands, Merck is neck-and-neck with Bristol in head-and-neck cancer and Roche in bladder cancer,” he asserted. “We await trial designs to see whether Merck will continue with PD-L1 biomarker-based patient selection in these additional tumors.”

Merck is counting on oncology, led by ‘3475, to be a significant driver of growth. Worldwide, there is significant opportunity, said Adam Schechter, Merck President, Global Human Health, as global sales of oncology drugs are expected to increase from $76 billion in 2013 to more than $120 billion in 2020.

“There are three factors that are driving that growth,” he told the R&D day assembly. “The first one is the number of cases [expected to rise from 14 million annually to 22 million annually over the next two decades]. The second one is as new therapies and treatments are available, we expect [increased] duration of treatment, that each person will be treated for a longer period of time. But importantly, we believe that in the future, if you have new innovative products that really make a difference, that you will be able to continue to get a good price for those products. So price plays a role as well.”

Merck Expands Immuno-Oncology Efforts, Calls MK-3475 A Pipeline In Itself

More from Clinical Trials

More from R&D