Immuno-Oncology: Execs Talk About Tumor Response, Biomarkers, Lessons Learned

Leaders from Novartis and other companies developing cellular gene therapies share insights they've gleaned on manufacturing, clinical trials, and value-based pricing.

Executives in the immunotherapy space discussed the challenges that lie ahead, such as finding ways to measure the effect of a therapy against a constantly changing tumor and distinguishing biomarkers that may not predict response in all tumor types. But they also noted that the field could shake up the way companies approach drug development and commercialization.

Speaking on a panel at the BIO CEO & Investor Conference held in New York Feb. 12-13, Novartis AG's Samuele Butera, global cell & gene therapies business leader, emphasized that innovation isn't limited to the clinical space, but also has to happen in the manufacturing and commercial spheres to make sure as many patients as possible get these therapies.

Novartis' Kymriah (tisagenlecleucel) was the first chimeric antigen receptor T cell (CAR-T) therapy to be approved by FDA. It cleared the agency in August for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. Gilead Sciences Inc.'s Yescarta (axicabtagene ciloleucel) CAR-T therapy was approved in October for treatment of adults with relapsed or refractory large B-cell lymphoma.

Alluding to Butera's comment about the three pillars of cellular gene therapies, Sadik Kassim, VP, process and analytical development at Mustang Bio Inc., said the immuno-oncology field offers "an opportunity to integrate some of those line functions, which traditionally have been siloed, to enhance overall clinical response."

Kassim cited work done by a researcher at the University of Pennsylvania who analyzed T cells isolated from patients and "was able to find the cell population in the study material of non-responding CLL patients that essentially predicted whether a patient responds or doesn't respond." Within a manufacturing context, the researcher was "able to identify something which may subsequently enable a combination strategy."

"Traditionally you never would have viewed manufacturing or CMC [chemistry, manufacturing and controls] as being an enabling component of your translational medicine strategy. This is an opportunity to really evaluate the way we use different line functions to enhance responsiveness and overall efficacy of these trials," Kassim said. He noted that the UPenn research is to be published soon in Nature Medicine.

Hurdles In Measuring Tumor Response

Moderator Asthika Goonewardene, a senior biotech analyst at Bloomberg Intelligence, asked the panelists if they are doing the right thing in terms of measuring tumor response and identifying responders.

Butera replied that in terms of identifying the right targets and tumor response, it is not simply about the specific tools that are used, but how we think about tumor response over time. He suggested that in addition to safety and effectiveness, it is important to look at a therapy's long term effect on quality of life.

Tito Serafini, president and CEO of Atreca Inc., questioned what tumor response means. He said there is an ongoing immune response in patients as the immune system fights an ever-changing foe.

"There are going to be classic measurements of tumor shrinkage, survival" that are important to regulatory review, he said. "But when we are thinking about this being a chronic disease that could potentially be managed from multiple entry points it will be more important to look at the steps of the immune system and how that is constantly acting and reacting in these patients."

"Some subgroups of patients clearly are being changed with immunotherapy in ways that we don’t understand," NewLink's Charles Link said, whose patient went into remission after 29% progression.

Adelene Perkins, chair and CEO of Infinity Pharmaceuticals Inc., noted that in many cases FDA is still requiring companies developing drugs to use the RECIST criteria for evaluating treatment response, although there are new irRECIST criteria that are interesting but not yet validated.

The RECIST (Response Evaluation Criteria In Solid Tumors) criteria is used for determining when patients progress in clinical trials. The irRECIST response criteria combines elements of RECIST and the immune-related response criteria (irRC), which is based on World Health Organization criteria.

Durable responses "might not show up clearly on RECIST scans," Perkins said. "But if people can keep their disease in check and live with the cancer as a chronic condition that's what we're all working for and we are in the process of defining those measures."

FDA has explored modifying existing tumor response criteria or developing novel intermediate endpoints. In October 2016, the agency co-sponsored a two-day meeting with the American Association for Cancer Research to discuss new ways to measure immunotherapy efficacy in clinical trials. (Also see "Cancer Immunotherapies Have FDA, Industry Looking For New Endpoints" - Pink Sheet, 19 Oct, 2016.)

Charles Link, CEO and chief scientific officer of NewLink Genetics Corp., noted that in immuno-oncology it seems clear that there are subsets of patients who achieve stable disease after CAR-T therapy or checkpoint blockade or some combination, but there is no good methodology to classify a patient with stable disease in terms of what's happening immunologically in the tumor bed.

"Some subgroups of patients clearly are being changed with immunotherapy in ways that we don’t understand," Link said. He noted that he had a patient who progressed by 29% and a year-and-a-half later went into remission. "I don't understand how that's possible," he said.

Biomarkers Are Not Universal

Kassim noted challenges in using biomarkers to predict response to a therapy.

"There are biomarkers that are emerging, like tumor mutation burden, and we need to keep in mind as we design trials, these biomarkers may not be universally applicable across tumor types and indications" and across patients, he stated.

Kassim noted that the majority of immunotherapies are directed against T-cells so traditionally T-cell infiltration in tumor would be viewed as a positive prognostic marker of response, that the higher the frequency of T cells the more likely the patient is to respond to therapy.

He cited a study that analyzed tumor samples of 20,000 patients and found infiltration of T cells was a positive prognostic in the majority of tumors, but in renal cancer it was a negative prognostic indicator. He added that one cell type that was negatively associated with response across the board was M2 macrophages.

Novartis' Marketing Experience

The moderator asked Butera what issues Novartis has faced bringing Kymriah to market and when cell therapy may become a more commonly accepted therapy.

Butera replied that Novartis is taking a measured approach for the next few years focusing on centers that have experience in transplantation and the ability to deal with side effects.

The company noted at the time of approval that Kymriah would initially be limited to 30-35 centers that meet Foundation for the Accreditation of Cellular Therapy standards and have experience with T-cell therapies and leukemia. (Also see "Novartis CAR-T Therapy's Swift Approval Aided By REMS And New US FDA Review Model" - Pink Sheet, 30 Aug, 2017.)

Butera reiterated the crucial need to integrate the three broad functional areas of clinical development, manufacturing, and commercialization, which encompasses access and reimbursement strategy, account management, and medical affairs. "The key is ensuring the feedback loop that exists between those functions is accelerated and tightened," he said.

He added that Kymriah's small patient population – about 600 patients are eligible for treatment – has enabled Novartis to work on the integration of these functions "so we can roll out this experience to a 10, 15, 20 times larger population."

As for pricing, he noted that the Institute for Clinical and Economic Review (ICER) gave Kymriah a positive review. (Also see "ICER Views CAR-T Therapies Kymriah, Yescarta As Cost Effective" - Scrip, 21 Dec, 2017.) And he said that as of Jan. 1, the therapy has a Q code from the Centers for Medicare & Medicaid Services, which should help centers gain clarity on reimbursement.

Kymriah has a list price of $475,000 before discounts. However, under an innovative outcomes-based pricing strategy with CMS, for Kymriah's initial indication there will be no charge for the therapy if the patient does not respond by the end of the first month of treatment.

Butera said Novartis is active with both CMS and private payers in preparing them for launch of Kymriah for treatment of B-cell lymphoma. He added that Novartis will continue to pursue a value-based approach.

Novartis announced on Jan. 17 that FDA had accepted its supplemental biologics license application for Kymriah for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma who are ineligible for or relapse after autologous stem cell transplant.

Mustang Bio's Kassim commented that payers haven't explicitly addressed the issue of secondary costs with CAR-T and immune therapies, such as management of toxicities. "If you just look at the price of a product that's probably deceptively simple," he said. "The question becomes what's the threshold, what can the systems tolerate in terms of these additional costs."