Drug Developers Share Thoughts on the Oncology Pipeline and the Changes in Clinical Trials

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Two oncologists who are now heads of oncology development for pharmaceutical companies discussed the future of cancer drugs at the Community Oncology Alliance’s 2022 Community Oncology Conference. They were ­Johanna Bendell, MD, Global Head of Oncology, Pharma Research, and Early Development at Roche, and Jeffrey Infante, MD, Global Head of Oncology Early Clinical Development and Translational Research at the Janssen Pharmaceutical Companies of Johnson and Johnson. The ASCO Post captured their thoughts from a panel discussion at this meeting.

Johanna Bendell, MD

Johanna Bendell, MD

Jeffrey Infante, MD

Jeffrey Infante, MD

Building on the Successes of Precision Medicine

Precision medicine has not rested on its many laurels but continues to grow as more mutations and pathways become identified and druggable. Profiling has moved into the earlier-stage setting, where the targeting of molecular aberrations can truly change the course of a patient’s cancer. Drug development continues to build upon this approach, “finding the right treatment for the right patient to create the right outcome,” Dr. Bendell said. “We see a huge bump in the number of targeted therapies coming out.” 

Dr. Infante agreed that “precision medicine is here to stay.” However, he remains concerned about the development of treatment resistance, which limits the duration of response to targeted agents. “I’m a little less positive than Dr. Bendell, as resistance often develops sooner than we would like,” he said. “That said, when an important target to treat cancer is identified, companies will design therapies to go after it every which way.”

They agreed that to optimize long-term outcomes, multiple drugs will probably be needed to target the original mutation, mutations that are acquired during treatment, and alterations in other pathways that are active in that tumor. “The future is in combinations,” Dr. Bendell said.

To better understand how and why tumors become resistant to otherwise-effective targeted therapies, “longitudinal” or “repetitive” molecular profiling of patients is important. Much of the data for this effort come from clinical trials, but profiling of patients who can offer “real-world data” is also important for designing drugs to target acquired mutations, she added. 

Dr. Bendell pointed to the tyrosine kinase inhibitor osimertinib as successfully “hitting” the original and resistance mutations in non–small lung cancer, elevating it to a treatment standard. Dr. Infante said he wants to see such drugs used earlier in treatment, “to get ahead of the resistance instead of waiting for a failed state.” Part of the challenge is patient heterogeneity and the likelihood that resistance results from not one but multiple mechanisms, he acknowledged.

Dr. Infante continued: “Often, early in the disease setting there is a dominant mutation that is driving the cancer to grow, sometimes termed a “truncal” mutation…. What if we can get smarter? What if we can identify and potentially target these ‘truncal’ mutations earlier?” Dr. Bendell agreed: “Maybe this would lead to bigger benefits, before mutations evolve. I think you’ll see a bigger push toward understanding the patient’s molecular profile as early as you possibly can.”

With combinations come the potential for overlapping toxicities, so it is important to determine how best to give multiple drugs: concurrently, alternating, or sequentially. The best approach will be one that is not only effective but “patient-centric,” Dr. Bendell added. “There is a huge focus now on determining better ways to give drugs.”

She was referring to regimens that patients can tolerate for years without negatively affecting their quality of life. This could mean more oral agents, more drugs given subcutaneously rather than intravenously, and regimens that offer extended dosing intervals. Telemedicine as an approach to monitoring patients could also be useful to staff and patients. “These themes are starting to emerge,” she added.

Cellular Therapies

Cellular therapies, in particular chimeric antigen receptor (CAR) T-cell therapy, are an example of technology that delivered on its promise. “When Dr. Carl June presented the first CAR T-cell data, I thought, ‘Wow, even though this is a small numbers of patients, these are impressive outcomes, but there is no way can you pull this off on a large scale…. Well, I was wrong,” Dr. Infante said. “The technology and manufacturing are getting better, managing patients is getting easier, and cellular therapy can be really active with deep and durable responses,” Dr. Infante continued. “That being said, I still think cellular therapy is complex…. It’s hard to get the therapy to the patient in time. I think the onus is on the pharmaceutical industry to optimize cellular therapy and make it more feasible.”

The technology and manufacturing of cellular therapy is getting better, managing patients is getting easier, and the clinical activity can be deep and quite durable.
— Jeffrey Infante, MD

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Moving forward, Dr. Infante predicted that CAR T-cell therapy will move into earlier lines of treatment, may even become a part of first line regimens or sequencing of therapies. He is also hopeful the technology can be adapted to treatment settings outside of specialized centers, for greater patient access.

Bispecific Antibodies and Antibody-Drug Conjugates

The speakers briefly touched on two other emerging classes of drugs that are exploding in the oncology pipeline: bispecific antibodies and antibody-drug conjugates. “Some tumor types will be more immune-sensitive, and others will be more sensitive to chemotherapy,” Dr. Infante noted. These two classes will play an expanding role. Interestingly, patients on bispecific antibodies designed to redirect your infection-fighting cells toward the cancer may experience some of the same toxicities as those on CAR T-cell therapy.

“There is also a huge boom in vaccine therapy,” according to Dr. Bendell. “We are thinking about mRNA vaccines—we started before COVID—to help treat cancer, and we already have dendritic vaccines. Much of the thinking is that the best place for vaccines is in patients with very minimal residual disease.”

Dr. Infante cautioned that vaccine therapy alone will probably not be sufficient to eradicate tumors, which would require a “massive” immune response that may not be achievable with vaccines alone. He also pointed out a flaw in the development process; both pharmaceutical sponsors and health authorities typically begin or request that trials be initiated in the advanced setting, whereas if vaccines are going to work in cancer, it seems it would be most effective in the early disease setting. Unless we start thinking differently, these issues could be stumbling blocks for vaccines in cancer care.

Managing Toxicities: New Skill Set Needed

The speakers emphasized the need for clinicians to adapt to the arrival of cellular therapies into outpatient settings. One thing they will need is a better skill set for managing unique toxicities, some of which can overlap with those of other types of treatment. Some of the toxicities associated with CAR T-cell therapy are also seen with bispecific antibodies and antibody-drug conjugates.

“This is probably the future we will have to prepare for. I think it’s key that large practices in particular start to develop these abilities…. This is something to think about as you look at your own practice,” Dr. Bendell suggested.

Dr. Infante pointed out that step-up dosing, supportive care, and drugs such as tocilizumab for cytokine-release syndrome now allow patients to be treated with doses surpassing what would have been dose-limiting toxicities at ineffective exposure levels. “There are ways to manage patients in the clinic, where you can start low and escalate over 1 or 2 weeks and achieve active therapeutic doses,” he said.

Dr. Bendell added that the use of step-up dosing creates some new logistical issues in the clinic, such as additional chair time. “You’re going to see a lot of intravenous therapies become more complicated. The patient is probably in there 3 to 4 days a week for the first week, then every other week, and then will require monitoring for cytokine-release syndrome afterward. How are you prepping for this?” she asked attendees. “These issues are things to think about. How do we evolve, and how do we manage our practices to accommodate these things?”

Changes in Clinical Trials

Clinical trials are predicted to have a wider reach in the future as more community practices participate. Dr. Bendell and Dr. Infante said they welcome this. “That’s where the bulk of patients receive their care, so the possibility of bringing clinical trials to patients in the real-world setting is really important,” Dr. Bendell commented.

I think you’ll see a bigger push toward understanding the patient’s molecular profile as early as you possibly can.
— Johanna Bendell, MD

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She added that among the 2021 new drug approvals, 60 were anticancer drugs that were first-in-class molecules. “Providers treating patients in the community must learn about those new molecules, their toxicity profiles, how to give them, and how patients respond to them. The way you stay ahead of that in the community is to participate in the trials. It’s a great way to stay on top of what’s next, and it’s offering the next best thing to your patients,” she emphasized.

Bringing clinical trials into the community, however, will not be easy unless simpler protocols and structures are in place to facilitate the process for both patients and staff. Telemedicine can be useful in reaching a wider patient population and in managing subjects on trials. New processes should also be put in place to assure the data obtained are “high quality and clean,” Dr. Infante added.

Niche Drug Development

One problem in the clinical trials setting, however, is the increase in “niche” drugs, Dr. Infante added. “It’s not like you are testing a drug for lymphoma anymore, or even a big subset of lymphoma like diffuse large B-cell lymphoma,” he said. “Actually, no, it could be for a very specific sub-set such as non-GCB [germinal center B-cell like] diffuse large B-cell. It’s become niche, niche, niche. It’s rare to have a drug that works across the board. It becomes unmanageable for a busy cancer center to have an infinite number of trials open that can fit every individual patient. Also, as a principal investigator it’s hard to oversee more than 18-20 oncology trials and not start to feel overwhelmed.”

One way to ease this might be to have multiple sponsors for a single trial in which companies could place a compound to be evaluated within a master protocol. Although this approach may solve some problems, it also is problematic in terms of oversight and in “getting everyone to play in the sandbox together.” Even though oncology drug development is complex, there is clearly a lot of momentum to find new and better therapies. The field is moving at a rapid pace which hopefully will translate directly to improved treatments for cancer patients. 

DISCLOSURE: Dr. Bendell is employed by Roche. Dr. Infante is employed by Janssen.