Toxicity Management Crucial When Combining Novel Agents


Off-label drug combinations are increasingly being used in cancer treatments, but there is the potential for overlapping or additive toxicities, explained a speaker at the 2023 HOPA Annual Conference.

As cancer treatment continues to evolve, novel agents are increasingly being combined off label to address a variety of clinical needs; however, special concern should be paid in these scenarios to the potentially overlapping or additive toxicities associated with this approach, said Carolyn Oxencis, PharmD, BCOP, during a breakout session at the 2023 HOPA Annual Conference.

"If you develop a stepwise approach and have a regimented way of looking at toxicity, it will help you," said Oxencis, from Froedtert & the Medical College of Wisconsin Cancer Center. "We need to be very honest with patients and tell them they have an increased chance for toxicities, and because of that we may need to check on them sooner. For some, it's as early as day 3."

The standard paradigm in drug development is to identify single-agent activity and safety and then seek to expand that efficacy or overcome resistance through combination strategies; however, the limiting factor is typically the combined adverse events. One common way to overcome this challenge is to give each therapy at a lower dose, said Oxencis.

A literature review of all novel combinations was conducted, to better uncover the most common percentages of dose reductions. As a literature review there was a caveat that most of the data came from clinical trial populations, which are not generally representative of the full population, noted Oxencis. The literature review captured the dose percentage measured against a recommended phase 2 dose, maximum tolerated dose, or FDA-approved dose. It also looked at additive dose percentage, which would combine the dose percentage for each agent.

For the combination of cytotoxic and targeted therapies, the review examined 372 studies and 24,326 patients. Overall, only 38% of studies were able to effectively deliver full doses of both medications. When looking at specific types of agents, PARP inhibitors and histone deacetylase inhibitors required dose reductions 41% of the time when combined with cytotoxic agents.

"The cytotoxic were generally given at full dose, and those are older therapies with more experience. For the new therapies, we're still learning," said Oxencis.

When looking at targeted doublets, 144 studies were analyzed that enrolled 8568 patients and explored 95 different combinations. The full dose of the medications could only be delivered in 51% of cases. Looking at the trends, Oxencis said, "drug antibodies were less likely to have toxicities than some of the small molecule inhibitors." The lowest safe additive percentage was 60%, typically for agents with overlapping mechanisms and especially with mTOR inhibitors. If the class did not overlap and there was not an mTOR inhibitor involved, the lowest additive percentage increased to 143%.

For triplet therapies using a targeted agent, there was data from 386 published studies with 37,763 patients that explored 243 combinations. In this case, full dosing was only capable 28% of the time. When the triplet contained 2 targeted gents and a cytotoxic the lowest additive dose percentage was 133%. This increased to 250% when antibodies were used vs small molecule inhibitors. For 1 targeted agent and 2 cytotoxic agents, the lowest safe percentage was 137%. In 56% of studies, both cytotoxics could be administered at 100%, resulting in a lowest safe dose percentage of 225%.

"When combining targeted agents and cytotoxic agents, antibodies had less toxicities and small molecular had more toxicities, and 100% dosing of the agents was not able to be achieved based on safety parameters," Oxencis said.

For immune checkpoint inhibitor combinations, data were available from 84 studies that included 3526 patients and explored 59 different combinations. The full dose of each medication could be delivered in approximately 50% of cases. When the checkpoint inhibitor was a PD-1/PD-L1 agent, the full dose was delivered in 63% of studies compared with 36% for CTLA-4 inhibitors.

"We observed dose modifications of immunotherapy in clinical practice," said Oxencis. "In some settings, they started at a 50% dose, and in some they started with 1 agent and then added the other. There are different strategies when adding the agents together."

When considering a novel combination, the first thought should be a clinical trial. If they are combined off study, the starting dose should be decreased. "There are a few drug classes that are problematic, but I would say a 25% reduction at a minimum," said Oxencis. "After this, you can titrate up. There's no reason the dose can't be increased if tolerated."

A greater dose reduction may be warranted for agents with the same target, agents in the same drug class, and those with overlapping toxicities. When agents have similar toxicity profiles, it can also be challenging to know which agent to dose reduce, Oxencis noted. "It's our job as oncology pharmacists to understand the kinetics of these adverse effects," she added.

At the patient level, individual characteristics should also be taken into consideration when deciding the dose. It is also important to get written patient consent, and to educate the patient on precision medicine and the fact that as off-label medications they are not FDA-approved and there may not be insurance coverage. Overall, it is important to balance hope vs the hype, she concluded.

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