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The Cancer Letter – Oncologists, advocates, FDA call for an end to MTD and the “more is better” era in cancer drug dosing

The Cancer Letter – Oncologists, advocates, FDA call for an end to MTD and the “more is better” era in cancer drug dosing

Finding the MTD, or maximum tolerated dose, was a rarely challenged rule in trials of cytotoxic drugs. But drugs change—and ideologies change with them. Today, a growing number of oncologists, drug developers, patient activists, and FDA officials are calling for setting the dose by means more refined than a sledgehammer.

“There are other models besides ‘Let’s go in there and be macho and slug our patients with as much as they can stand, assuming that most of them will get up off the mat after we slug them,’” said gastrointestinal oncologist Richard Goldberg, former director of West Virginia University Cancer Institute. “All of us who have written orders for cytotoxic drugs have had patients die of the side effects of the drugs that we’ve ordered.”

On May 3-5, FDA and ASCO will host a workshop on dose-setting. The title: “Getting the Dose Right: Optimizing Dose Selection Strategies in Oncology.”

FDA has become a supporter of dose optimization. Richard Pazdur, director of FDA’s Oncology Center of Excellence, said in June 2021 that drug companies will soon be expected to complete optimal dose-finding studies before testing safety and efficacy in pivotal trials (The Cancer LetterJune 11, 2021).

“Finally, FDA is saying, it’s no longer what you should do. It’s what you must do,” Mark Ratain, the Leon O. Jacobson Professor of Medicine at University of Chicago Medicine and one of the founders of the Optimal Cancer Care Alliance, a group seeking to end “oncology overdosing,” said to The Cancer Letter.

Technically, FDA doesn’t have explicit authority to force companies to implement optimal dose-finding studies before drugs hit the market. However, the agency can promulgate guidance documents that point to best practices—and in situations where a poorly selected dose may be contributing to excessive toxicity or lack of efficacy, FDA is clearly able to take action. Also, the agency can request dose-finding studies and issue post-market requirements.

Last week, the subject of dose optimization came up at the Oncologic Drugs Advisory Committee, as the agency’s advisors discussed phosphoinositide 3-kinase (PI3K) inhibitors. In clinical trials of this class of drugs, dosage was based largely on MTD. This may have contributed to a survival deficit on the experimental arms of registration trials, FDA officials said (The Cancer LetterApril 15April 22, 2022).

Brian Booth, director of FDA’s Division of Cancer Pharmacology I, delivered a presentation on dose optimization in oncology at the ODAC meeting April 21. The transcript of his presentation appears here.

Last year, FDA’s Pazdur made a series of comments on dose optimization in the context of the agency’s dramatic decision to require Amgen to conduct a post-marketing, randomized clinical trial of its KRAS inhibitor sotarisib, comparing the labeled dosage (960 mg daily) to a 75% lower dosage (240 mg daily). According to a paper co-authored by UChicago’s Ratain, Amgen had moved forward with the higher dose despite significant toxicities and “no evidence of a dose-response relationship.”

“When you look at the Amgen development program of sotorasib, the phase I and dose-finding trials, all you can do is shake your head,” Ratain said. “They either weren’t thinking, they weren’t looking at their data, or they had decided they were going to do it a certain way, come hell or high water.”

In a paperpublished in the Oct. 9, 2021 issue of The New England Journal of Medicine, FDA officials similarly addressed the need for updated dosing strategies for cancer drugs.

FDA’s Mirat Shah said at the 2021 Friends of Cancer Research annual meeting, held Nov. 9-10, that the agency is working on optimal dosing guidance. This will be conducted under Project Optimus, an initiative that works with drug developers as they consider dose optimization for new therapies.

Also at the meeting, a group of contributors presented a white paper called “Optimizing Dosing in Oncology Drug Development,” laying out rationale and recommendations for integrating dose-finding studies into drug development pathways.

The FDA guidance on the subject is pending.

Dose optimization studies have encountered resistance from regulatory agencies, drug companies, and even oncologists.

“You’re taking an approach that’s been ingrained in oncology drug development for many, many years, and so there’s not just a switch you flip that’s going to make people change how they conduct their development programs,” Mark Stewart, vice president of science policy at Friends of Cancer Research, said to The Cancer Letter.

“People are still arguing about this,” Ratain said. “There’s pretty good consensus, but there are definitely some outliers who don’t think we need to do randomized dose ranging trials. The bottom line is, investigators who say, ‘Well, we don’t need to do this,’ or, ‘Companies won’t like this,’ or, ‘Companies won’t do it,’ they’re wrong, because the FDA’s going to make them do it, and other regulatory agencies are going to make them do it.”

FDA’s stance signals a new phase in this fundamental doctrinal disputation.

“Many of the founders of oncology, people like Emil Freireich and Vincent DeVita, who developed the notion of chemotherapy—the use of cytotoxic drugs to kill cancer—were great believers in giving as much drug as you could to kill as many cancer cells as you could, but allowing the patient in the end to recover from the toxicity,” Goldberg said to The Cancer Letter.

Newer precision treatments—molecular targeted agents and immunotherapy—often have target saturation limits below the MTD. These drugs may be able to deliver the same benefits with fewer side effects, the Friends white paper says.

“Over the past decades, life-changing therapy, such as targeted therapy, immunotherapy, and chimeric antigen receptor T-cell therapy, have revolutionized cancer treatment,” Nam Atiqur Rahman, division director of the Division of Cancer Pharmacology II at FDA’s Office of Clinical Pharmacology, said at the 2021 Friends meeting. “However, the prevailing mindset in drug development that ‘more is better’ is loud and clear from our patients: the drugs are too toxic and the physicians are tied to the dosing schedule in the package insert.”

“Why did it take 25 years?”

Two factors have created a tipping point in favor of dose optimization: the advent of targeted cancer therapies, and a slew of studies demonstrating that the MTD is higher than necessary for some drugs, Goldberg said.

Ratain and Allen S. Lichter, chair of the Optimal Cancer Care Alliance, have been at the forefront of the push for optimal dosing in oncology—focusing on sotarisib and, earlier, Pharmacyclics and Janssen’s ibrutinib (The Cancer LetterApril 13May 18, 2018).

“Oncology drug development has changed minimally from that used for chemotherapy: it has focused on determining the maximally tolerated dose as quickly as possible and using that dose in registration trials to get to market as quickly as possible,” Ratain, Lichter, and colleagues from the Optimal Cancer Care Alliance wrote in a recent guest editorial. “FDA’s policy shift is a major tailwind in this effort; guided by FDA-mandated dose-optimization trials, oncologists will increasingly come to reject the notion that ‘more is always better’” (The Cancer LetterJune 11, 2021).

A 1994 global guidance called ICH-E4, adopted by FDA in 1996, notes that “even in indications involving life-threatening diseases, the highest tolerated dose, or the dose with the largest effect on a surrogate marker, will not always be the optimal dose.”

“The question is, well, why did it take 25 years to institute this requirement?” Ratain said. “We have more than 25 years of drug approvals, including dozens of drugs at excessive doses. Companies basically didn’t care, or simply believed ‘more is better.’ But their primary objective was to get their drugs approved as quickly as possible.”

ICH-E4 still holds true, even as FDA drafts a new guidance for dose optimization, Ratain said.

“Quite frankly, they really don’t need to do a guidance. There is the ICH-E4 guidance. All you have to do is read and quote from ICH-E4, where it says, ‘Don’t use the MTD,’” Ratain said. “They can write a more specific updated current guidance. When I point people to ICH-E4, they go, ‘That’s a 1994 document, and thus it’s out of date.’ You could say the same thing about the Torah.”

Ratain’s work advocating for dose-finding studies in oncology began in the early 2000s. A 2004 study of temsirolimus served as early evidence that MTD is flawed, Ratain said.

“I’ve been studying exposure-toxicity relationships my entire career, but I think the first example that made it very, very clear [was] the temsirolimus trial that Mike Atkins did,” Ratain said. “They discovered, not really surprisingly, that 25 mg was as good as 250, and they went on to do a registration trial of 25.

“I think the first time I said, specifically, ‘You need to do randomized dose-ranging phase II trials,’ was a review I wrote with Dan Sargent in 2009.”

Goldberg said the issue of dose optimization figured in a 2019 paper that prompted reconsideration of regorafenib, a colorectal cancer drug that was approved for colorectal cancer in 2012. Seven years after the FDA approval, the study, published in The Lancet, found that regorafenib could be given at half the standard dose doctors had been using for years. At a reduced dose, the drug produced fewer side effects and had similar activity.

“I was actually involved in the study that led to the licensing of regorafenib, and was working with the drug company, saying that I thought that the dose that we used in the defining study was too high and not tolerable to patients,” Goldberg said. “But, that was what they got FDA-approved, and that’s what they pushed for many years after the drug was approved, until finally they listened to the clamor from oncologists and did a study where they randomized patients to various doses of the drug as a starting dose.

“It turned out that the tolerable dose for most patients was half of the dose that was in the package insert. That is, I think, one of the most egregious examples of a company that seemed to want to sell more drug, so they were happy to promote a dose that was poorly tolerable to patients and not test lower doses until they were pushed by the investigator community.”

Despite the evidence, it has taken continued effort from people in the academic and regulatory spheres, including FDA’s Pazdur, to jump-start conversations about optimal dosing.

“Oncologists, patients and pharmaceutical companies work together in drug development, and clearly the three groups have concordant interests to identify and test new drugs. The drug development process is a very carefully choreographed dance, and we’ve gotten good at the choreography,” Goldberg said. “Drug developers at pharmaceutical companies like playing by the rules they have grown used to, just like oncologists, who take comfort in playing by the rules that we are used to.”

Patient advocates have been a part of this effort. Anne Loeser, a Friends white paper co-author and founder of the Patient Centered Dosing Initiative, presented the results from two PCDI surveys—one of 1,221 metastatic breast cancer patients, another of 119 oncologists—at the 2021 American Society of Clinical Oncology annual meeting.

Of the patients interviewed, 86% reported experiencing at least one “bad” treatment-related side effect and 43% said they had skipped at least one treatment due to these side effects.

“When you miss a treatment, it could jeopardize the efficacy of your treatments,” Loeser said to The Cancer Letter. “Patients who are experiencing significant side effects may have to even stop treatment altogether. In certain cases, they may not be able to receive the very treatment that’s helping them.”

Drug sponsors may be resistant to change due to concerns about the speed of the drug development, worries about revenues, or just wanting to keep things as they are, Goldberg said.

“When pharmaceutical companies constantly testify to whomever will listen about how much it takes to develop a drug and how many drugs fall by the wayside after they’ve invested millions of dollars in them, because of some glitch that keeps them from crossing the finish line—they use that as an argument to say, ‘Because of that, we should get ‘pricing considerations’ for the drugs that do cross the finish line,’” Goldberg said.

The question of revenues 

Dose optimization, if completed before the price is set and the drug hits the market, doesn’t have clear implications for revenues, Ratain said.

Usually, the prices of new drugs aren’t set based on the drug’s volume.

However, if a drug is already priced and on the market at a time when the dose is found to be higher than necessary, lower doses need to be introduced. At that point, the sponsor may face uncomfortable questions about the price, Ratain said.

“If you do this before you set your price, it has no impact on price. If you are forced to do this after you set your price, it has a huge potential impact on revenues,” Ratain said. “The only way to save this is to come up with a new formulation and take your old one off the market, or alternatively, raise your price four-fold and hope nobody notices.”

In some cases, drug companies have been known to disregard compelling evidence against standard, MTD-based dosing regimens. Ratain cited an example of a company implementing a dose-finding trial, but not acknowledging the results.

“BMS actually did a randomized dose-ranging trial of Opdivo (nivolumab). They randomized over a dose range from 0.3 to 10 milligrams per kilogram, every three weeks, in kidney cancer,” Ratain said. “They found no difference. So what did they do? They ignored it.”

BMS officials didn’t respond to an email from The Cancer Letter.

Pharmaceutical companies aren’t solely to blame; making dose optimization the norm amounts to an enormous cultural shift for oncologists and drug developers alike, Goldberg said.

“We, as oncologists in my generation, were all trained with cytotoxics, to think about cancer drugs in the model of cytotoxic drugs,” Goldberg said. “Around 2000, we started getting more and more targeted drugs—and we still thought like we had been trained to think, so it took a long time to change our thinking.”

Conflicts of interest arise as well, particularly for oncologists whose income is tied to how much drug they prescribe. If such an oncologist is informed that a half a dose is as efficacious as the labeled dose, would they be reluctant to reduce the dose accordingly?

“In many circumstances, how much an oncologist takes home, particularly in private practice, depends on how much drug they sell,” Goldberg said. “So, there is, to some degree, a conflict of interest there—if you get paid by how many milligrams of the drug you sell, you want to sell more milligrams, whether you’re the doctor or the pharmaceutical company.”

“A way to get it done”

FDA should provide a framework for implementing successful dose-finding studies, FOCR’s Stewart said.

“We are quick to highlight the benefits [of newer therapies]—the unprecedented efficacy, the narrow toxicity profiles, yet when it comes to our clinical trial designs, we’ve not seen them reflecting that same type of precision, both in terms of eligibility criteria, but also in terms of how we are approaching the dosing for these types of drugs,” Stewart said. “I do think there’s a need to be more precise in how we are conducting these clinical trials, and that should be reflected in the protocols as well.”

Dosing guidance can come from sources other than FDA, including the National Comprehensive Cancer Network guidelines. In 2019, the Value in Cancer Care Consortium was successful in pushing for an update to the NCCN Prostate Guideline, based on a study showing that 25% of the standard dose of the prostate cancer drug abiraterone was just as effective—and far cheaper (The Cancer LetterMarch 29, 2019).

“That’s exactly the precedent,” Ratain said. “It obviously would go a lot easier if the studies were convened by the federal government, because it’s certainly in the federal government’s interest as a major payer to do these kinds of studies. We’re looking for ways to both improve the patient experience and to reduce costs.

“This is the way to go, and there should be a way to get it done, funded by the federal government, and there could even be a bill passed.”

In addition to regulatory and drug development pathways, the patient-oncologist relationship plays a key role in optimizing dosage, Loeser and Stewart said.

Loeser’s PCDI survey found that many oncologists are willing to lower their patients’ doses based on side effects—and 85% of oncologists do not believe the standard dose is always more effective than a lower dose.

Having multiple dose options on a package insert is important, but so is encouraging conversations between patients and their oncologists, Loeser said.

“The PCDI has developed a list of nine attributes that we feel patients and doctors should discuss when patients begin a new treatment and then throughout treatment, and determine what the best dose for that patient would be if the drug comes in multiple doses,” Loeser said.

“I think there’s a lot to be said in terms of the conversations between a patient and their physician, and [PCDI is] providing a lot of resources in terms of encouraging patients to have these conversations with their physicians around making sure that they’re receiving a dose that makes sense to them, based on their physical situation or even psychological factors, when they’re starting a new treatment,” Stewart said.

The increasing focus of FDA and drug sponsors on building optimal dose-finding into phase I studies brings forward new challenges.

“The real issue—from my perspective, as someone who’s not a regulator and is not in the business of developing new drugs for a company—is, what do we do with all the drugs that were approved between 1994 and 2021 for which there was no dose optimization, and which are labeled at excessive doses?” Ratain said.

Since talks between drug sponsors and FDA have mainly focused on drugs that are in development, many already-approved cancer drugs are floating in dosage limbo, Stewart said. But exploring different indications and combinations for these drugs could present an opportunity.

“I think drug sponsors can continue to explore the use of these drugs in different indications, for instance, or different lines of therapies that might open the door up to enable investigation to whether the dose that the drug was approved at is really the optimal dose,” Stewart said.

“Additionally, what we see in oncology is a lot of these drugs are beginning to be investigated in combinations,” Stewart said. “That also opens the door for exploring whether the initial dose is the optimal dose, particularly when you get into combination therapies where you might see some synergists, or you might see additive effects in terms of the toxicity.”

Of the oncology drugs already on the market, some—namely, checkpoint inhibitors—may require an urgent revisiting of dosage, Ratain said.

“Once you accept the principle that dose optimization is necessary, the logical thing is, that solves the problem for new drugs, but it also implies that every other drug that is approved may be labeled in excessive dose,” Ratain said. “We’ve written about this, and pointed out those that are most appropriate for dose optimization. The ones that we think have the most compelling evidence are immune checkpoint inhibitors.”

The key to making dose-finding studies the norm in oncology is communication between stakeholders, Stewart said.

“Having a communication tool that can enable the sharing of information so that both the sponsors and FDA can be more proactive rather than reactive to the data would be valuable,” Stewart said. “We’re in the process of working with sponsors and FDA on thinking through what a drug development dosing snapshot could look like and how that might serve as one communication tool to help facilitate these conversations.”

Friends white paper 

The Friends of Cancer Research white paper focuses on the importance of having discussions early in the drug development pipeline, Stewart said.

“I think the white paper certainly helped identify actionable opportunities to help support this shift, moving towards better dose-finding studies in oncology drug development,” Stewart said. “Again, one of those key issues is facilitating interactions with the agency, because earlier is better when it comes to these types of studies. If you wait too long in the development program, then you do face the potential issue of delaying a development program.”

The authors of the white paper are:

  • Gideon Blumenthal, vice president of Oncology Global Regulatory Affairs at Merck
  • Lokesh Jain, senior director of Quantitative Pharmacology and Pharmacometrics Oncology Clinical Development at Merck
  • Anne Loeser, patient advocate at Patient Centered Dosing Initiative
  • Yazdi K. Pithavala, senior director of clinical pharmacology at Pfizer Inc.
  • Atiqur Rahman, division director of the Division of Cancer Pharmacology II at FDA’s Office of Clinical Pharmacology
  • Mark Ratain, Leon O. Jacobson Professor of Medicine at University of Chicago Medicine
  • Mirat Shah, clinical reviewer at FDA’s Office of Oncologic Diseases
  • Laurie Strawn, senior director of Oncology Global Regulatory Affairs at Pfizer Inc.
  • Marc Theoret, deputy center director of FDA’s Oncology Center of Excellence

The white paper addresses several “perceived challenges”—ideas held by stakeholders—that stand in the way of implementing optimal dose-finding studies.

The first perceived challenge is: “Dose-finding studies are too time consuming and will prevent patients from quickly getting the drugs they need.”

The authors responded:

  • Performing dose-finding studies prior to registrational trials can save time down the line by preventing the need for clinical holds and post-marketing requirements.
  • Determining an optimal dose may give more patients access to the drug, thanks to improved tolerability and fewer missed treatments.
  • Discussions with FDA about dose-finding studies should start early in the drug development process, possibly before the Investigational New Drug application. (The white paper includes a table with key considerations for different points in the drug development pipeline.)

The second perceived challenge is: “Lower doses of drug are not as effective as higher doses.”

The authors responded:

  • Drug sponsors should tackle the risk of underdosing by carefully assessing the effects of different doses and considering intrapatient dose escalation mid-trial.
  • Stakeholder and patient education—through avenues such as updated FDA guidance—can help deconstruct the idea that a higher dosage is always better, especially since lower doses are often appropriate for targeted therapies.

The white paper also includes guidance and expectations for dose-finding studies.

Pre-clinical data can help drug developers identify a range of doses for further testing, based on drug toxicity and activity, the authors said. Well-defined biomarkers may be useful in measuring the pharmacokinetic and pharmacodynamic properties that define this dosage window.

In terms of trial design, the authors said pre-registrational dose-finding studies would ideally be randomized, include enough participants to “understand the general shape of the dose/exposure-activity/toxicity relationships, including the minimally active dose,” compare at least two doses, and identify an optimal dose—balancing benefit and risk—to be used in the registrational trial.

Doses tested in early trials should be two- to three-fold apart, or different enough to reveal clear patterns in exposure-response relationships. In the absence of a significant difference in safety and efficacy between two doses, the authors suggested moving forward with the lower dose.

Designing a dose optimization study necessitates several key considerations, the authors said. These include therapeutic properties of the drug, characteristics of the patient population, and whether or not there are previous clinical findings related to the exposure-response dynamics of the drug.

The white paper also enumerates findings from a 2013 Friends publication on the issue of cancer drug dosage, with the acknowledgement that many of the challenges identified then still exist.

In a future oncology landscape with dose optimization, “side effects would be regarded as possible but not inevitable,” the authors said.

“The issue is not that there aren’t dose-finding studies available—that’s not a new concept. And the issue isn’t necessarily that there’s a need for innovative trial strategies for determining the right dose—those are pretty well-established,” Stewart said. “It’s really the optimal timing and how to integrate dose optimization studies within the current oncology drug development paradigm.”