Cancer drug doses: More is not always better

Historically, the goal of cancer treatment has been to destroy as many cancer cells as possible through chemotherapy or radiation.

Guided by this “more-is-better” approach, researchers in phase 1 clinical trials typically have sought to establish dosing based on the maximum amount patients could tolerate.

However, in the era of targeted therapies and immunotherapies, which generally are well-tolerated, this approach may lead to doses that are excessively high and unnecessarily costly.

Source: Roswell Park Comprehensive Cancer Center.

“Traditionally, with chemotherapy, the paradigm had been to give as high of a dose as the patient can tolerate,” Grace Dy, MD, associate professor in the department of medicine at Roswell Park Cancer Center, told HemOnc Today. “That’s how traditional cytotoxic chemotherapy drugs (eg, antimitotic apparatus, anti-DNA synthesis agents) are formulated.

“However, with newer drugs, like targeted therapy and immunotherapy, the concept of using the highest dose that can be safely administered might not be ideal,” Dy added. “If they’re safe, there may not be dose-limiting toxicities to determine the maximum tolerated dose, or efficacy signals may be achieved even at lower dose levels with less toxicity, and so there comes a point when it is better to establish the optimal, biological dose. But, generally speaking, common practice is to use the highest dose that can be safely or feasibly administered, because that’s a long-tested model.”

Approaches to achieve similar efficacy with a lower dose may be as simple as extending time between doses or taking the therapy with food.

A decade ago, when targeted therapies were in early development, researchers began to notice that the typical practice to take treatment in a fasting state was associated with nausea, vomiting and increased toxicity with certain targeted therapies, Dy said.

“For example, they found that if ceritinib (Zykadia, Novartis) is taken with food, it not only improves tolerability, but antitumor efficacy can be maintained with lower dosing,” she said.

HemOnc Today spoke with medical oncologists and researchers about challenges associated with studying lower drug dosages, how food can improve the bioavailability of cancer drugs, whether weight-based dosing may be more effective than fixed dosing for newer cancer drugs, and whether these dosage-lowering principles can be extended to chemotherapy to reduce its toxic effects.

Setting doses during research

Monoclonal antibodies have undergone essentially the same early development process as chemotherapy, a much different class of drugs, to determine a maximum tolerated dose, according to Daniel A. Goldstein, MD, medical oncologist at Rabin Medical Center in Israel and a senior lecturer in medicine at Tel Aviv University.

“But, there was no maximum tolerated dose for these antibodies,” Goldstein told HemOnc Today. “They took the drug through trials and to the market as fast as possible without optimizing the dose. In essence, you end up with a batch of drugs where the dose is simply higher than is necessary. We think you can achieve the same clinical efficacy at much lower doses.”

Within the realm of cancer treatment, both patients and oncologists have come to expect adverse events, leading to a general acceptance of higher-dose drugs, according to Mark J. Ratain, MD, Leon O. Jacobson professor of medicine at University of Chicago.

“God forbid we have drug doses that don’t cause side effects,” he told HemOnc Today. “For other drugs, there is a fear of giving too little because if we give too little and fail, we’re in trouble. The simple remedy is to do studies to try to get the dose right, which are done in every specialty but oncology. The pharmaceutical industry doesn’t want to take the time to get the dose right, and nobody seems to care that they haven’t gotten the dose right.”

With many cancer drugs priced prohibitively high, researchers have been seeking novel ways to make these drugs more affordable without compromising efficacy.

This emerging discipline within oncology is called “interventional pharmacoeconomics,” Goldstein said.

In an article published in JAMA Oncology, Ratain, Goldstein and Allen S. Lichter, MD, defined interventional pharmacoeconomics as “actively seeking to disruptively decrease prescribing costs through the development of new dosing regimens while maintaining equivalent efficacy.”

“The high cost of cancer drugs is putting a strain on both individuals and societies, and there are many options for how to solve this problem,” Goldstein told HemOnc Today. “Some options can be policy-based, whereas others are based on negotiations with government, payers and drug companies. Another option is to look at the clinical efficacy and the doses of drugs that are actually required, and whether or not the dosages are higher than is necessary to achieve efficacy.”

Paradoxically, studies aimed at finding more cost-effective doses of cancer medications have their own associated costs, and pharmaceutical companies may be reluctant to fund such studies.

“Who would support doing such a study? There’s no incentive for a pharmaceutical company to do it,” Russell Z. Szmulewitz, MD, associate professor of medicine in the department of hematology and oncology at University of Chicago, said in interview with HemOnc Today. “We conducted such a study that was funded through philanthropy and institutional discretionary funds. The finances of doing such a study is one major hurdle.”

Goldstein agreed, adding that he and others are forming an international consortium of clinical trialists to develop a new mechanism of clinical trial funding.

“For such a study, half of the patients will be randomly assigned to standard treatment vs. reduced-intensity treatment,” he said. “That half of the patients receiving the reduced-intensity treatment is going to save the health care system half of the money associated with such a trial. We are trying to make health care payers return some of that savings to clinical investigators in order to run the trial.”

This would make the trial “self-funding,” Goldstein said.

“However, this is a completely new approach, as most health care payers are not used to the concept of funding clinical research for clinical trials,” he said. “But, it makes sense for them to have an interest in doing it, because not only will the trial itself save money, but also, if positive, results of the trial would also save them money.”

Improving bioavailability of drugs with food

One approach to reducing the dose of cancer drugs while maintaining efficacy is to prescribe the drug with food.

Szmulewitz, Ratain and colleagues conducted a study on the use of abiraterone acetate with food among men with castration-resistant prostate cancer. The study sought to determine whether low-dose abiraterone acetate (Zytiga, Janssen) taken with a meal could have anticancer activity comparable to that of standard-dose abiraterone by analyzing changes in serum PSA.

Men in the standard-dose arm received 1,000 mg abiraterone acetate after an overnight fast of at least 8 hours and a minimum 2 hours prior to any food intake. Men in the low-dose abiraterone acetate arm received 250 mg of the treatment concomitantly or within 30 minutes of a low-fat breakfast.

Results — published in 2018 in Journal of Clinical Oncology — showed that at 12 weeks, men in the low-dose arm had higher reduction of PSA than those in the standard-dose arm (mean log-change, –1.59 vs. –1.19), which indicated the low-dose regimen met the predefined criteria for noninferiority.

PSA response rate was 58% in the low-dose arm and 50% in the standard-treatment arm. The lower one-sided 90% confidence limit for the difference between the two arms in PSA response was –7%, which indicated that the low-dose regimen was, at most, 7% less effective than standard treatment.

“We used one-quarter of the dose, but the amount of drug that got into the patients’ system was much higher than a quarter,” Szmulewitz said. “We achieved approximately 50% of the drug level with significantly less drug-level variability and had comparable efficacy.”

Based on these results, lower-dose abiraterone acetate with food is now an option endorsed within National Comprehensive Cancer Network guidelines, Szmulewitz said.

Dy also cited the example of lapatinib (Tykerb, Novartis), a small-molecule tyrosine kinase inhibitor approved for use in HER2-positive breast cancer. Although it originally was recommended for use in a fasted state, lapatinib’s area under the serum-concentration curve increased by 60% when taken with a high-fat breakfast, and by 200% when taken with a low-fat breakfast.

Thus, taking some targeted drugs with food has the potential not only to reduce costs, but also to improve bioavailability of the drug, Dy said.

“When these drugs are initially being developed, the patients are instructed to take them on an empty stomach, in a fasting state to minimize variability,” she said. “Food-effect studies conducted later may demonstrated feasibility of using lower doses.”

Weight-based vs. fixed dosing

The dosage of immunotherapies such as nivolumab (Opdivo, Bristol-Myers Squibb) and pembrolizumab (Keytruda, Merck) also can be safely reduced, resulting in significant cost savings, by switching to weight-based dosing.

Ratain and Goldstein co-authored an article in Journal of Clinical Oncology looking at such an approach, prompted by the change in label for nivolumab from 240 mg every 2 weeks to 480 mg every 4 weeks. Prior to that switch, nivolumab had been approved at a dose of 3 mg/kg every 2 weeks.

“The initial development of drugs like nivolumab and pembrolizumab used weight-based dosing, and they compared the efficacy and toxicity of a number of different doses based on weight,” Goldstein said. “Then the strategy changed for the companies; they decided to switch to fixed dosing in an attempt at more convenience and a simplified process for the pharmacies.”

Goldstein said in the trials of weight-based dosing for nivolumab, the researchers compared dosages of 0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 3 mg/kg and 10 mg/kg.

“They essentially saw the same efficacy across all dosing levels,” he said.

In fact, the 2014 FDA Clinical Pharmacology Review of nivolumab’s initial application stated that the dose escalation and expansion study among patients with melanoma showed a flat overall response rate across these dosages, establishing the lack of a dose-response relationship.

At the fixed dosing schedule of 200 mg for pembrolizumab, patients may be overdosed, as 2 mg/kg provides the same effect, Goldstein said.

“The average weight of a patient is 75 kg, and so you really only need 160 mg for an average patient,” he said. “We calculated that if they switched back to weight-based dosing for patients with lung cancer in the United States, they could save almost $1 billion every year without any impact on efficacy.”

Extending time between doses

Goldstein said although he and his colleagues recommend a return to weight-based dosing for drugs like pembrolizumab, this approach is not entirely compatible with how these drugs are currently dispensed.

“Using weight-based therapy instead of fixed therapy was our original suggestion, but this is not so easy or practical to implement, due to the 100 mg vial sizes provided by the companies,” he said. “At least all patients who are 60 kg need 120 mg, which requires you to implement vial sharing, which has various reimbursement challenges.”

Instead, Goldstein said he has been exploring the idea of extended intervals between fixed doses.

“So, rather than changing back to weight-based dosing, we are looking at keeping the fixed doses at 200 mg, or whatever the fixed doses are, and extending the time between the treatments,” he said. “We are now suggesting that you can give 200 mg every 6 weeks instead of every 3 weeks.”

Ratain said that he and his colleagues of the abiraterone acetate study also may have been able to extend the time between doses.

“The early studies showed that the dose may last for a week,” he said. “We’re giving one-fourth the standard dose daily, and we might be able to get away with less than that. The drug might not even need to be given daily.

“But, such a study may not be worth our time now, because our strategy is about cost, and abiraterone is now available as a generic, at about $700 a month,” he added. “We could probably bring it down to a fraction of that, but we’ve moved on to bigger and better things.”

The same premise can be applied to radiation therapy.

In a study Goldstein conducted in collaboration with his colleague Assaf Moore, MD, at Rabin Medical Center, researchers evaluated shorter courses of radiotherapy in rectal cancer, an approach that is not typically used in the United States.

In the population-based analysis, results of which appeared in Clinical Colorectal Cancer, researchers assessed the total annual cost of short-course radiotherapy and long-course chemoradiotherapy for locally advanced rectal cancer in the U.S. They found that the cost of chemoradiotherapy with 3D treatment planning was $15,882 per patient, and the cost of chemoradiotherapy with intensity-modulated radiotherapy was $23,745 per patient.

Using short-course radiotherapy, the cost was only $5,458 with the 3D approach and $7,323 with IMRT. In total, the use of short-course radiotherapy would yield annual savings ranging from $106 million to $232 million.

“Traditionally, patients with rectal cancer receive extended periods of radiation over a number of weeks,” Goldstein said. “However, you can do this treatment over a period of 4 weeks instead of 8 weeks while maintaining the same level of efficacy and toxicity, yet saving substantial amounts of societal money, as well as substantial savings for these individuals in the form of copays.”

In another area of research, experts are looking into whether targeted therapies and immunotherapies, which may have longer-lasting effects, need to be taken indefinitely.

“The biological effect can linger for months,” Dy said. “I have been part of the early development of some of these drugs 10 years ago. I’ve observed that some of my patients are able to remain well with their cancer responding to treatment despite going off the drugs or after prolonged treatment delay for reasons other than toxicity. A few may have needed no additional therapy beyond one or two doses of immune checkpoint inhibitors.”

Many trials now suggest stopping treatment at 2 years, Goldstein said.

“Other trials don’t put a stopping time on it at all and may continue for longer,” he said. “The question is, do you really need 2 years of therapy? Is 1 year or even 6 months sufficient? We don’t fully know the answer, but it’s a question of vital importance given the financial impact of that, and subsequent trials should be developed in order to answer that question.

“But, thinking scientifically about this, it doesn’t completely seem logical from the basic science and immunological perspective that you should need a whole 24 months of treatment,” he added.

‘Old habits die very hard in medicine’

Given the momentum to lower drug dosages for targeted therapies and immunotherapies, some researchers are now investigating whether the same methods can be applied to chemotherapy.

Although chemotherapy is still given at or close to the maximum tolerated dose, some clinicians maintain that these doses also can be decreased without compromising efficacy.

“It all depends on context,” Dy said. “For example, high-dose chemotherapy with stem cell rescue was a standard treatment for metastatic breast cancer that emerged in the late 1980s until this approach was debunked as harmful and not at all beneficial in the late 1990s.”

Chemotherapy acts to damage and destroy cancer cells through a variety of mechanisms. According to Yogen Saunthararajah, MD, medical oncologist at Cleveland Clinic and professor in the department of medicine and co-leader of the developmental therapeutics program at Case Comprehensive Cancer Center, most traditional chemotherapy regimens involve a combination of various therapies.

“The concept was to bring to bear as many of these damaging drugs as possible, and they would all have different profiles of damage: some would damage DNA, some would damage the membrane, some would damage cellular metabolism,” Saunthararajah told HemOnc Today. “It’s a kind of tough love — it’s difficult for patients, but because we believe we are going to cure their cancer, it is considered worthwhile.”

However, Saunthararajah said this type of multiple-drug attack works only on certain types of cancers, such as pediatric leukemia. Even for these children, the efficacy of this aggressive approach comes with long-term repercussions, he said.

“They all suffer consequences,” he said. “Even if they survive the treatment — and most do — they may have damage to their hearts, their lungs and their brains. In addition, this approach doesn’t work in most cancers in adults. It works in a very restricted few.”

Saunthararajah cited two of the guiding principles that historically have justified the “maxing out” of toxic therapies in cancer treatments.

“One is that damage is directly related to dose, so the higher the dose, the better,” he said. “The other is that if we do enough damage, we can cure people’s cancer. We already know by now that doesn’t work for most disseminated cancers in adults, but old habits die very hard in medicine.”

He said lowering doses of chemotherapy drugs may result in less damage to cancer cells, but it also will result in less damage to healthy cells. Because the “maxing out” strategy has limited value in adults, there is little point in subjecting the patient to such toxicities, he added.

“For some chemotherapy drugs, lowering doses to avoid damage to healthy cells, then giving these nontoxic doses more often, can even increase damage to cancer cells,” he said.

For instance, studies published in Journal of Clinical Investigation by Saunthararajah and colleagues and in British Journal of Hematology by Awada and colleagues showed that lowering doses of the nucleoside analog chemotherapeutic decitabine by 80% to 90% from FDA-approved doses, then administering these well-tolerated doses frequently to increase cancer treatment exposure times, was effective even against myeloid malignancies that were resistant to standard doses of chemotherapy.

“One of the paradoxes is that you don’t have to get rid of all of the cancer cells for someone to feel better,” he said. “Moreover, if you give a lower dose, you may be able to continue treating them with it over time even though it’s not a cure. We’re not going to cure it with the lower dose, but we weren’t curing it with the higher dose, either. We’re essentially turning the cancer into a chronic disease.”

Patients may be resistant to the idea of receiving a lower drug dose, but learning this will come with lower toxicity and costs may alleviate any concerns, Goldstein said.

“For other patients, reducing the dose might come with better convenience for them, which is obviously beneficial,” he said. “It’s important to emphasize that we’re doing this and developing these trials because we have very strong pharmacologic and pharmacokinetic data to inform our basis of understanding. There are some drugs we studied that, ultimately, we decided if we reduced the dose, we may cause harm or we may not maintain the same level of efficacy. We are choosing to focus on drugs that we have a very, very strong chance of demonstrating an equivalent level of efficacy.” – by Jennifer Byrne

Click here to read the , “Is it feasible to change the immunotherapy dose schedule for a patient in complete response?”

References:

Awada H, et al. Br J Haematol. 2019;doi:10.1111/bjh.16281.

Gu X, et al. J Clin Invest. 2018;doi:10.1172/JCI97117.

Koch KM, et al. J Clin Oncol. 2008;doi:10.1200/JCO.2008.18.3285.

Moore A, et al. Clin Colorectal Cancer. 2019;doi:10.1016/j.clcc.2019.05.005.

Negrotto S, et al. Leukemia. 2012;doi:10.1038/leu.2011.207.

Ng KP, et al. Leukemia. 2011;doi:10.1038/leu.2011.

Ratain MJ and Goldstein DA. J Clin Oncol. 2018;doi:10.1200/JCO.18.00045.

Ratain MJ, et al. JAMA Oncol. 2019;doi:10.1001/jamaoncol.2019.1341.

Saleh MF and Saunthararajah Y. Clin Case Rep. 2017;doi:10.1002/ccr3.1221.

Saunthararajah Y, et al. J Clin Invest. 2015;doi:10.1172/JCI78789.

Szmulewitz RZ, et al. J Clin Oncol. 2018;doi:10.1200/JCO.2017.76.4381.

Ueda M, et al. Biol Blood Marro Transplant. 2019;doi:10.1016/j.bbmt.2018.12.764.

Velcheti V, et al. Am Soc Clin Oncol Educ Book. 2018;doi:10.1200/EDBK_199753.

For more information:

Grace Dy, MD, can be reached at Roswell Park Comprehensive Cancer Center, 100 College Parkway, Buffalo, NY 14221.

Daniel A. Goldstein, MD, can be reached at Rabin Medical Center, 39 Jablonski St., Petah Tikva, 4941492, Israel; email: danielagoldstein@gmail.com.

Mark J. Ratain, MD, can be reached at University of Chicago Medical Center, 5841 S. Maryland Ave. #J341, Chicago, IL 60637; email: mratain@medicine.bsd.uchicago.edu.

Yogen Saunthararajah, MD, can be reached at Cleveland Clinic Taussig Cancer Center, 10201 Carnegie Ave., Cleveland, OH 44106; email: saunthy@ccf.org.

Russell Z. Szmulewitz, MD, can be reached at 5841 S. Maryland Ave., Chicago, IL 60637 email: rszmulew@medicine.bsd.uchicago.edu.

Disclosures: Saunthararajah reports equity in, an advisory board/consultant role with and royalty interests from EpiDestiny. Szmulewitz reports advisory boards roles with Janssen, Merck and Pfizer. Dy, Goldstein and Ratain report no relevant financial disclosures.