News feature

https://doi.org/10.1038/s41591-024-02845-7

Dozens of precision cancer drugs

tested at lower doses to reduce
side effects and cut costs
Growing evidence shows that lower doses or shorter treatments of precision cancer therapies
could reduce toxicity and save money — but more clinical trials are needed. By Sofia Moutinho
Credit: VladSt / DigitalVision Vectors / Getty

M
ark Ratain, an oncologist discussed several aspects of the clinical But what interested Ratain the most were
and pharmacologist at the trials conducted by Amgen on sotorasib the results of a complementary trial the FDA
University of Chicago, was (Lumakras), a lung cancer drug that received had requested that Angem conduct. The study,
closely following a US Food accelerated approval in 2021 for patients made publicly available in the documents
and Drug Administration with a specific KRAS G12C mutation. In the released during the hearing, compared the
(FDA) meeting webcast on 5 October 2023. end, the experts voted that the confirmatory 960-mg dose already being marketed with a
In the hearing, experts from the agency trial was uninterpretable. four-times-lower dose of 240 mg. The findings

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on efficiency because cancer was a lethal dis-

Reduce dose based on de-escalation trial Change from fixed dose to dosage per kg
ease, and that was what was expected of them,”
he says. “But now is the time to change.”
The old logic came from chemotherapy, a
treatment that shows a strong and steep rela-
tionship between exposure and response:
higher doses have better results. But that is
Take with food to increase bioavailability Take less often, later, or for a shorter duration
not necessarily true for newer treatments
such as immunotherapy and precision medi-
cine approaches. These therapies are more
precise and are designed to bind to specific
molecules; drug efficacy usually stops after
a certain point, which makes higher doses no
Fig. 1 | Four ways to reduce drug doses. Drug doses can be reduced in several ways, on the basis of data from better and sometimes more toxic.
de-escalation or other clinical trials. Source: Serritella, A. V. et al. Clin. Pharmacol. Ther. 108, 487–493 (2020). “Drug development in oncology has
Credit: Marina Spence, Springer Nature. focused on finding the maximally tolerated
dose as quickly as possible and using that dose
in registration trials to get to market as quickly
showed nearly no difference between the two and lapatinib (Tykerb) for breast cancer, can as possible too,” says Ratain. “It is a religion.
doses in their effect. Both provided about 5 be taken at lower doses with meals1, taking A religion that believes that more is better.”
months of progression-free survival after treat- advantage of the fact that food increases
ment and a similar tumor response, with one dif- their bioavailability up to fourfold. This alter- De-escalation trials
ference: the higher dose was much more toxic native prescription of abiraterone has been Efforts such as the FDA’s Project Optimus
and expensive. recommended by most national guidelines might help change this approach for new drugs
“Four times the dose gives you only more since 2019. coming into the market, but they will not solve
side effects and no more benefit,” says Ratain. “The most important drugs in oncology are the problem of the medicines already sold at
Diarrhea and liver issues were among the most all approved at excessive doses,” says Ratain. high doses and high costs. Some experts are
common problems reported in the trials. At Regulators are also starting to pay attention pushing for post-approval de-escalation trials
the labeled dose, patients have to take eight to the problem. The FDA’s request to Amgen on to test the efficacy of lower doses and other
pills a day. A month of treatment costs US sotorasib is part of the agency’s Project Opti- alternative regimens for these drugs.
$24,000. With a one-quarter dose, patients mus to reform the dose-selection paradigm in These studies are relatively new in the field
would need only two pills a day. “Basically, eve- oncology drug development. The agency has but have been gaining momentum, pushed
rybody has been paying four times as much been collaborating with companies, academia by the need to reduce costs and amplify treat-
for this drug.” and patients to encourage dose regimens that ment access. Cancer drug prices are high and
maximize not only the efficacy of a drug but growing. Global oncology spending rose to
Reduced costs also its safety and tolerability. $185 billion in 2021 and is expected to reach
Sotorasib is far from the only cancer drug For oncologist Ian Tannock, professor more than $300 billion by 2026, according to
labeled at a higher dose than necessary. A 2018 emeritus at the Princess Margaret Cancer a report from IQVIA2.
analysis by Ratain and colleagues identified Centre and the University of Toronto, the However, conducting studies to evaluate
56 oral cancer drugs that could have their effort is a good sign. Tannock, like Ratain, is lower doses is challenging. First, it is outside
costs reduced by at least 33% with alternative part of the Optimal Cancer Care Alliance, a the economic interest of the pharmaceutical
prescribing. Among these, 21 could have their volunteer organization that aims to facilitate companies, the most common sponsors of
dose reduced without diminished efficacy. dose-finding trials. He thinks regulators and clinical trials. Additionally, in countries with
They estimated that through lowering of the governments should take the lead to change private health care systems, such as the United
dose or a reduction in treatment frequency, this logic and incentivize better trial designs to States, prescribing less might not be in the
costs for more than half of these drugs could make sure drug dosages benefit the patients. interest of doctors and clinics either, as they
be reduced by up to 89%. Using US prices, they “Unless they are forced to do so, pharma often get paid for their prescription volume.
calculated an average saving of $94,000 per companies are unlikely to recommend lower De-escalation trials are especially necessary
patient and a reduction of $16 billion in global doses,” he says. in low- and middle-income countries, where
sales annually. most patients and healthcare systems cannot
Ratain is part of a small but growing group More is not always best afford the price of new therapies. In Brazil,
of doctors and researchers who have been Unlike most other drugs, cancer drugs are newer cancer treatments such as immuno-
scrutinizing cancer drugs that could be tested often tested only for the maximum tolerated therapy are unavailable in the public health
and prescribed at lower doses or with shorter dose instead of the minimum effective dose. system because of their high costs and are
durations or even taken with food to maximize This approach is a natural response to the accessible only to the 20% of the population
their strength. deadly nature of cancer, says pharmacist Roe- that can afford private insurance.
Studies have shown that many drugs that lof van Leeuwen at the Erasmus Medical Center “We are generating a larger gap each day
are labeled to be taken while fasting, such in the Netherlands. “In the last 50 years, the between those who have money to access these
as abiraterone (Zytiga) for prostate cancer pharmaceutical companies were only focused drugs and those who don’t,” says oncologist

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Rachel Riechelmann at the AC Camargo Cancer “There is an urgent need for more research regimens or even refrain from being treated.
Center, in São Paulo, Brazil. Riechelmann is on this, especially in developing countries.” Some will go for adding days to their lives,
among the few oncologists trying to conduct while others choose to go for adding life to
de-escalation and alternative dose trials in Reduced toxicity the days.”
Latin America. She has already designed two Changes in the timing of therapy can also
studies and is seeking funding from private reduce the costs and toxicity of cancer drugs. Old habits die hard
health insurance companies. In the Netherlands, where several studies on Resistance to lower doses can come from phy-
Stephen Stefani, another Brazilian oncolo- alternative doses are ongoing, a recent trial sicians themselves. “It would really be hard for
gist and a member of the International Soci- showed that delaying some newer treatments me to prescribe a drug at anything other than
ety of Phamacoeconomics and Outcome can, counter-intuitively, improve patient care. that approved dose and say that I’m meeting
Research, puts his hopes on insurance com- The SONIA trial found no difference in over- the standard of care,” says Aaron Mitchell, an
panies that play a double role by running their all survival or disease progression in women American oncologist at the Memorial Sloan
own hospitals and clinics. He thinks these with breast cancer treated with a CDK4/6 Kettering Cancer Center who researches
kinds of businesses are the perfect sponsors inhibitor (abemaciclib, palbociclib or ribo- health policy in cancer drug prices. “It’s more
for de-escalation experiments. Lower doses ciclib) in the first line in combination with of a regulatory issue than it is a medical issue,”
of drugs that are usually administered in the endocrine therapy versus those who received he says, adding that most doctors in the United
hospital setting, such as intravenous infu- the treatment in the second line after disease States would avoid this approach because of
sions, could save these companies money and progression4. Using the CDK4/6 inhibitors fear of facing legal liabilities, such as being
improve the treatment of patients. Stefani is upfront prolongs the treatment by 16 months, sued by a patient.
planning studies with immunotherapy drugs increases the toxicity by 42% and raises the Even in well-documented cases in which
sponsored by Unimed, the largest private cost by $200,000 per patient. de-escalation works, many doctors do not
health insurance company worldwide, with “There is this standard way of thinking that change their prescriptions. Some are simply
15 million clients, over 100,000 associated if there is a drug that is active, you have to give accustomed to prescribing a specific dose,
physicians, and 157 hospitals of their own. it as soon as possible to patients,” says the trial says oncologist Daniel Vilarim Araújo, at Hos-
In India, oncologist Kumar Prabhash and lead investigator oncologist Gabe Sonke of the pital de Base de São José do Rio Preto, São
colleagues have a head start. In 2021, his team Netherlands Cancer Institute in Amsterdam. Paulo, Brazil.
published a study in the Journal of Clinical “Using a soccer analogy: it’s not the score at That is the case for the treatment of HER+
Oncology showing that an ultra-low dose of halftime that counts, but you need to look at breast cancer with trastuzumab. A meta-analysis
the PD-1 inhibitor nivolumab (Opdivo) helped the full game.” of five randomized trials presented at the ESMO
people with advanced head and neck cancer Sonke points out that studies like his, Congress 2021 showed that 6 months of treat-
live longer3. The researchers used 6% of the regardless of the results, pay for themselves ment with the drug, which is associated with
usual dose, combined with the standard of with the money saved from drug use. That considerable cardiac toxicity and cost, works as
care for this disease in India. The combination money can be used to reinvest in other trials well as the standard 12-month treatment5. How-
more than doubled the percentage of patients to help patients. “Not doing these trials is more ever, most doctors do not adopt this alternative
still alive after 1 year. expensive than doing the trials.” regimen, even in low-income countries such as
The study was criticized by some for not He also highlights the importance of involv- Brazil. “We won’t have better evidence than this,”
directly comparing the low and full doses head ing patients in the study design and discussing Villarim points out. “It is a prescription vice.”
to head, but this would have made the trial too with them the possible benefits of these trials.
costly. Still, Prabhash says the results suggest a “When we started the idea, there was some Real-world data
path for settings such as India, where immuno- resistance [from patients], but we had a com- Some doctors and pharmacists, however,
therapy is out of reach for most. He and other mittee to try to get as many people involved,” argue that when clinical trials are not available,
oncologists have been implementing this he recalls. “One of the first things I did was to alternative dosing strategies can be adopted
alternative treatment in the country. About talk to the breast cancer patient organization on the basis of evidence from initial studies
30% of eligible patients at the Tata Memorial and ask if they had any input and whether they from pharmaceutical companies or even data
Hospital in Mumbai, where Prabhash is head wanted to be in the study.” from prospective clinical studies.
of the solid medical oncology unit, are now Pauline Evers, a Dutch Federation of Cancer Take the case of nivolumab and pembroli-
using the low-dose regimen. Before, only 3% Patients Organisation representative, thinks zumab, two inhibitors of PD-1 that are widely
of patients could afford the drug. clinical trials are fundamental to support any used to treat numerous cancer types, such as
“Patients used to struggle to get treat- dose regimen different from the approved melanoma and lung cancer. Initial studies of
ment and consequently would have limited medicine label. “It is unacceptable to switch to these medicines tested a weight-based dosing
survival,” says Prabhash. “Now, we have a fair something else just for costs in the absence of regimen (mg per kg body weight (mg/kg)).
number of patients surviving for years.” evidence that this can be done without losing Pembrolizumab was first approved as a
Tata Memorial Hospital and a patient organ- efficacy,” she says. Once the evidence is clear 2-mg/kg dose every 3 weeks. But it was later
ization funded the trial. Now, researchers are that a different dosing regimen can be applied labeled as a 200-mg fixed dose every 3 weeks
expanding their de-escalation studies to other without jeopardizing efficacy, then the most and 400 mg every6 weeks. Nivolumab was
cancers. Prabhash says his team has been con- cost-effective regimen could be chosen in a initially approved as a 3-mg/kg dose every 2
tacted by researchers in Nepal, Bangladesh process of shared decision-making between weeks, then was changed to a 240-mg fixed
and France who are willing to join efforts doctor and patient, Evers adds. “Sometimes dose and then to a 480-mg fixed dose every 4
for further research into alternative dosing. patients would like to switch to less-intensive weeks and, more recently, to a 360-mg fixed

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dose every 3 weeks for the treatment of non– evidence to support alternative dosing strat- with lung cancer with the Dutch Institute for
small-cell lung cancer. egies and lower doses of pembrolizumab and Clinical Auditing.
These fixed doses were calculated through nivolumab7. The publication has been guiding Roelof and colleagues hope to publish some
the use of different weight references. The many oncologists in Europe and worldwide. analyses soon, and he is positive about the
pembrolizumab fixed dose is based on a In the Netherlands, several teams, includ- upcoming results. “We must not forget that
100-kg patient as a reference, whereas dos- ing the researchers at Erasmus, have also cancer drugs are heavy on side effects,” says
ing for nivolumab uses an 80-kg reference. started a pioneering movement to find Roelof. “If the patient can get a little bit less of
Doctors and pharmacists argue that these the optimal dose, interval and duration of it, it is better not only for the financial burden
weight references are higher than those of new cancer treatments by directly testing but also for the patient’s quality of life.”
the real-world patients with cancer they usu- patients’ responses in the clinic. They have
ally encounter. Therefore, the flat dose is been lowering doses, extending dosing inter- Sofia Moutinho
usually higher (and more expensive) than the vals and shortening the duration of treat- Freelance writer, Rio de Janeiro, Brazil.
weight-based dose, which better fits diferent ment for several types of treatments step
profiles of patients. by step, and have been closely monitoring Published online: xx xx xxxx
Studies using real-world data show that, on treatment efficacy, toxicity and the levels
average, patients receive a dose that is 10% or of the drugs in the patients’ blood to find the References
22% higher through fixed dosing than through optimal treatment. 1. Szmulewitz, R. Z. et al. J. Clin. Oncol. 36,
1389–1395 (2018).
weight-based dosing for nivolumab or pem- “Of course, randomized clinical trials are 2. Iquiva. https://go.nature.com/3uNj5xY (26 May 2022).
brolizumab, respectively6. still the gold standard, but if you want to 3. Patil, V. M. et al. J. Oncol. 41, 222–232 (2023).
4. Sonke, G. S. et al. J. Clin. Oncol. 41, LBA1000 (2023).
In 2021, the oncology team at Erasmus speed things up, you must have a combina-
5. Earl, H. M. et al. Ann. Oncol. 32, S1283 (2021).
MC Cancer Institute in the Netherlands pub- tion of real-world evidence and randomized 6. Bayle, A., Besse, B., Annereau, M. & Bonastre, J. Eur. J.
lished a personal view paper in The Lancet clinical trials,” says Roelof van Leeuwen, who Cancer 113, 28–31 (2019).
7. Malmberg, R. et al. Lancet Oncol. 23, e552–e561 (2022).
Oncology presenting these data and other is currently consolidating data on patients

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