Taking a Break From TKIs Unlikely to Shorten Survival

Patients with advanced renal cell carcinoma who are taking a tyrosine kinase inhibitor (TKI) to prolong their lives will typically keep going without a break until the disease progresses or toxicities such as severe fatigue and diarrhea become intolerable.

That might soon change with the publication of a unique study. Lasting 10 years, the phase 3 STAR trial involved 920 patients across 60 cancer centers. These patients had advanced kidney cancer and were taking either sunitinib (Sutent) or pazopanib (Votrient).

The results showed that taking an occasional respite from TKI therapy had little impact on the patient’s survival.

The study was published online February 13 in The Lancet Oncology.

The study was funded by the UK’s National Institute for Health and Care Research (NIHR) because drug companies never run studies on how to reduce the use of their drug, commented lead author Janet Brown, MD, of the University of Sheffield, United Kingdom.

“We rely on the NIHR to do these important trials that…companies wouldn’t do,” she commented to Medscape Medical News.

Commenting on the rationale for STAR, co-author Jenny Hewison, PhD, of Leeds University School of Medicine in the UK, explained that patients often find it difficult to tolerate TKIs. “Although these patients are getting the best treatment that we can offer them, it’s very demanding…It could make them feel tired, quite unwell. And there can be a range of other effects including sickness and diarrhea.”

As an example, 77% of patients in the pivotal trial of sunitinib in kidney cancer experienced grade 3 or 4 adverse events such as hypertension (13%), fatigue (15%), diarrhea (10%) and hand-foot syndrome (8%).

Both sunitinib and pazopanib carry label warnings of severe and fatal hepatotoxicity.

Also, in contrast to conventional chemotherapy, which is usually given in a finite number of courses, treatment with TKIs carries on indefinitely.

“It feels like you’re taking [TKIs] for the whole of the rest of your life,” said Brown.

Study Details

The STAR trial, an open-label, non-inferiority, randomized controlled study, is the first phase 3 study of treatment breaks in renal cell carcinoma. The participants had inoperable loco-regional or metastatic clear cell renal cell carcinoma (ccRCC) and had received no systemic therapy for advanced disease.

They were randomly assigned before TKI treatment to a conventional continuation strategy or a drug-free interval approach. The treating physician decided whether a patient would take sunitinib or pazopanib.

All participants took their drugs for four cycles (6-weeks each cycle). At the 24-week point, those with a complete response, partial response, or stable disease began their randomized assignment.

Individuals who took a break continued until their disease progressed, at which point therapy was resumed. They could take further treatment breaks once their disease was back under control. The group on continuous treatment kept going until disease progression or intolerable toxicities. Median follow up was 58 months.

In both the per-protocol and intent-to-treat (ITT) populations, overall survival was 28 months for the people who received continuous treatment vs 27 months for those who took a break. Statistical non-inferiority was established in the ITT population but not in the per-protocol population.

The median length of all treatment breaks was 87 days. Many people took two or more breaks; one patient took nine breaks overall. The breaks were popular: only 3% of participants who were meant to stop therapy withdrew from the study in order to continue their treatment.

Said Hewison: “In the very early days of planning the study there were some doubts as to whether it would succeed because of potential unwillingness of people to stop treatment for a while.”

Brown agreed: “People did worry about that initially but it actually seemed to be more the other way around. By that time — 6 months — people were relieved to be there…We actually had some people from the other arm asking, could they also have a break?”

To understand better the benefits of treatment breaks to patients, Janine Bestall, PhD, a senior research fellow in applied health research at the University of Leeds, conducted a qualitative study in parallel with the main trial.

Summing up the patients’ experiences, Bestall said the drug-free periods “gave them more time.”

Bestall quoted one patient who said: “I know that things can happen and it grows back but you’ve always got the buffer there knowing that you can go back and get help. But you actually lead a normal life and the advantage is, yeah, you can go on holiday, you can actually do more things in the garden, cleaning up, painting, whatever needs doing, you do it.”

Brown said, “I had a lady who, when she was on the trial, had four breaks in total, one when her daughter got married, and [she said] that was really nice for her to do all the shopping and all the normal things that you do, and not be on something that was making her tired and causing sore hands and diarrhea.” 

The drug-free interval strategy provided annual cost savings of £3235 ($3850) and a non-inferior quality-adjusted life-year (QALY) benefit in both the ITT and per-protocol populations.

Serious adverse reactions occurred in 9% of patients in the treatment-break group versus 12% of the continuous-treatment group.

The authors of the study concluded, “Treatment breaks might be a feasible and cost-effective option with lifestyle benefits for patients during tyrosine kinase inhibitor therapy in patients with renal cell carcinoma.”

Changes in Treatment Strategies 

The STAR trial started recruiting in January 2012.

Since that time, immunotherapy has taken over as first-line treatment for many patients with advanced ccRCC in both the UK and the United States.

However, TKIs still have a place. The NCCN Kidney Cancer 2022 Guidelines recommend both sunitinib and pazopanib as options for first-line therapy in advanced disease. The 2022 ASCO Metastatic ccRCC guidelines recommend either drug as first-line treatment in combination with an immune checkpoint inhibitor or in monotherapy if there are “co-existing medical problems.”

In the US, intermittent sunitinib in metastatic RCC was tested in a small study in 2017, with little activity in the literature since then. The authors, led by Moshe Ornstein, MD, from the Cleveland Clinic, Cleveland, Ohio, concluded at the time that sunitinib treatment breaks were feasible and “clinical efficacy does not seem to be compromised.” Ornstein was approached for comment on this latest UK study but declined.

Back in the UK, the results of STAR arrived just in time.

Said Brown: “This has…been really helpful in the UK in the pandemic when people said, can these patients have extra breaks? At the worst of the pandemic we were able to say, sure, if it’s stable, we can keep them off for 3 to 6 months…And so that’s already had a powerful impact.”

Brown concluded, “I think what the trial does allow us to do, as individual oncologists, is to look at the patients that this might be suitable for — it won’t be everybody — and to say yes, it’s okay to personalize things.”

The study was funded by the UK’s National Institute for Health and Care Research.

Bestall reported no relevant financial relationships. Hewison reported funding to her institution from the NIHR Health Technology Assessment. Brown reports having served as a consultant or adviser for Novartis, Ipsen, Amgen, Merck Sharp & Dohme, Bristol-Myers Squibb, and Bayer; honoraria from Novartis, Ipsen, Amgen, Merck Sharp & Dohme, Bristol-Myers Squibb, and Bayer; research funding paid to their institution from the National Institute for Health and Care Research; and travel expenses from Ipsen. Other co-authors report relationships with industry. The full list can be found with the original article.

Helen Leask, PhD, CPF, is a freelance science journalist and certified facilitator. She has written for the Canadian Broadcasting Corporation and other outlets, and has worked on books for patients, including The Canadian Guide to Prostate Cancer, 2nd Edition. She can be reached on Twitter @leask_helen.

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