In TAPUR, the targeted therapies under investigation were donated by their respective manufacturers. The pharmaceutical companies listed as trial collaborators included AstraZeneca, Bayer, Bristol-Myers Squibb, Eli Lilly and Company, Genentech, Inc., Merck Sharp & Dohme Corp., and Pfizer.5

As of September 2018, the drugs that are being examined in TAPUR are axitinib, bosutinib, crizotinib, palbociclib, sunitinib, temsirolimus, cetuximab, dasatinib, regorafenib, olaparib, and pembrolizumab. Also under examination across patient cohorts: specific drug combinations, such as, nivolumab and ipilimumab; trastuzumab and pertuzumab; and vemurafenib and cobimetinib.5

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The initial cohort of patients for each arm will include 10 evaluable individuals who are grouped by tumor type and genomic alteration. They will be tracked for at least 16 weeks.

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If 2 or more patients experience an objective response to or stable disease from the study treatment after at least 16 weeks, the investigators wrote they plan to enroll an additional 18 participants in that study arm. However, if fewer than 2 patients see a benefit from a treatment within a cohort, that cohort would subsequently be closed to further enrollment.

Dr Schilsky pointed to a poster presentation from the June 2018 ASCO meeting as an example of the sort of insight that this type of clinical research approach could yield.7  In that study, researchers reported that patients with pancreatic or gallbladder cancer who had CDKN2A alterations did not respond to treatment with palbociclib, so both cohorts were closed.

Assessing Circumstances

When considering off-label treatment, a physician should also keep in mind the vulnerability of the already-ill patient, including the existence of comorbidities, Dr Prasad said. “A lot of these drugs are approved in ideal patient populations [and demonstrate a] very small benefit,” he said. He added that when clinicians start using these therapies off-label — in patients for whom the therapies were not explicitly approved, or across patient groups for which the drug was not originally intended — the drugs likely don’t work nearly as well.

Yousuf Zafar, MD, MHS, associate professor of medicine and public policy, Duke Cancer Institute, Durham, North Carolina, said that there might be a greater risk for adverse events with off-label prescribing, “where there isn’t a great deal of evidence to fully map out the toxicities of a particular treatment in a new patient. And that may be a bigger issue for sicker patients,” he added.

Financial circumstances shouldn’t be ignored, either, Dr Zafar told Cancer Therapy Advisor. He recently served as coauthor of a review article about financial and other considerations for the new therapies in a study published in Annals of Translational Medicine.8 Even when the insurer does cover an off-label treatment, the proliferation of plans with high deductibles may mean that the patient could be left responsible for a large chunk of the bill, he said.

Physicians should ensure that the patient understands the potential risks of the proposed off-label treatment, as well as any gaps in knowledge about the therapy, Dr Zafar said. While the physician doesn’t need to detail every study underpinning a recommendation for a medication’s off-label use, Dr Zafar asserted that “patients should understand, at least to some degree, the level of evidence that is supporting the decision” to use a medication in a manner that falls outside of the indications on the product label.


  1. Wagner J, Marquart J, Ruby J, et al. Frequency and level of evidence used in recommendations by the National Comprehensive Cancer Network guidelines beyond approvals of the US Food and Drug Administration: retrospective observational study [published March 7, 2018]. BMJ. 2018;360:k668. doi: 10.1136/bmj.k668
  2. US Food and Drug Administration. FDA announces approval, CMS proposes coverage of first breakthrough-designated test to detect extensive number of cancer biomarkers. Published November 30, 2017. Accessed November 5, 2017.
  3. Conti RM, Bernstein AC, Villaflor VM, Schilsky RL, Rosenthal MB, Bach PB. Prevalence of off-label use and spending in 2010 among patent-protected chemotherapies in a population-based cohort of medical oncologistsJ Clin Oncol. 2013;31(9):1134-1139.
  4. Mitchell AP, Basch EM, Dusetzina SB. Financial relationships with industry among National Comprehensive Cancer Network guideline authorsJAMA Oncol. 2016;2(12):1628-1631.
  5. TAPUR: Testing the Use of Food and Drug Administration (FDA) Approved Drugs that Target a Specific Abnormality in a Tumor Gene in People with Advanced Stage Cancer (TAPUR). NCT02693535. Updated September 11, 2018. Accessed November 5, 2018.
  6. Mangat PK, Halabi S, Bruinooge SS, et al. Rationale and design of the targeted agent and profiling utilization registry study [published online July 11, 2018]. JCO Precis Oncol. 2018;2:1-14. doi: 10.1200/PO.18.00122
  7. Baghdadi TA, Halabi S, Garrett-Mayer E, et al. Palbociclib in patients with pancreatic cancer and gallbladder or bile duct cancer with CDKN2A alterations: results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study. J Clin Oncol. 2018;36(15_suppl):2532-2532. doi: 10.1200/jco.2018.36.15_suppl.2532 
  8. Tran G, Zafar SY. Financial toxicity and implications for cancer care in the era of molecular and immune therapies. Ann Transl Med. 2018;6 (9):166. doi: 10.21037/atm.2018.03.28