'Tumor-Agnostic' Drug Approvals a Paradigm Shift in Cancer, With Many Unanswered Questions

Kate M. O'Rourke


June 19, 2017

Late last month, just ahead of the 2017 annual meeting of the American Society of Clinical Oncology (ASCO), the US Food and Drug Administration (FDA) granted accelerated approval for pembrolizumab in adult and pediatric patients with locally advanced or metastatic solid tumors that are mismatch-repair deficient or microsatellite instability-high (MSI-H) who have progressed after prior treatment and who have no satisfactory alternative treatment options.[1] Though the phrase may be overused in medicine, the approval truly represented a paradigm shift in cancer drug approvals.

"The tissue-agnostic approval of pembrolizumab has, in essence, defined a new disease entity," said Steven Lemery, MD, MHS, FDA's lead medical officer for regulatory considerations regarding tissue-agnostic development. He spoke about tumor-agnostic drug approvals during an education session at the 2017 ASCO annual meeting.

The FDA generally approves drugs for cancer on the basis of a therapy studied in a clinical trial with patients with particular tumor types. "Although the FDA has approved drugs based on a biomarker, these drugs have generally been approved for specific biomarker-positive tumor types," said Dr Lemery. "With the new pembrolizumab approval, patients with MSI-H can now benefit regardless of whether they have colorectal cancer, endometrial cancer, gastric cancer, pancreatic cancer, or any other tumor type. With this approval, the existence of the biomarker in essence defines the disease rather than the organ defining the disease."

With this approval, the existence of the biomarker in essence defines the disease rather than the organ defining the disease.

The definition of disease does not preclude the idea of granting a tissue-agnostic indication. As described in US regulations [21 CFR 201, CFR 201.57(c)(2)], the indications and usage section of drug labeling must state that a drug is indicated for the treatment, prevention, mitigation, cure, or diagnosis of a recognized disease or condition or of a manifestation of a recognized disease or condition, or for the relief of symptoms associated with a recognized disease or condition.[2]

Dr Lemery said it was important to separate out the concepts of tissue-agnostic trials and tissue-agnostic drug development. Tissue-agnostic trials can be signal seeking and include basket trials or NCI-MATCH (Molecular Analysis for Therapy Choice).[3,4] Tissue-agnostic development strategy, on the other hand, includes nonclinical data, clinical data, pharmacokinetic data, and drug-drug interaction studies. "Tissue-agnostic trials can provide valuable information as to where future development should be directed, whether that is based on specific tumor types or more broadly," said Dr Lemery. "Separate from tissue-agnostic trials, tissue-agnostic development is an approach to openly seek approval agnostic of tumor type."

Investigating the effects of a drug agnostic of tumor type may be one pathway for drug development, but every drug presents unique circumstances regarding the population of patients that might benefit from it.[2] Dr Lemery said that premarket data requirements for tissue-agnostic development include sufficient data to make a risk-benefit determination and sufficient data that the effect is real. Premarket data requirements are influenced by the magnitude of benefit, known toxicity profile, unmet need, or lack of available therapies, and risk to the patient with no treatment.

In the case of pembrolizumab and MSI-H/DNA mismatch repair (dMMR) tumors, tissue-agnostic development made scientific sense, according to Dr Lemery. MSI-H tumors share common pathologic characteristics; they have increased mutation load and neoantigen burden, and improved outcomes to immunotherapy in different tumors. "There are also data regarding improved association between improved outcomes and mutation load in lung cancer and melanoma for those tumors that have high mutation loads due to smoking or UV exposure," said Dr Lemery. In addition, he said, clinical results from pembrolizumab in patients with MSI-H tumors also support the tissue-agnostic approach. Responses have been observed, irrespective of type of tumor in both gastrointestinal and non-gastrointestinal tumors (Table).

Table. Clinical Data Supporting Pembrolizumab Tumor-Agnostic Approval

 NObjective Response
Colorectal Cancer 9036
Non-Colorectal Cancer 5946
Biliary cancer1127
Gastric or gastroesophageal junction cancer956
Pancreatic cancer683
Small intestine cancer838
Breast cancer2PR, PR
Prostate cancer2PR, SD
Bladder cancer1NE
Esophageal cancer1PR
Thyroid cancer NE
Retroperitoneal adenocarcinoma1PR
Small cell lung cancer1CR
Renal cell cancer1PD

Source: Keytruda® (pembrolizumab) package insert[5]
CR = complete response; NE = not evaluable; PR = partial response; SD = stable disease

The new tumor-agnostic indication for pembrolizumab was based on data from 149 patients with MSI-H or dMMR cancers enrolled across five uncontrolled, multicohort, multicenter, single-arm clinical trials. Ninety patients had colorectal cancer, and 59 patients were diagnosed with one of 14 other cancer types. The objective response rate was 39.6%; responses lasted 6 months or more for 78% of those who responded to pembrolizumab. There were 11 complete responses and 48 partial responses. Overall response rate was similar, irrespective of whether patients were diagnosed with colorectal cancer or a different cancer type. The identification of MSI-H or dMMR tumor status for the majority of patients was prospectively determined using local laboratory-developed, investigational polymerase chain reaction tests for MSI-H status.

Accelerated approval status requires a meaningful therapeutic benefit over existing treatments. "For pembrolizumab, improved OS and PFS was observed in tumors with similar ORR and a high mutation burden," said Dr Lemery. The label says that colorectal cancer patients must have progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan. Merck will further clarify overall response rate and duration of response as a postmarketing requirement.

Dr Lemery pointed out that randomized controlled trials to assess overall survival in rare biomarker tumor types with unprecedented effects on overall survival may not be feasible and are probably not ethical in the refractory setting. This is where real-world data or studies such as the TAPUR trial may be able to fill the gap.

Tissue-agnostic drug trials will vary in design. The list of issues to consider in tissue-agnostic development is considerable: the substantial evidence of heterogeneity of drug effects in different biomarker-positive tumor types; differences in biology; differences in the natural histories of different cancers; differences in mutation frequencies among cancers; and differences in concomitant therapies.[2] There are differences, said Dr Lemery, in resistance mutations among tumors (eg, KIT) and in central nervous system penetration as well. A big issue is how treatment effects should be measured in tissue-agnostic trials. "PFS or OS may not be appropriate in assessing the effects in many different tumor types," said Dr Lemery.

There are several logistical considerations regarding tissue-agnostic development that may not apply to sponsors seeking claims in specific tumor types, including companion diagnostic development and identifying patients for trials. For example, if a mutation is common in lung cancer, the most expeditious route to approval may be conducting trials in sites that see a high volume of patients with lung cancer, rather than trying to identify patients in general solid tumor clinics. However, this may limit the indication to patients with mutation-positive lung cancer.

One unfortunate effect of the tissue-agnostic approach may be missing powerful drug combinations. "If a drug works best in combination, the tissue-agnostic approach might not work, in that there are different standard therapies for the treatment of different cancers," said Dr Lemery. Any diagnostic development may require additional analytical testing among different tumor types.

Looking to the future, studies will reveal whether there might be a role for earlier treatment with pembrolizumab in patients with other MSI-H tumors. "Hopefully, there will be additional research about which patients don't respond to therapy or respond and subsequently progress," said Dr Lemery. Research might lead to combination strategies.

"Clearly, absolute certainty will not exist for every biomarker-tumor drug combination at the time of initial approval," said Dr Lemery. "For approvals, sponsors will need to make the case that the approach makes sense based on scientific and clinical data."

Each drug development is unique, and sponsors should carefully consider the appropriate indication in order to maximize the efficiency in which the drug will get to market. Dr Lemery said that logistically it will be difficult for drug companies to have sites up and running in order to enroll patients across all of the United States, and that the FDA can consider approaches to facilitate data to support approval. "Some sponsors have initiated just-in-time clinical site initiation enrollment," said Dr Lemery.

Expanded access can provide data to support approval of tissue-agnostic cancer drugs. "There is the perception that expanded access puts companies' development at risk. I disagree with this assessment," said Dr Lemery. "For tissue-agnostic development in rare tumor types, expanded access might provide supportive data and benefit across a larger range of tumor types." In the postapproval setting, there may be an opportunity for real-world data to better define which patients will or will not benefit from a tissue-agnostic drug, said Dr Lemery. Standardization of data may be needed in order to optimize the efficiency of this approach.

Pembrolizumab is one of what is expected to be a wave of tumor-agnostic drug approvals. The FDA has granted breakthrough designation to entrectinib for NTRK fusion-positive solid tumors, and the ongoing multicenter, open-label phase 2 STARTRK-2 trial is evaluating this drug.[4] Also recently receiving breakthrough designation is larotrectinib for the treatment of solid tumors with NTRK-fusion proteins. Attendees at the 2017 annual ASCO convention were impressed by data on larotrectinib, which showed remarkably good response rates in all 17 tumor types that it has been tested in. The overall response rate was 76%.[6]

"Tissue-agnostic development should be scientifically and clinically supportable. It is unlikely to be a one-size-fits-all approach to drug development, and we have to try to do our best to balance pre- and postapproval requirements," said Dr Lemery.

In his talk during the education session, Keith Flaherty, MD, director of Henri and Belinda Termeer Center for Targeted Therapies at Massachusetts General Hospital Cancer Center, pointed out that genetically altered therapeutic targets may need to be subclassified by amplification, mutation, fusion, and by individual variants.

"There are examples but no rules yet regarding target type and tissue-specific versus tissue-agnostic drug development," said Dr Flaherty.

Dr Flaherty has disclosed numerous relevant financial relationships, including being on the board of directors at Loxo Oncology, Clovis Oncology, and Strata Oncology; stock and other ownership interests in Loxo Oncology; serving as an advisor or consultant to Sanofi; and receiving research funding from Novartis.

Dr Lemery has disclosed no relevant financial disclosures.


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