April 2018 Edition Vol.11, Issue 4

A Powerful Force: Novel Endpoints Speed Up Drug Development

By Christina Bennett, MS

Although overall survival (OS) is still hailed as the gold standard of drug performance in trials, the reality is the cancer landscape is evolving and novel surrogate endpoints are emerging. Novel endpoints aim to speed up drug development and drug approval, granting patients greater access to life-saving therapies. However, the contrary is also true. Greater access also exposes patients to potentially harmful, ineffective therapies.

Regulatory and Cancer Landscape Evolve

Conventional surrogate endpoints, like progression-free survival (PFS) and response rate, have been around for decades. Their popularity was catalyzed in 1992 when the FDA created the Accelerated Approval pathway which “allowed drugs for serious conditions that filled an unmet medical need to be approved based on a surrogate endpoint.” Although the accelerated approval pathway relied on surrogate endpoints, manufacturers had to demonstrate clinical benefit in post-marketing studies if they wanted to obtain regular approval and continue marketing their product.1

Since 1992, conventional surrogate endpoints have been increasingly replacing OS as primary endpoints in clinical trials.2 In fact, 100% of accelerated approvals (25 approvals) and 51% of traditional approvals (30 approvals) between 2009 and 2014 were based on surrogate endpoints.3

“The FDA has been much more liberal lately in terms of [approving drugs based on surrogate endpoints] in the last ten years, and you can see this in terms of the number of drugs approved, which has changed dramatically over the last two decades,” said Bruce Chabner, MD, director of clinical research at Massachusetts General Hospital Cancer Center.

As the cancer landscape evolves and cancer patients live longer, the conventional surrogate endpoints, like PFS, are becoming harder to achieve because they take longer and longer to reach. For instance, the time between diagnosis and death can be long for patients with prostate cancer, explains Scott Tagawa, MD, oncologist at Weill Cornell Medicine and NewYork-Presbyterian.

“That average length [between diagnosis and death] can be the patent protection for a drug, so some pharmaceutical companies might not want to go into that space,” he said.

In contrast, novel surrogate endpoints can offer quicker insights into the long-term clinical benefit of a drug. However, as Dr. Chabner points out, the newer endpoints must be “well-established.”

A well-established or validated surrogate endpoint is not just a biological measure that is strongly correlated with clinical benefit. Similarly, proof of a correlation at the individual patient level does not validate an endpoint. To be valid, the surrogate endpoint should have trial-level evidence in which a meta-analysis is done of all relevant randomized trials.4

Also, the evidence should be in the same disease setting and class of agents. For example, an endpoint validated in prostate cancer cannot be generalized to breast cancer. Similarly, an endpoint that works for an immunotherapeutic agent does not necessarily translate to another class, like hormone therapy.5

 

Novel Endpoints Emerge

Several novel surrogate endpoints have emerged recently, and although some are not exactly new, their context and use are. Take, for example, metastasis-free survival (MFS) in prostate cancer, for which there is strong evidence of its surrogacy in prostate cancer.6 Although not new, MFS recently reached a milestone.

Earlier this year in February, the first FDA-approved treatment for non-metastatic, castration-resistant prostate cancer, Erleada® [apalutamide; Janssen Biotech], was based on an MFS endpoint. It was the first time that the FDA approved a drug based on this endpoint.7

The FDA acknowledges the novelty of this approval in a statement, where the Director of the FDA’s Oncology Center of Excellence, Richard Pazdur, MD, said, “This demonstrates the agency’s commitment to using novel endpoints to expedite important therapies to the American public.”8

Dr. Tagawa also noted that because prostate cancer has such a long survival, MFS as an endpoint has particular importance in evaluating interventions for earlier disease settings.

Another recent example of a surrogate endpoint gaining increased acceptance is minimal residual disease (MRD), in certain blood cancers.

Amgen has been seeking to expand the label for Blincyto® (blinatumomab) to include patients with MRD-positive B-cell precursor acute lymphoblastic leukemia (ALL). On March 7, 2018, FDA’s ODAC panel voted 8 to 4 in favor of Amgen expanding the indication of Blincyto, and on March 29 the FDA granted the expanded indication accelerated approval. The approval was based on the phase II single-arm BLAST study, which met its primary endpoint by showing 70 of 86 patients (81%) achieved undetectable MRD within the first treatment cycle.  Blinatumomab is the first drug to receive an indication for which MRD positivity is a requirement and MRD negativity is a surrogate endpoint in ALL.9

“With MRD, context is very important,” said Christopher Benton, MD, medical oncologist and assistant professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center. “There are other leukemias where minimal residual disease doesn’t carry the same kind of risk as it does in AML or ALL. So, for instance, in hairy cell leukemia, we sometimes see some minimal residual disease in the peripheral blood that we do not think is going to lead to impending relapse.”

According to an FDA analysis, there is interest in using MRD as a potential surrogate endpoint in trials for blood cancers. Between 2014 and 2016, 38% of new drug applications and biologics license applications submitted for blood cancer indications included MRD data.10Depending on the exact context, Dr. Benton said that the detection of MRD is becoming, and will become, a standard for interpreting responses to therapy.

Although not at the drug approval stage yet, circulating tumor cells (CTCs) have been further validated as a surrogate endpoint in clinical trials evaluating hormone therapies for prostate cancer. Published in February, a meta-analysis evaluated the results of five randomized controlled phase III trials and reported that CTC count at 13 weeks was a sufficient surrogate for OS. Four of the five trials were for hormone therapies.11

“CTCs have the potential to speed [drug development] up a lot,” said Dr. Tagawa.

Although the emergence of novel endpoints offers great potential, Richard Schilsky, MD, Chief Medical Officer of the American Society of Clinical Oncology (ASCO), captures the patient perspective.

“Patients don’t really care if their circulating tumor cell counts are going down. What they care about is if they live longer,” said Dr. Schilsky. “If the CTC count is known as the result of research studies to be a reliable predictor of survival, then that’s fine, but if it turns out that that’s not the case, then measuring it can give a lot of misinformation and false hope to patients.”

 

From Drug Approval to Clinical Practice

Whether a drug is approved based on a novel surrogate endpoint depends on the FDA’s assessment of cost-benefit and the level of unmet medical need. Dr. Schilsky describes this decision as managing uncertainty. “At what point does the FDA feel that they have sufficient information about the safety and the effectiveness of a drug to allow it to be deployed in the market place?”

Regardless of endpoint used, a degree of uncertainty about a drug’s performance remains, though the degree is likely greater for novel and conventional surrogate endpoints. The FDA said in a statement to OBR, “there remains some degree of uncertainty about the risks for any drug at the time of marketing approval.”

This fact underscores the importance of post-approval marketing; however, it does not resolve the challenge of conducting post-marketing studies.

“We have a lot to learn about drugs after they are in fact licensed by the FDA,” said Dr. Schilsky. “Therefore, there is sort of a burden that’s incumbent upon both the drug sponsors and the clinical community more broadly to help generate the additional information that is lacking at the time of approval.”

Beyond drug approval, novel surrogate endpoints will need to complete another hurdle: adoption in clinical practice.

Because their approval is based on less evidence, oncologists, payers, and healthcare systems may be hesitant to adopt the drug.

“It depends on what else is available in that field or for that use,” reasons Dr. Chabner. “For example, it’s going to be hard to replace regimens that are known to produce survival benefits by using surrogate endpoints for new regimens because oncologists don’t like to give up a known curative regimen for something that is based on a surrogate endpoint.”

He adds, “If you’re thinking of competing with or replacing existing therapies you have to be very confident that it has the same benefit.”

Also, although a drug may indicate a clinical benefit, less is known about long-term toxicity.

“You just don’t know what the long-term outcome will be, so that’s a major consideration, and particularly in a population of patients where a number of those patients are being cured by current regimens,” said Dr. Chabner.

As history has shown, toxicity issues can emerge. For example, bevacizumab was granted accelerated approval in 2008 for use in combination with paclitaxel for metastatic HER2-negative breast cancer on the basis of PFS. It was withdrawn in 2011 after confirmation studies found increased toxicity and no true clinical benefit.2

 

Less Evidence Yields Uncertain Value

As medicine enters the era of value-based care and drug prices remain sky high, oncologists, payers, and health systems are increasingly trying to pin down the value and cost of cancer drugs. Tools, such as the ASCO Value Framework, offer aid in this search. However, drugs that are approved using novel surrogate endpoints that have less available evidence of drug performance may create even more uncertainty.

“The drug prices are high, and if the clinical community and payer community and so on don’t have much certainty about how well the drug is going to perform and in which patients, then it makes it more challenging to assess what is the true value of the drug,” said Dr. Schilsky. “Even now, there’s often times no good way to make that assessment until the drug has been out there in clinical use for some time.”

How some of these endpoints could affect the ASCO Value Framework is unclear.

ASCO told OBR in a statement, “ASCO is still assessing and refining the society’s value framework and its methodology to best meet the needs of the oncology community, so at this point, it’s too early to make predictions regarding future iterations of the framework or to say how new surrogate end points might be incorporated.”

“It’s challenging and it’s a moving target,” said Dr. Schilsky. “The value assessment is, in a sense, going to mature over time as more experience and more data about the drug continue to accrue.”

 

Editor’s Note: On June 22, ASCO and the FDA will hold the Third Annual FDA Clinical Outcome Assessments in Cancer Clinical Trials Workshop. This year the workshop will focus on patient-reported outcomes (PROs).12 Although the FDA acknowledges the meaningfulness of PROs, this measure is infrequently included in drug labels and inconsistently measured and reported in clinical trials.13 ASCO has cited the latter as the reason for not including PROs in their value framework.14 During the workshop, the FDA Oncology Center of Excellence will clarify its position on measuring PROs and a framework for PRO assessment in trials will be proposed.12

 

References

  1. FDA.gov. Accelerated approval. https://www.fda.gov/ForPatients/Approvals/Fast/ucm405447.htm. Accessed March 16, 2018.
  2. Kemp R, Prasad V. Surrogate endpoints in oncology: When are they acceptable for regulatory and clinical decisions, and are they currently overused? BMC Medicine. 2017;15(1):134.
  3. Kim C, Prasad V. Strength of validation for surrogate end points used in the US Food and Drug Administration’s approval of oncology drugs. Mayo Clin Proc. 2016.
  4. Prasad V, Kim C, Burotto M, Vandross A. The strength of association between surrogate end points and survival in oncology. JAMA Intern Med. 2015;175(8):1389-1398.
  5. Fleming TR. Surrogate endpoints and FDA’s accelerated approval process. Health Affairs. 2005;24(1):67-78.
  6. Wanling X, Regan M, Buyse M, Halabi S, Kantoff P, Sartor O, et al. Metastasis-free survival is a strong surrogate of overall survival in localized prostate cancer. J Clin Oncol. 2017;35(27):3097-3104.
  7. FDA Voice. FDA’s new pilot program aims for more transparency about new drug approvals. March 19, 2018. https://blogs.fda.gov/fdavoice/index.php/2018/03/fdas-new-pilot-program-aims-for-more-transparency-about-new-drug-approvals. Accessed March 20, 2018.
  8. FDA.gov. FDA approves new treatment for a certain type of prostate cancer using novel clinical trial endpoint. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm596768.htm. Accessed March 16, 2018.
  9. FDA.gov. FDA expands approval of Blincyto for treatment of a type of leukemia in patients who have a certain risk factor for relapse. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm603151.htm.  Accessed April 2, 2018.
  10. Gormley N, Bhatnagar V, Ehrlich L, Kanapuru B, Lee HZ, McKee A, et al. FDA analysis of MRD data in hematologic malignancy applications. J Clin Oncol. 2017;35(suppl; abstr 2541).
  11. Heller G, McCormack R, Kheoh T, Molina A, Smith M, Dreicer R, et al. Circulating tumor cell number as a response measure of prolonged survival for metastatic castration-resistant prostate cancer: a comparison with prostate-specific antigen across five randomized phase iii clinical trials. J Clin Oncol. 2018;36(6):572-580.
  12. ASCO.org. ASCO to co-host June 22 event with FDA on oncology clinical trial outcomes. https://www.asco.org/advocacy-policy/asco-in-action/asco-fda-cohost-june-22-2018-event-oncology-clinical-trial-outcomes. Accessed March 19, 2018.
  13. Atkinson T, Wagner J, Basch E. Trustworthiness of patient-reported outcomes in unblinded cancer clinical trials. JAMA Oncol. 2017;3(6):738-739.
  14. ASCO.org. ASCO Value Framework update: Frequently Asked Questions. https://www.asco.org/sites/new-www.asco.org/files/content-files/advocacy-and-policy/documents/2016-May-Updated-Value-Framework-FAQ.pdf. Accessed March 19, 2018.

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