The speed with which we are now developing effective immunotherapies for cancer, including CAR-T and monoclonal antibodies, is extraordinary.
As remarkable are the recent advancements in the discovery of molecular markers, proteomics, transcriptomics and genomics enabling scientists to develop novel targeted therapies to treat several cancers.
Importantly, immunotherapies and targeted therapies, often combined, have rendered chemotherapy obsolete in various (and growing) treatment settings.
Despite this Progress…
Troubling facts have recently emerged about several expensive FDA-approved anticancer drugs, whereby the manufacturer failed to conduct ‘confirmatory’ studies to provide data on longer-term results.
Timelines, Trust, and Guidelines
As healthcare consumers, including those undergoing cancer treatment and hosting disease as survivors, we put a lot of trust—essentially, with our lives—into the scientific rigor that incontrovertibly proves the safety and efficacy of anticancer drugs.
Those approved anticancer drugs become the standard of care; they become the backbone of NCCN Guidelines. Major institutions and community cancer clinics alike adhere to them closely when developing treatment plans for their patients.
However, the accelerated approval process is predicated on early data using surrogate instead of primary endpoints—in this case, focusing on progression-free survival versus overall survival.
Let’s review the definitions of the various surrogate and primary endpoints that shape the drug development, clinical trial, and FDA approval process. I touched on this in a recent article, Beyond Standard Cancer Care: Intelligent Considerations.
Objective Response Rate
Objective response rate (ORR) is specific to the impact a drug has on reducing the size of a tumor burden—solid tumors or, in the case of blood cancers, the volume of detectable malignant cells in the bloodstream or bone marrow.
A measurement is made, prior to and after cancer treatment, using imaging (typically a CT scan, PET/CT scan, or MRI for solid tumors), and via blood tests and/or bone marrow biopsies for blood cancers such as leukemia and lymphoma.
The accurate measurement of ORR is not a perfect science, when quantifying various types of therapeutic responses across different types of tumors.
Progression-free survival (PFS) is the length of time during and after the treatment of cancer that a patient lives with the disease—still detectable through various testing—but it does not worsen.
Similarly, disease-free survival (DFS) is the duration of time after a patient has received treatment (through a clinical trial) and has no detectable disease, otherwise known as a complete response or complete remission.
Overall survival (OS) is the percentage of subjects in a clinical trial or treatment group who are alive for a certain period of time after diagnosis or the start of cancer treatment. OS rates are generally based on a five-year period after diagnosis or commencement of treatment.
What is a Confirmatory Trial?
A confirmatory trial is a controlled study where hypotheses are examined based on specific protocol. It is put in place when it is necessary to provide additional or clear evidence of efficacy or safety.
The basic process of a confirmatory trial involves four key points which include:
- design justification and statistical aspects be a part of the initial protocol;
- concision—addressing a certain number of questions;
- questions relating to efficacy; and a precise outline of the specific patient population.
Across several types of malignant disease, people are truly living longer because novel anticancer therapeutics can significantly improve cancer control and overall survival rates. These remarkable drugs and interventions include various immunotherapies, Bruton’s tyrosine kinase inhibitors (TKIs), checkpoint inhibitors, combination targeted therapy, vaccines, and CAR-T—the first FDA-approved cell-based gene therapy also considered immunotherapy.
…The Bad and The Ugly
There are several FDA-approved drugs that only marginally extend survival time. The threshold for statistical significance when measuring one ‘old’ anticancer drug versus a ‘new’ drug can be a matter of a few weeks or a couple months. In fact, almost one-third (30%) of FDA-approved cancer drugs show zero overall survival improvement.
But most patients are not aware of this systemic problem, and can be overpaying for similar, and sometimes less efficacious, treatment (see next section).
Bad Policy and Bad Science Failing Cancer Patients
A recent retrospective study published in the British Medical Journal looked at a group of 10 anticancer drugs that were FDA-approved for 18 different cancer indications.
These cancer drugs received accelerated approval on the basis of surrogate endpoints that require the manufacturer to follow-up confirmatory trials showing the primary endpoint of overall survival.
Findings by The Numbers
In an investigation into the regulatory handling of cancer drugs approved by the FDA, under accelerated approval, the retrospective study established that…
- 10 cancer drugs failed to improve the primary endpoint.
- Out of 18 indications (various specific cancer types) for these 10 cancer drugs, 11 were voluntarily withdrawn by the manufacturer—6 in the year 2021 alone.
- 6 indications remain on the ‘label’.
- 1 indication was revoked by the FDA.
- NCCN endorsement remains in effect on 8 accelerated FDA approved drugs that have failed post-approval trials. Many trials are delayed years after accelerated approval.
Their conclusion: “Clinical guidelines should better align with the results of post-approval trials of cancer drugs that received accelerated approval.”
Alarmingly, the following FDA-approved anticancer drugs should have been pulled from the market as soon as these confirmatory trials were completed and reviewed.
Summary of ‘Negative’ Confirmatory Trial Results
- Olaratumab in sarcoma and durvalumab in urothelial cancer showed shortened progression-free survival;
- Bevacizumab in glioblastoma revealed that the drug failed to improve both overall survival and quality of life;
- Gemtuzumab in acute myeloid leukemia showed that the drug failed to improve overall survival, disease-free survival, and response rates;
- Nivolumab in small cell lung cancer, investigated in two separate confirmatory trials, showed failure to improve overall survival. But the effects of the drug on progression-free survival were beneficial in one trial and detrimental in the other;
- Tositumomab to treat follicular lymphoma (for which a different trial showed no benefit for progression-free survival and overall survival) and fludarabine to treat chronic leucocytic leukemia, were voluntarily withdrawn before the completion of post-approval trials.
Cancer Drug Trials and Quality of Life Scores
Quality of life (QoL) is a critical consideration in cancer treatment, particularly because drugs have become more expensive and often result in only modest overall survival gains.
Inevitably, some form and level of drug-related toxicity during active treatment exists. And subsequent impairments in health-related quality of life can persist, sometimes indefinitely. Despite this, long-term outcomes are inconsistently assessed as no validated methods exist to integrate health-related data into the evaluation of therapeutic agents.
This cross-sectional analysis of 149 studies published in high impact journals found that most cancer drug trials (69.8%) assessed QoL during the intervention, whereas only 3.4% of studies assessed QoL through time of death.
Buyer (aka Patient) Beware
No doubt, this is complex stuff. It falls at the feet of those living with cancer, their families and caregivers, to navigate this maze as best they can. Because, with few exceptions: smarter patients get better outcomes.
Determine your unique, overarching goals for the management of the disease you are hosting, and in the context of procuring the most relevant information for accurate decision-making.
Join my private Facebook Group Anticancer Thrivers—a community forum for achieving your best life while living with cancer.
Photo credit: bigstockphoto.com/New_Africa