You can read part 1 of this series, The Critical Path Initiative: 10 years later, here.
Despite the fact that the rate of breast cancer has been decreasing since 2000 (most likely due to decreased use of hormone replacement therapy), 40,000 women will die this year from the disease. On the positive side, survival rates in women diagnosed with breast cancer are improving, largely thanks to new, more effective treatment options. But there is a still an unmet medical need for the treatment of the most aggressive, hardest-to-treat forms of breast cancer.
On October 7, the FDA issued new final guidance developed as part of the Critical Path Initiative focusing on ways to speed up the approval process for treating women with high-risk, early-stage breast cancer. In order to accelerate drug development for these women—those who are most likely to die of breast cancer—the FDA is allowing the use of certain surrogate endpoints beyond the standard ones used in breast cancer clinical trials, i.e., disease-free survival (DFS) and overall survival (OS).
Pathologic Complete Response
Under the new guidance, researchers can now use pathologic complete response (pCR) as an endpoint in breast cancer trials. pCR is defined as the absence of residual invasive cancer, or as the absence of residual invasive and in situ cancer. The underlying logic is that high-risk, early-stage breast cancer patients can benefit from interventions that might take more than a decade to discover or develop in clinical trials with traditional endpoints. Why? Often, post-operative, or adjuvant, treatment of breast cancer delays or eliminates recurrence for many patients. Because this process takes time to unfold, large sample sizes are needed to generate the OS and DFS survival data that a company has traditionally relied on to seek a treatment approval.
Oncologists and researchers have been mulling pathologic complete response for several years now. The point of using pCR as a surrogate marker is not to be lax about long-term clinical trial data, but to determine which treatments are likely to work in women with high-risk, early-stage breast cancer. Oncologic researchers have determined that pCR is a suitable endpoint for a subgroup of breast cancer patients, including women with luminal B/HER2-negative, HER2-positive (nonluminal), and triple-negative disease. However, it is not suitable for patients with luminal B/HER2-positive tumors or luminal A tumors.
A suitable surrogate
The use of pCR as a surrogate endpoint has been heavily scrutinized. A Cochrane meta-analysis that involved 14 different trials of preoperative and postoperative chemotherapy in women with breast cancer found that pCR was a suitable proxy for long-term outcomes. The analysis evaluated results from 5,500 patients with a median follow-up of 18 to 24 months. Based on the researchers’ findings, the risk of death in patients who achieved pCR was almost 50% lower than patients who had residual tumors when they went in for surgery.
The FDA takes a stand
According to the new FDA guidance, “There remains a significant unmet need for certain high-risk or poor prognosis subsets of early-stage breast cancer patients…It is our hope that considering pCR as an endpoint for accelerated approval in the neoadjuvant setting will encourage industry innovation and expedite the development of novel therapies to treat high-risk, early-stage breast cancer.”
As companies continue to do research and innovate in the breast cancer space, the option of using pCR as a surrogate endpoint provides much-needed flexibility and offers hope to women with the most aggressive forms of this deadly disease.