Why Keytruda is essential for treating early-stage triple-negative breast cancer

It has been more than two years since MSD Korea's anti-PD-1 immuno-oncology drug Keytruda (pembrolizumab) won approval from the Ministry of Food and Drug Safety (MFDS) for perioperative adjuvant treatment of high-risk early-stage triple-negative breast cancer patients.

Keytruda perioperative adjuvant therapy is recognized as a treatment for triple-negative breast cancer that is refractory to hormonal and targeted therapies and has a significant unmet need to increase pathologic complete response (pCR) rates, prevent recurrence and metastasis, and improve long-term survival.

At the European Society for Medical Oncology Annual Congress (ESMO 2023) in September last year, Keytruda presented five-year (60-month) follow-up data from the licensed Phase 3 KEYNOTE-522 study, further solidifying its efficacy as an adjuvant perioperative therapy. At ESMO Asia 2023 in December, Korean data were presented, confirming treatment trends consistent with the global patient population.

With these validated data, the U.S. NCCN guidelines recommend Keytruda perioperative adjuvant therapy as the preferred regimen for the treatment of patients with high-risk early-stage triple-negative breast cancer. ASCO guidelines, NICE in the U.K., and CADTH in Canada have also recommended this treatment. Still, Korea's patients face significant barriers to access due to the lack of reimbursement.

At the Global Breast Cancer Congress (GBCC 2024) held late last month, data from the KEYNOTE-522 study were presented again, highlighting the clinical value of Keytruda for treating early-stage triple-negative breast cancer.

On the sidelines of GBCC 2024, Korea Biomedical Review caught up with Dr. Lee Dae-won Lee, professor of hematology/oncology at Seoul National University Hospital, to learn more about the implications of the five-year KEYNOTE-522 data and the clinical value of perioperative adjuvant therapy with Keytruda in Korean clinical practice.

Question: Please describe your presentation at GBCC 2024.

Answer: We presented on the KEYNOTE-522 trial, which studied the effectiveness of perioperative adjuvant therapy with Keytruda in high-risk early triple-negative breast cancer patients. In the KEYNOTE-522 study, the Keytruda treatment arm demonstrated significantly higher pathologic complete response (pCR) rates and improved event-free survival (EFS) compared to the control arm, with consistent benefits at three years of follow-up and through five years of data.

Notably, the KEYNOTE-522 trial was the largest study in Asia to include Korean patients, which was also analyzed in detail. While the data is not statistically significant due to the small number of patients, Koreans responded better to Keytruda than Westerners in absolute numbers. In general, lower-stage triple-negative breast cancer is associated with a higher pCR rate, and the Korean patients in the KEYNOTE-522 study included a slightly higher proportion of patients with lower-stage disease than the overall population. However, even when these factors are considered, it is clear that the Korean patients did not have worse outcomes than the global patients.

The data from the KEYNOTE-522 study to date are sufficient to support relapse prevention. We have confirmed that treatment with Keytruda is associated with a significant reduction in relapse rates.

Q: Many researchers regretted that the KEYNOTE-522 study included perioperative and postoperative adjuvant therapy as one treatment strategy. We wonder if separating the treatment effects of upfront and postoperative adjuvant therapy would have been more accurate.

A: Perhaps this is based on the data from previous oncology studies. Some data suggest that a year of immune checkpoint inhibitor use is beneficial, and it takes about a year to complete both pre-and postoperative adjuvant therapy with Keytruda. Also, not all patients who achieve a pCR will relapse.

Relapse is highly dependent on the stage at initial diagnosis, and in the high-stage population, there is a high likelihood of relapse even after achieving pCR. The best approach would be to use preoperative adjuvant therapy for six months and then follow up postoperatively to see if a pCR is achieved, which is being studied in the U.S. We can speak more clearly when the results are available.

Q: The question of surrogate endpoints is always raised in early cancer trials. Can pathologic complete remission (pCR) and event-free survival (EFS) ultimately surrogate endpoints for overall survival (OS)?

A: It is already established that patients who achieve pCR have fewer relapses than those who do not. Importantly, some patients achieve complete remission with conventional chemotherapy, and some patients achieve complete remission with Keytruda. Of the two groups, the relapse rate is lower in the Keytruda group. Pathologic complete remission is when pathologists and medical staff look under the microscope and determine no cancer cells. In contrast, pathologic complete remission is when you can't tell the difference, but there is a deeper remission. Based on the study's results, it can be interpreted that more complete and deeper remissions are seen with Keytruda.

Also, the KEYNOTE-522 study was not designed to examine overall survival data. This would require a much larger number of patients to see a difference in overall survival. Currently, EFS data have confirmed a reduced risk of metastasis and recurrence.

Q: However, the insurance authorities in Korea prioritize overall survival (OS) data in their benefit review process. Should we look at event-free survival (EFS) data in this case?

A: Event-free survival (EFS) is more likely to serve as a surrogate for overall survival (OS) than pathologic complete response (pCR), which is why EFS outcomes are important in this study.

Q: It's been two years since Keytruda perioperative adjuvant therapy was approved in Korea. How many patients in your practice are treated with perioperative adjuvant therapy for Keytruda?

A: Perioperative adjuvant therapy for Keytruda is a non-reimbursed treatment in Korea, so it is entirely up to the patient's decision after explaining it to them. However, the government has implemented the “Catastrophic Medical Expenses Support Program” that covers part of the treatment costs, and we provide relevant information at the hospital level. Patients eligible for the Catastrophic Medical Expenses Support Program can be treated with Keytruda with financial assistance.

Q: For triple-negative breast cancer, Keytruda is available for both metastatic and early-stage disease. We wonder which stage you think is considered more urgent regarding insurance coverage.

A: Both are urgent, indeed. But if I had to choose one, I would choose preoperative adjuvant therapy (also known as neoadjuvant therapy) for early-stage breast cancer.

The goal of treatment for metastatic breast cancer is to relieve symptoms and prolong life, and there are no treatments that have significantly increased cure rates. However, upfront chemotherapy is a treatment that can actually "increase the chances of cure and change a patient's life."

In practice, upfront chemotherapy involves increasing the intensity of treatment. In metastatic cancer, the goal is to prolong the patient's life by treating them without making it too difficult. Still, early cancer treatment is aimed at curing them, so the priority is to increase the chances of cure by treating them strongly, even if it is a little difficult.