New Pembrolizumab Data Presented at ESMO Show Promise in a Variety of Cancers

Multiple new trial results have been presented at the European Society for Medical Oncology (ESMO) Congress 2024 supporting the use of pembrolizumab (Keytruda; Merck) in a variety of cancer types, including breast cancer, melanoma, hepatocellular carcinoma, and cervical cancer.

Pembrolizumab is an anti-programmed death receptor 1 (PD-1) therapy designed to increase the immune system’s ability to detect and fight tumor cells. The treatment blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.¹

In the US, pembrolizumab is currently indicated for non–small cell lung cancer, head and neck squamous cell carcinoma, Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, urothelial carcinoma, triple-negative breast cancer, renal cell carcinoma, and gastric cancer, among others.²

Cancer cell illustration | Image credit: TensorSpark | stock.adobe.com

New Findings in Breast Cancer

In late-breaking results selected for presentation during a Presidential Symposium session at the ESMO Congress 2024 and published in the New England Journal of Medicine, neoadjuvant treatment with pembrolizumab plus chemotherapy and continued as a single agent adjuvantly reduced the risk of death by 34% compared with neoadjuvant chemotherapy in patients with high-risk early-stage triple-negative breast cancer (TNBC).³

These findings, from the KEYNOTE-522 (NCT03036488) study, mark the fourth study of a pembrolizumab-based regimen in an earlier stage of cancer to demonstrate an overall survival (OS) benefit. The 5-year OS rate was 86.6% with the pembrolizumab regimen versus 81.7% for patients who received a chemotherapy and placebo regimen. The median OS was not reached in either group.³

“These impactful overall survival results add to the previously reported pathological complete response and event-free survival data from the KEYNOTE-522 trial,” Peter Schmid, MD, PhD, FRCP, lead investigator in the Centre for Experimental Cancer Medicine at the Barts Cancer Institute in London, said in a news release. “In this study, pembrolizumab plus chemotherapy as neoadjuvant treatment and continued as a single agent after surgery reduced the risk of death by more than one-third compared to neoadjuvant chemotherapy, reinforcing the important role this regimen plays in the treatment of high-risk early-stage triple-negative breast cancer.”¹

Furthermore, in a prespecified exploratory subgroup analysis of OS, the benefit of pembrolizumab was consistent across prespecified subgroups, including those defined by PD-L1 expression, tumor size, and nodal status.³

Merck had previously announced that the KEYNOTE-522 trial met its dual primary end points of pathological complete response (pCR) and event-free survival (EFS) at earlier interim analyses. Based on these findings, pembrolizumab is approved in combination with chemotherapy as neoadjuvant treatment and then continued as a single agent after surgery for high-risk early-stage TNBC.¹

Pembrolizumab in Melanoma

Ten-year follow-up data from the KEYNOTE-006 (NCT01866319) trial demonstrated sustained OS benefit versus ipilimumab in patients with advanced melanoma, at 34% and 23.6%, respectively. Pembrolizumab reduced the risk of death by 29% and, at 10 years, more than doubled the median OS compared with ipilimumab (32.7 months vs 15.9 months).⁴

“Ten years ago, Keytruda became the first anti-PD-1/L1 therapy approved in the US, setting the stage for transformative breakthroughs in the treatment of advanced melanoma and other types of cancer,” said Marjorie Green, MD, senior vice president and head of oncology, global clinical development, at Merck Research Laboratories, in a news release.⁴

The KEYNOTE-006 study was an open-label, randomized phase 3 study comparing the efficacy and safety of pembrolizumab versus ipilimumab in participants with advanced melanoma. The primary end points were progression-free survival (PFS) and OS. At the study’s conclusion, participants were eligible to transition to the KEYNOTE-587 (NCT03486873) extension study for long-term follow-up, which has the primary end point of OS.⁴

With a median follow-up of 123.7 months (range, 122-127.3) from the time of study entry in KEYNOTE-006 to the data cutoff for KEYNOTE-587, researchers found that pembrolizumab continued to demonstrate improved OS and PFS. The median modified PFS was 9.4 months for pembrolizumab and 3.8 months for ipilimumab.⁴

“The prognosis for patients diagnosed with melanoma has been steadily improving, with a 30% reduction in mortality compared to a decade ago,” said Carolina Robert, MD, PhD, head of dermatology at Gustave Roussy, Villejuif and Paris-Sud University Cancer Campus, Grand Paris, in a news release. “These latest data from KEYNOTE-006 illustrate the progress we’ve made in patient care. It is remarkable to see that more than one-third of patients treated with Keytruda are still alive today, 10 years after treatment.”⁴

Pembrolizumab Plus Lenvatinib in Hepatocellular Carcinoma

In findings from the phase 3 LEAP-012 (NCT04246177) trial, researchers found that pembrolizumab plus lenvatinib (Lenvima; Eisai) in combination with transarterial chemoembolization (TACE) reduced the risk of disease progression of death by 34% compared with TACE alone among patients with unresectable, non-metastatic hepatocellular carcinoma. Lenvatinib is an orally available multiple receptor tyrosine kinase inhibitor (TKI).⁵

“Hepatocellular carcinoma is one of the leading causes of cancer-related deaths worldwide, highlighting the need for new treatment options,” Josep Llovet, MD, PhD, director of the Liver Cancer Program and professor of medicine at the Icahn School of Medicine at Mount Sinai, said in a news release. “These findings from the LEAP-012 trial demonstrate the potential of pembrolizumab plus lenvatinib in combination with TACE to extend PFS for patients diagnosed with unresectable, non-metastatic disease.”⁵

The LEAP-012 study is a multicenter, randomized, double-blind phase 3 trial with primary end points of PFS and OS. Secondary end points include objective response rate (ORR), duration of response (DoR), disease control rate (dCR), and time to progression (TTP). The study randomized treatment with either pembrolizumab plus lenvatinib or placebo to 480 participants.⁵

After a median follow-up of 25.6 months (range, 12.6-43.5), the combination treatment in addition to TACE demonstrated a statistically significant and clinically meaningful improvement in PFS, with a 34% reduced risk of disease progression or death compared to TACE alone. Median PFS was 14.6 months for the combination regimen vs 10 months for TACE alone.⁵

At the time of analysis, a trend toward improvement in OS was observed for the pembrolizumab and lenvatinib regimen versus TACE alone, although the OS data are not mature and did not reach statistical significance at the time of interim analysis. The trial is ongoing.⁵

“These results reflect our commitment to exploring therapeutic options for these patients, including in earlier stages in disease,” Gregory Lubiniecki, MD, vice president of global clinical development at Merck Research Laboratories, said in a news release. “We’re encouraged by the potential for another treatment option for patients with unresectable non-metastatic hepatocellular carcinoma in addition to the existing monotherapy indications for Keytruda and Lenvima.”⁵

Pembrolizumab Plus Chemoradiotherapy in Locally Advanced Cervical Cancer

Finally, OS findings from the pivotal phase 3 KEYNOTE-A18 (NCT04221945) trial were presented at the ESMO Congress 2024 and simultaneously published in The Lancet. According to the data, at a median follow-up of 29.9 months (range, 12.8-43), pembrolizumab in combination with concurrent chemoradiotherapy (CRT) reduced the risk of death by 33% for patients with newly diagnosed high-risk (stage IB2-IIB with lymph node-positive disease and stage III-IVA with and without lymph node-positive disease) locally advanced cervical cancer.⁶

Among patients who received the pembrolizumab-based regimen, the 36-month OS rate was 82.6% vs 74.8% for those who received concurrent CRT alone. Median OS was not reached in either group.⁶

"Cervical cancer is one of the leading causes of cancer-related deaths for women across the globe, but treatment advanced in recent years have not demonstrated a significant survival benefit for patients with high-risk, locally advanced forms of the disease,” Domenica Lorusso, MD, PhD, principal investigator of the study, lead investigator for ENGOT, and professor of obstetrics and gynecology at Humanitas University, said in a news release. “These are the first positive OS results for an immunotherapy-based regimen for newly diagnosed patients with high-risk locally advanced cervical cancer and have the potential to change the treatment paradigm for these patients.”⁷

The KEYNOTE-A18 study is 1 of 4 phase 3 studies of a pembrolizumab-based regimen in an earlier stage of disease to demonstrate an OS benefit. The other trials include KEYNOTE-522 in newly diagnosed, high-risk early-stage triple-negative breast cancer; KEYNOTE-671 (NCT03425643) in resectable stage II, IIIA, or IIIB non–small cell lung cancer; and KEYNOTE-564 (NCT03142334) in renal cell carcinoma for patients at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions.⁷

These new findings are being discussed with regulatory authorities worldwide, according to the news release. In the US, pembrolizumab has 2 additional approved indications for cervical cancer, including in combination with chemotherapy, with or without bevacizumab, for patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1; and as a single agent for recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1.⁶

Conclusion

Taken together, these and other developing findings suggest that pembrolizumab could continue to have a growing role in cancer treatment for a wide array of patient populations. Merck currently has more than 1600 clinical trials investigating pembrolizumab across many cancers and treatment settings.¹

“Keytruda has reshaped the treatment of certain types of cancers, extending its benefits to a broader range of tumor types and patients, and we look forward to the prospect of more innovation for patients over the next 10 years and beyond,” Green said in the news release.⁴

REFERENCES

1. KEYTRUDA (pembrolizumab) Plus Chemotherapy Before Surgery and Continued as Single Agent After Surgery Reduced Risk of Death by More Than One-Third (34%) Versus Neoadjuvant Chemotherapy in High-Risk Early-Stage Triple-Negative Breast Cancer (TNBC). News release. Merck. September 15, 2024. Accessed September 17, 2024. https://www.merck.com/news/keytruda-pembrolizumab-plus-chemotherapy-before-surgery-and-continued-as-single-agent-after-surgery-reduced-risk-of-death-by-more-than-one-third-34-versus-neoadjuvant-chemotherapy-in-high-ri/

2. Selected Indications for Keytruda (pembrolizumab). Accessed September 17, 2024. https://www.keytrudahcp.com/approved-indications/

3. Schmid P, Cortes J, Dent R, et al. Overall survival with pembrolizumab in early-stage triple-negative breast cancer. New Engl J Med. September 15, 2024. Accessed September 17, 2024. https://www.nejm.org/doi/full/10.1056/NEJMoa2409932

4. Ten-Year Data for Merck’s Keytruda (pembrolizumab) Demonstrates Sustained Overall Survival Benefit Versus Ipilimumab in Advanced Melanoma. News release. Merck. September 15, 2024. Accessed September 17, 2024. https://www.merck.com/news/ten-year-data-for-mercks-keytruda-pembrolizumab-demonstrates-sustained-overall-survival-benefit-versus-ipilimumab-in-advanced-melanoma/

5. Keytruda (pembrolizumab) Plus Lenvima (lenvatinib) in Combination With Transarterial Chemoembolization Significantly Improved Progression-Free Survival Compared to TACE Alone in Patients With Unresectable, Non-Metastatic Hepatocellular Carcinoma. News release. Merck. September 14, 2024. Accessed September 17, 2024. https://www.merck.com/news/keytruda-pembrolizumab-plus-lenvima-lenvatinib-in-combination-with-transarterial-chemoembolization-significantly-improved-progression-free-survival-compared-to-tace-alone-in-patients-w/

6. Merck’s Keytruda (pembrolizumab) Plus Chemoradiotherapy (CRT) Reduced Risk of Death by 33% Versus CRT Alone in Patients With Newly Diagnosed High-Risk Locally Advanced Cervical Cancer. News release. Merck. September 14, 2024. Accessed September 17, 2024. https://www.merck.com/news/mercks-keytruda-pembrolizumab-plus-chemoradiotherapy-crt-reduced-risk-of-death-by-33-versus-crt-alone-in-patients-with-newly-diagnosed-high-risk-locally-advanced-cervical-cancer/

7. Lorusso D, Xiang Y, Hasegawa K, et al. Pembrolizumab or placebo with chemoradiotherapy followed by pembrolizumab or placebo for newly diagnosed, high-risk, locally advanced cervical cancer (ENGOT-cx11/GOG-3047/KEYNOTE-A18): overall survival results from a randomized, double-blind, placebo-controlled, phase 3 trial. The Lancet. September 14, 2024. Accessed September 17, 2024. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(24)01808-7/abstract