Results from a first preplanned interim analysis, a median follow-up at 14.2 months, of the randomized phase III KEYNOTE-426 trial, demonstrated that the first-line treatment of patients with untreated metastatic renal cell carcinoma (mRCC) with pembrolizumab (Keytruda®; Merck & Co; previously known as MK-3475), in combination with axitinib (Inlyta®; Pfizer; previously known as AG013736), resulted in a prolonged overall survival (OS) and progression-free survival (PFS), as well as a higher objective response rate (ORR), than treatment with sunitinib (Sutent®; Pfizer). [1]

These findings, reported by Chihiro Kondoh of the department of Medical Oncology of the Toranomon Hospital in Tokyo, Japan, during the ESMO Asia Virtual Congress 2020, held from 20 to 22 November 20 – 22, 2020, confirm pembrolizumab in combination with axitinib to be a standard of care. Participating patients enrolled in the randomized phase III KEYNOTE-426 study (NCT02853331) included patients from Eastern Asia (Japan, South Korea, and Taiwan.

Metastatic renal cell carcinoma (mRCC) is a kidney cancer that originates in the lining of the proximal convoluted tubule, a part of the very small tubes in the kidney that transport primary urine. The disease is the most common type of kidney cancer in adults, responsible for approximately 90–95% of cases. Most patients diagnosed with kidney cancer, including metastatic renal cell carcinoma, are older. Their average age at diagnosis is 64 years of age with most people being diagnosed between ages 65 and 74. RCC, which is about twice as common in men than in women, is very uncommon in people younger than age 45.

Current standard of care
The treatment of mRCC offered, for a long time, a great therapeutic challenge. Predominantly refractory to treatment with traditional cytotoxic chemotherapies, the management options were generally limited to immunotherapy or palliative care. However, with the introduction of novel targeted therapies, new treatment options have emerged, bringing hope to patients. These treatment options included the tyrosine kinase inhibitors sunitinib, pazopanib, and sorafenib, the antibody bevacizumab (in combination with interferon-α), and the rapamycin analogs, temsirolimus, and everolimus.

One of these agents, sunitinib is a current standard of care for mRCC. The drug also serves as the active comparator in several ongoing mRCC clinical trials, including KEYNOTE-426.

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Trial design
KEYNOTE-426 enrolled patients with clear cell metastatic RCC and Karnofsky performance status score ≥70%. Following 1:1 randomization, patients were treated with pembrolizumab at 200 mg IV every 3 weeks for a maximum of 35 cycles plus oral axitinib at 5 mg twice daily or oral sunitinib at 50 mg daily in 4 weeks on 2 weeks off cycle until disease progression, unacceptable toxicity, death, or study withdrawal.

Primary endpoints included OS and PFS per RECIST v1.1 and the secondary endpoints were ORR and safety.

Overall survival in the intent-to-treat population. © 2020 Chihiro Kondoh.

Based on data reported from the first pre-planned interim analysis of KEYNOTE-426, the combination of pembrolizumab and axitinib became a standard of care for patients with untreated advanced or mRCC. With a median follow-up of 14.2 months, the combination significantly prolonged OS, PFS, and improved ORR in this patient population. Updated findings after a median of 30.6 months of follow-up showed that pembrolizumab plus axitinib continued to demonstrate efficacy that was superior to sunitinib with respect to the same endpoints. [2][3]

The results demonstrated that fewer patients receiving pembrolizumab in combination with axitinib required subsequent therapy.

Asian patients
Of the 130 patients enrolled in Eastern Asia, 62 were treated with pembrolizumab plus axitinib, and 68 received sunitinib. In the Eastern Asian population, 44 (71.0%) patients on the pembrolizumab plus axitinib combination and 58 (86.6%) patients treated with sunitinib discontinued treatment.

With a median follow-up of 29.8 (range, 24.6 to 37.7) months for pembrolizumab plus axitinib and 29.9 (range, 24.6 to 37.9) months for sunitinib in this population, median OS was not reached in either treatment arm (hazard ratio [HR] 0.71; 95% confidence interval [CI] 0.38-1.31) and the 24-month OS rates were 77% versus 68%, respectively.

Treatment-related adverse events in the study. © 2020 Chihiro Kondoh.

With pembrolizumab plus axitinib median PFS was 18.0 months (95% CI 12.5-23.5) compared to 10.0 months (95% CI 7.1-15.0) with sunitinib (HR 0.59; 95% CI 0.37-0.93). The 24-month PFS rates were 34% and 19%, respectively.

The ORR was 64.5% with pembrolizumab plus axitinib versus 44.1% with sunitinib and 14.5% versus 5.9% of patients achieved complete response.

Subsequent therapy with a PD-1/L1 inhibitor in patients who discontinued treatment was administered to 5 (11%) patients on pembrolizumab plus axitinib compared to 33 (57%) patients on sunitinib, and 28 (64%) versus 36 (62%) patients, respectively, received subsequent treatment with a VEGF/VEGFR inhibitor.

Adverse events
Grade 3-5 treatment-related adverse events occurred in 43 (69.4%) patients on pembrolizumab plus axitinib and 50 (74.6%) patients on sunitinib.

According to Chihiro Kondoh and his colleagues, patients enrolled from Eastern Asia in KEYNOTE-426 demonstrated treatment benefit and improved tolerability when treated with pembrolizumab plus axitinib compared to sunitinib. The findings were consistent with those observed in the global study population and support pembrolizumab plus axitinib as a first-line treatment option for RCC in East Asian patients.

The study was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Clinical trials
Study to Evaluate the Efficacy and Safety of Pembrolizumab (MK-3475) in Combination With Axitinib Versus Sunitinib Monotherapy in Participants With Renal Cell Carcinoma (MK-3475-426/KEYNOTE-426) – NCT02853331

Highlights of prescribing information
Pembrolizumab (Keytruda®; Merck & Co) [Prescribing Information]
Axitinib (Inlyta®; Pfizer) [Prescribing Information]
Sunitinib malate (Sutent®; Pfizer) [Prescribing Information]

[1] Kondoh CN, Bae WK, Tamada S, et al. Pembrolizumab Plus Axitinib (pembro + axi) vs Sunitinib in Metastatic Renal Cell Carcinoma (mRCC) Outcomes of the KEYNOTE-426 Study in Patients From Eastern Asia. ESMO Asia Virtual Congress 2020 (November 20-22). Annals of Oncology (2020) 31 (suppl_6): S1319-S1324. 10.1016/annonc/annonc357
[2] Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, Pouliot F, Alekseev B, Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019 Mar 21;380(12):1116-1127. doi: 10.1056/NEJMoa1816714. Epub 2019 Feb 16. PMID: 30779529.
[3] Powles T, Plimack ER, Soulières D, Waddell T, Stus V, Gafanov Ret al. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncology 2020; DOI:

Featured image: ESMO Asia 2018, Singapore. Photo courtesy: © 2018 – 2020 ESMO. Used with permission.

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