Final KEYNOTE-006 Findings Confirm Pembrolizumab Superiority For Advanced Melanoma

Pembrolizumab given on a 2- or 3-week schedule offers significantly longer overall survival than ipilimumab for patients with inoperable, advanced melanoma

medwireNews: Final overall survival (OS) findings from the KEYNOTE-006 trial confirm that pembrolizumab is superior to ipilimumab for the treatment of patients with stage III or IV unresectable melanoma who had previously received no more than one systemic therapy.

After a median follow-up of 22.9 months, median OS was unreached in the 279 patients who received pembrolizumab 10 mg/kg on a 2-week schedule and the 277 patients given the same dose on a 3-week schedule.

This was significantly longer than the median OS of 16.0 months for the 278 patients who were given four doses of ipilimumab 3 mg/kg at 3-week intervals, and the OS benefit was found across all patient subgroups, including age, gender, tumour size, prior therapy, BRAF V600E/K mutation status, and lactate dehydrogenase (LDH) level.

“In terms of patient selection, it is encouraging to see that both pembrolizumab regimens were equally advantageous over ipilimumab in patients with a larger tumour burden, and with higher levels of LDH (presumably reflecting tumour burden), given reports that the clinical success of PD-1 blockade is sensitive to tumour size”, say the authors of a comment discussing the KEYNOTE-006 findings in The Lancet.

“It is also encouraging to see that even patients with PD-L1-negative tumour cells (using a PD-L1 staining cut off of 1% positivity) are still better off with the anti-PD-1 antibody”, write the commentators, Kilian Wistuba-Hamprecht and Graham Pawelec, from the University Medical Centre Tuebingen in Germany.

Compared with ipilimumab, both the 2-week and 3-week pembrolizumab schedules also offered significantly longer progression-free survival (PFS; 5.6 and 4.1 vs 2.8 months), as well as a significantly higher objective response rate (37 and 36 vs 13%).

The KEYNOTE-006 investigators highlight difficulties in comparing safety profiles for the regimens because almost all of the patients using ipilimumab had completed treatment by week 12; the reporting period for adverse events was shorter in these patients than their pembrolizumab-treated counterparts, at an average of 50 days versus 292–312 days.

Treatment-related adverse events were reported in 82% and 77% of patients in the 2-week and 3-week pembrolizumab groups and 74% of the ipilimumab-treated patients, with grade 3–5 treatment-related events occurring in 17%, 17% and 20%, respectively.

Toxicity led to treatment discontinuation in 7% and 11% of patients given the 2-week and 3-week pembrolizumab regimens, respectively, and 9% of ipilimumab-treated patients. Of the 202 patients who received pembrolizumab for at least 1 year, grade 3–4 toxicity was reported in 19%, while 4% discontinued treatment.

"Pembrolizumab provides a favourable benefit-risk profile in comparison with ipilimumab, supporting pembrolizumab as a standard of care for advanced melanoma", write lead investigator Jacob Schachter, from Sheba Medical Center in Tel Hashomer, Israel, and co-authors.

Given the “substantiated superiority” of pembrolizumab in this setting, the commentators question whether ipilimumab should be offered, but note that a combination of nivolumab plus ipilimumab has shown better PFS than either agent alone, albeit with greater toxicity.

“Combined pembrolizumab and ipilimumab is currently in a phase 1 study, with preliminary data suggesting a manageable toxicity profile and durable antitumor activity”, remark Kilian Wistuba-Hamprecht and Graham Pawelec.

“The main task for the future will be to better understand the mechanisms that underlie checkpoint inhibition with different antibodies against other targets, and to predict which patients will respond best to each regimen”, they write. “For this, the identification of robust, predictive biomarkers will be important for individual patient selection.”

References

Schachter J, Ribas A, Long GV, et al. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet; Advance online publication 16 August 2017. DOI: http://dx.doi.org/10.1016/S0140-6736(17)31601-X

Wistuba-Hamprecht K, Pawelec G. KEYNOTE-006: a success in melanoma, but a long way to go. Lancet; Advance online publication 16 August 2017. DOI: http://dx.doi.org/10.1016/S0140-6736(17)31816-0