Immunotherapy on its own is better than aggressive chemotherapy as a first-line treatment for advanced head and neck cancer, according to surprising new data from a major phase III clinical trial. Patients lived for longer and had far lower rates of side-effects if they took the immunotherapy drug pembrolizumab than those who received an “extreme” combination of two chemotherapies and a targeted drug.
People with an immune hallmark called PD-L1 in their tumours did particularly well on pembrolizumab – living for around 40% longer. And while only around a fifth of patients overall responded to pembrolizumab, those who did so often did spectacularly well – with a median length of response of 20.9 months compared with only 4.2 months with aggressive chemotherapy.
The trial was led in the UK by a team at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust, and involved 206 research centres worldwide.
Its findings could in future see immunotherapy become a standard, first-line treatment for advanced head and neck cancer, and spare many patients the side-effects associated with combination chemotherapy.
The study was presented at the European Society for Medical Oncology (ESMO) Congress 2018 in Munich and was sponsored by Merck & Co.
Patients would normally be given aggressive chemotherapy if diagnosed at an advanced stage when the cancer has begun to spread to try to get rid of all the cancer cells as quickly as possible. But the new trial sought to see if immunotherapy, in combination with chemotherapy or on its own, could be a more effective and kinder option.
The researchers randomly assigned 882 patients in equal numbers to one of three treatment groups – receiving the “extreme” chemotherapy combination, and the immunotherapy pembrolizumab with platinum chemotherapy or on its own.
Patients with high levels of the immune marker PD-L1 in their tumours received the biggest benefit from pembrolizumab – living for a median of 14.9 months after diagnosis compared with 10.7 months with the aggressive combination.
But patients with lower levels of PD-L1 also saw benefit, living 12.3 months taking pembrolizumab compared with 10.3 for those who received the combination.
Importantly, only 17% of patient experienced serious side-effects with pembrolizumab, compared with 69% of those taking the ‘extreme’ therapy.
The only downside to pembrolizumab on its own was that fewer people in total responded. Even in the group with high levels of PD-L1, 23% of patients who received the treatment responded, compared with 36% for chemotherapy.
The response rate was higher, at 36%, for patients who received platinum chemotherapy alongside pembrolizumab – but these patients had the same high rate of side-effects as those on the aggressive chemotherapy combination.
Pembrolizumab is an immune checkpoint inhibitor that targets PD-L1 on the surface of cancer cells. Blocking PD-L1 in this way takes the ‘brakes’ off the immune system, setting it free to attack cancer cells.
The findings are consistent with previous studies of checkpoint inhibitor immunotherapies and illustrate the pros and cons of these drugs – their excellent responses in some patients, but the fact that only a minority of patients respond.
Professor Kevin Harrington, professor of biological cancer therapies at The Institute of Cancer research, London and consultant clinical oncologist at The Royal Marsden Foundation Trust, said: “Our study has shown that the immunotherapy pembrolizumab on its own is better than an aggressive triple-whammy of two types of chemotherapy plus a targeted drug as first-line treatment for advanced head and neck cancer.
“We couldn’t believe it when we saw the results. None of us expected pembrolizumab on its own to work so well in some of these patients – and it raises the prospect that we could spare some people chemotherapy altogether.
“The study could have major implications for the treatment of advanced head and neck cancers – taking immunotherapy from a last resort to the treatment we turn to first for some patients. The trial is still ongoing, but we expect some patients to go on to live for years longer than they would have done had they received standard chemotherapy.”
Professor Paul Workman, CEO of The Institute of Cancer Research, London, said: “We’re used to seeing immunotherapy trialled in patients who have exhausted other options – but this trial has shown its true potential as a smarter, kinder and more effective first-line treatment for cancer, where it can have the biggest impact on a patient’s life.
“This trial showed the benefits of immunotherapy in head and neck cancer, but I’m optimistic that the same will hold true for other cancers.
“We now need to do two things to ensure more patients can benefit from immunotherapy – develop ways of getting these drugs to work in a higher proportion of patients, and come to an agreement over the cost of these drugs to make them more affordable for the NHS.”
Background: KEYNOTE-048 was an open-label, randomized phase 3 study of P or P + chemotherapy (C) vs EXTREME (E) as first-line systemic therapy for R/M HNSCC (NCT02358031).
Methods: Patients (pts) with R/M HNSCC not curable by local therapy and with no prior systemic therapy (R/M setting) who provided a tumor sample for PD-L1 testing were randomized to P 200 mg Q3W, P + C (cisplatin 100 mg/m2 or carboplatin AUC 5 Q3W + 5-FU 1000 mg/m2/d for 4 d Q3W), or E (cetuximab 400 mg/m2 loading/250 mg/m2 QW + C) given until PD, unacceptable toxicity, 6 cycles (C), or 24 mo (P). Primary end points for P vs E and P + C vs E were PFS and OS in the PD-L1 combined positive score (CPS) ≥20 and ≥1 and total populations (pop). Cutoff date for this final PFS/interim OS analysis was Jun 13, 2018 (minimum follow-up, ~17 mo).
Results: 882 pts were randomized: 301 to P, 281 to P + C, 300 to E. P was superior to E for OS in CPS ≥20 (N = 255; median 14.9 vs 10.7 mo; HR 0.61 [95% CI 0.45-0.83]; P = 0.0007) and ≥1 (N = 512; median 12.3 vs 10.3 mo; HR 0.78 [95% CI 0.64-0.96]; P = 0.0086); OS for P was non-inferior to E in the total pop (N = 601). P did not prolong PFS in CPS ≥20 (P = 0.5); per the analysis plan, no further PFS testing was done for P vs E. Confirmed ORR (P vs E) was 23% vs 36% for CPS ≥20, 19% vs 35% for CPS ≥1, and 17% vs 36% for the total pop; median DOR was 20.9 vs 4.2 mo, 20.9 vs 4.5 mo, and 20.9 vs 4.5 mo. Gr 3-5 drug-related AE rates were 17% (P) vs 69% (E). P + C was non-inferior and superior to E for OS in the total pop (N = 559; median 13.0 vs 10.7 mo; HR 0.77 [95% CI 0.63-0.93]; P = 0.0034); OS for P + C was not significantly superior to E in CPS ≥20 and ≥1 at this interim analysis. PFS was not prolonged with P + C (P = 0.2). For P + C vs E, confirmed ORR was 36% vs 36%, median DOR was 6.7 vs 4.3 mo, and gr 3-5 drug-related AE rates were 71% vs 69%.
Conclusions: For first-line R/M HNSCC, P significantly improved OS over E in the PD-L1 CPS ≥20 and ≥1 populations and was noninferior in the total population with favorable safety. P + C significantly improved OS in the total population with safety comparable to E. P and P + C responses were durable. These data support pembrolizumab and pembrolizumab + platinum + 5-FU as new first-line standards of care for R/M HNSCC. The study continues to the final OS analysis.
B Burtness, KJ Harrington, R Greil, D Soulières, M Tahara, G De Castro Jr, A Psyrri, N Baste Rotllan, PC Neupane, Å Bratland, T Fuereder, BGM Hughes, R Mesia, N Ngamphaiboon, T Rordorf, WZ Wan Ishak, A Roy, J. Cheng, F Jin, D Rischin