Immunotherapy used with chemotherapy or on its own is a better first-line treatment for people with head and neck cancer that has returned than standard aggressive chemotherapy, clinical trial results show.
At diagnosis, people with head and neck cancer that has come back or spread are currently given an ‘extreme’ cocktail of two chemotherapy drugs and a targeted antibody treatment.
But the new trial found that the immunotherapy pembrolizumab in combination with platinum chemotherapy extended survival, while immunotherapy alone also worked well for some patients with much lower rates of side effects.
The clinical trial results offer strong evidence in favour of pembrolizumab, either on its own or in combination with chemotherapy, becoming the first treatment of choice for people with head and neck cancer that has come back and spread.
The UK‘s National Institute for Health and Care Excellence (NICE) has started an analysis of whether pembrolizumab is cost-effective for use on the National Health Service (NHS), and is expected to announce its decision in February 2020.
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.
Scientists found patients lived longer when they were given pembrolizumab in combination with a platinum chemotherapy in the first instance, instead of the current standard treatment of aggressive chemotherapy.
Patients with high levels of the immune marker PD-L1 who received pembrolizumab with chemotherapy lived for an average of 14.7 months, compared with 11.0 months in patients given the aggressive chemotherapy treatment.
Remarkably, a third of patients treated with pembrolizumab and chemotherapy were alive three years after starting treatment, compared with only one in twelve of those receiving extreme chemotherapy.
People with lower levels of PD-L1 also saw benefit from the combination of immunotherapy and chemotherapy, with survival extending to an average of 13.6 months compared with 10.4 months with standard ‘extreme’ chemotherapy.
The final results of the trial were presented at the ASCO Annual Meeting in Chicago. The trial was sponsored by the drug’s manufacturer, Merck & Co, known as MSD outside the US and Canada.
Pembrolizumab on its own extended survival in people with the PD-L1 immune marker – who make up the majority of patients – compared with the standard, aggressive chemotherapy combination.
Fewer people responded when given the immunotherapy alone – 16.9% compared with 36% with chemotherapy – but this did not prevent pembrolizumab from delivering markedly improved survival rates compared to extreme chemotherapy. For those people for whom pembrolizumab did work, it worked extremely well – with the average duration of response being 22.6 months compared with just 4.5 months on aggressive chemotherapy.
Importantly, compared with chemotherapy, pembrolizumab treatment came with much lower rates of serious side effects, which occurred in just 55% of people treated with the immunotherapy alone. Side effects occurred in 85% of people given pembrolizumab with platinum chemotherapy, and in 83% of people who received the aggressive chemotherapy combination.
Professor Kevin Harrington, professor of biological cancer therapies at the ICR and consultant clinical oncologist at The Royal Marsden, said: “We have shown that pembrolizumab either on its own or in combination with platinum chemotherapy is effective as a first-line treatment for patients with advanced head and neck cancer – where currently the first choice of treatment is an aggressive chemotherapy.
“We had started to see strong indications of the promise of pembrolizumab as a first-line treatment while the trial was still ongoing, and I am delighted to see the preliminary results of the trial confirmed in the final analysis.
“Patients with advanced head and neck cancer are currently given a highly aggressive chemotherapy combination, so I’m hopeful that the results of our trial will soon be translated into pembrolizumab approval on the NHS so patients can start benefiting right at the start of treatment. We can imagine that many patients might be treated with pembrolizumab alone, allowing patients the twin benefits of prolonged survival and fewer side effects. Where necessary some might need to receive a combination of pembrolizumab and chemotherapy and we now know that this can be highly beneficial.”
Professor Paul Workman, CEO of The Institute of Cancer Research, London, said: “Immunotherapy has already revolutionised the outlook for patients with melanoma, and is showing huge promise in other cancer types as well. Based on the results of the new clinical trial, pembrolizumab looks set to do the same for people diagnosed with recurrent head and neck cancer.
“Until now, immunotherapy had only been tested in patients with head and neck cancer at a later stage of treatment, when other therapies had stopped working. I’m keen to see innovative new treatments assessed earlier in the course of treatment where the potential for benefit can be greater, and it’s excellent news that in this case pembrolizumab is indeed proving effective at the first-line stage.”
Background: KEYNOTE-048 is a phase 3 study of P or P + chemo (C) vs EXTREME (E) as 1L therapy for R/M HNSCC (NCT02358031). At the second interim analysis (IA2), P significantly improved OS in the PD-L1 combined positive score (CPS) ≥20 and ≥1 populations and had noninferior OS in the total population with favorable safety; P+C significantly improved OS in the total population with comparable safety. We present the protocol-specified final results.
Methods: 882 pts with locally incurable R/M HNSCC and no prior systemic therapy in the R/M setting who provided a tumor sample for PD-L1 testing were randomized to P 200 mg Q3W for 24 mo (n = 301), P for 24 mo + 6 cycles of C (cisplatin 100 mg/m2 or carboplatin AUC 5 Q3W + 5-FU 1000 mg/m2/d for 4 d Q3W) (n = 281), or E (cetuximab 400 mg/m2 loading/250 mg/m2 QW + 6 cycles of chemo) (n = 300). OS superiority was tested sequentially for P+C vs E in the CPS ≥20 population, then the CPS ≥1 population, and for P vs E in the total population (superiority thresholds: one-sided P = .0023, .0026, and .0059, respectively). Data cutoff was 25 Feb 2019 (~25 mo after last pt randomized).
Results: P+C significantly improved OS vs E in the CPS ≥20 (HR 0.60, 95% CI 0.45-0.82, P = .0004; median 14.7 vs 11.0 mo) and CPS ≥1 (HR 0.65, 95% CI 0.53-0.80, P< .0001; median 13.6 vs 10.4 mo) populations. HR (95% CI) for PFS was 0.76 (0.58-1.01) for CPS ≥20 and 0.84 (0.69-1.02) for CPS ≥1. ORR (P+C vs E) was 42.9% vs 38.2% for CPS ≥20 and 36.4% vs 35.7% for CPS ≥1; median DOR was 7.1 vs 4.2 mo and 6.7 vs 4.3 mo, respectively. P did not significantly improve OS vs E in the total population (HR 0.83, 95% CI 0.70-0.99, P = .0199; median 11.5 vs 10.7 mo). HR (95% CI) for PFS was 1.29 (1.09-1.53). ORR (P vs E) was 16.9% vs 36.0%; median DOR was 22.6 vs 4.5 mo. All-cause gr 3-5 AE rates were 54.7% for P, 85.1% for P+C, and 83.3% for E.
Conclusion: Overall, KEYNOTE-048 showed that compared with E, P+C had superior OS in the PD-L1 CPS ≥20, CPS ≥1, and total populations with comparable safety and P had superior OS in the CPS ≥20 and ≥1 populations, noninferior OS in the total population, and favorable safety. These results support pembrolizumab and pembrolizumab + platinum + 5-FU as new 1L standards of care for R/M HNSCC. Clinical trial information: NCT02358031
Danny Rischin, Kevin J Harrington, Richard Greil, Denis Soulieres, Makoto Tahara, Gilberto de Castro, Amanda Psyrri, Neus Baste, Prakash C Neupane, Ase Bratland, Thorsten Fuereder, Brett Gordon Maxwell Hughes, Ricard Mesia, Nuttapong Ngamphaiboon, Tamara Rordorf, Wan Zamaniah Wan Ishak, Yayan Zhang, Fan Jin, Burak Gumuscu, Barbara Burtness