Immunotherapy with pembrolizumab improves survival in patients with head and neck cancer that has recurred or metastasized according to the most recent results of the KEYNOTE-048 study presented at the Congress of the European Society of Medical Oncology, ESMO 2018 that is celebrated until on the 23rd in Munich.
The current reference treatment for metastatic or recurrent head and neck cancer is platinum-based chemotherapy (5-fluorouracil (5-FU) with cisplatin or carboplatin) plus the EGFR inhibitor cetuximab. About 35% of patients respond to treatment, which leads to a median survival of just ten months.
The phase 3 study KEYNOTE-048 examined whether the anti-PD-1 monoclonal antibody pembrolizumab could prolong survival and delay the development of cancer compared with the reference treatment. KEYNOTE-048 recruited patients with head and neck cancer who had not previously received chemotherapy or biological therapy for recurrent or metastatic disease. Patients were randomized in a 1: 1: 1 ratio to: 1) baseline treatment with platinum-based chemotherapy (5-FU with cisplatin or carboplatin) and cetuximab (the control group); 2) pembrolizumab monotherapy or 3) a new combination of pembrolizumab and platinum-based chemotherapy.
At the 2018 ESMO Congress the researchers presented the results of pembrolizumab as a monotherapy compared to the reference treatment in patients expressing PD-L1, a marker of immune activity and with the new combination compared to the reference treatment in all patients independently of the expression of PD-L1.
In the first comparison, 301 patients received pembrolizumab and 300 patients the reference treatment, with a median follow-up of 11.7 and 10.7 months, respectively. In patients with tumor and / or surrounding cells expressing PD-L1 (combined positive score [CPS]> 20), overall survival was significantly longer with pembrolizumab (14.9 months) than with the reference treatment (10.7 months). months, risk ratio [CR] 0.61, p = 0.0007). 23.3% responded to pembrolizumab and 36.1% responded to the reference treatment. The median duration of the response was longer with pembrolizumab (20.9 months) than the reference treatment (4.5 months). There was no difference in progression-free survival between groups (RR 0.99, confidence interval [CI] 95% 0.75-1.29).
“Patients with PD-L1 expression live longer when they receive initial treatment with pembrolizumab,” said Professor Barbara Burtness of the Yale School of Medicine, first author and co-director of the Development Therapeutics Research Program at the Yale Cancer Center in New Haven (EE .UU.).
The results were similar in patients with a lower cut-off of PD-L1 expression (CPS> 1). Overall survival was significantly longer with pembrolizumab (12.3 months) compared with the reference treatment (10.3 months, RR 0.78, p = 0.0086). About 19.1% of patients who received pembrolizumab responded to treatment compared to 34.9% who received reference chemotherapy. The median duration of the response was longer with pembrolizumab (20.9 months) than the reference chemotherapy (4.5 months). There was no difference in progression-free survival between the groups (CR 1.16, 95% CI 0.75-1.29).
In the second comparison, 281 patients received the new combination of pembrolizumab and platinum-based chemotherapy and 278 received the reference treatment, with a median follow-up of 13.0 and 10.7 months, respectively. Overall survival was prolonged with the combination (13.0 months) compared with the reference treatment (10.7 months, RR 0.77, p = 0.0034). The response rates were 35.6% for the combination of pembrolizumab and 36.3% for the reference treatment. There was no difference in progression-free survival between groups (RR 0.92, 95% CI 0.77-1.10).
Burtness noted that compared to the reference treatment, pembrolizumab monotherapy had a lower response rate and a numerically less progression-free survival, but significantly greater overall survival. He noted that “Pembrolizumab seems to prolong life even if the cancer continues to develop, suggesting that this would be a first-line therapy in metastatic and recurrent head and neck cancer. Regardless of whether pembrolizumab is given in monotherapy or with chemotherapy, it may depend on the expression of PD-L1 and we are conducting analyzes to answer this question. ”
Commenting on these findings, Dr. Tanguy Seiwert, director of the head and neck cancer program, director and assistant professor of Medicine at the University of Chicago (USA), said: “This is the first study that demonstrates a global survival over the reference treatment of the last decade, platinum-based chemotherapy and cetuximab and establishes PD-L1 (CPS) as a valid marker for head and neck cancer that should be measured routinely in these patients. ”
But he added: “The challenge is that the benefit of the treatment is not distributed equally, but depends on a biomarker. Therefore, the expression of PD-L1 (CPS) will probably suggest the choice between the two new options, pembrolizumab monotherapy, with a profile of favorable side effects and pembrolizumab combined with chemotherapy, which can be used in a larger group of patients . A higher expression of PD-L1 is associated with a greater benefit, but exact cut points have yet to be established and the characteristics of the individual patient will also play an important role. Independent analyzes are needed in patients who have tumors with low expression of PD-L1 or absence of expression, where there is potentially less benefit. ”
Regardless of the need for more research, Seiwert noted that “the utility of other biomarkers to select patients for treatment, such as a mutational load of the tumor, should also be examined.”
According to another recent study presented at the ESMO 20183 Congress, patients with throat cancer with human papilloma virus (HPV) positive should receive chemo-radiotherapy instead of cetuximab with radiotherapy.
“Many patients have been receiving cetuximab with radiotherapy assuming it was as effective as chemotherapy with radiotherapy and with fewer side effects, although there was no direct comparison of the two treatments,” said Professor Hisham Mehanna, study author and director of surgery. of head and neck at the Institute of Cancer and Genomic Sciences of the University of Birmingham (United Kingdom).
Throat cancer is becoming increasingly common in Western countries. This increase has been attributed to HPV, an infection transmitted sexually. Before, most cases of throat cancer were caused by tobacco and alcohol and affected working class men of 65-70 years of age. Currently HPV is the main cause and patients are around 55 years of age, are middle class, workers and have young children.
Positive HPV throat cancer responds well to a combination of cisplatin chemotherapy and radiation therapy and patients can survive 30-40 years, but the treatment causes chronic side effects that include dry mouth, difficulty swallowing and loss of taste. Patients considered unfit to tolerate chemotherapy, for example, due to kidney failure or at an advanced age, receive cetuximab, an inhibitor of epidermal growth factor (EGFR) and radiotherapy.
This study compared side effects and survival with the two treatments in 334 patients with positive HPV throat cancer recruited from 32 centers in the United Kingdom, Ireland and the Netherlands. The patients were randomized to radiotherapy and to cisplatin or cetuximab. Eight out of ten patients were male and the average age was 57 years.
During the two-year study, there were ten recurrences and six deaths with cisplatin compared with 29 recurrences and 20 deaths with cetuximab. The patients who received cisplatin had a significantly higher overall survival rate of two years (97.5%) than in the patients treated with cetuximab (89.4%, p = 0.001, risk ratio [CR] 4, 99, confidence interval [CI] 95% 1.70? 14.67). The probability of recurrence of cancer at two years was three times higher with cetuximab compared to cisplatin, with recurrence rates of 16.1% versus 6.0%, respectively (p = 0.0007, RR 3.39, 95% CI 1.61? 7.19).
Mehanna noted: “Cetuximab was not associated with less toxicity and resulted in a worse overall survival and more cancer recurrence than cisplatin. This was a surprise, we thought it would be associated with the same survival rates, but with better toxicity. Patients with positive HPV throat cancer should as far as possible receive cisplatin and not cetuximab. ”
Commenting on the study for the ESMO Congress, Dr. Branislav Bystricky, director of the Department of Medical Oncology and Radiotherapy at the University Hospital Tren? Ín (Slovakia), explained: “It was believed that cetuximab causes fewer side effects and that, therefore, , is a good option for patients with positive HPV throat cancer who are young and with a life expectancy of several decades, as well as for those who tolerate chemotherapy. This study shows that the best treatment option for patients with positive HPV throat cancer is cisplatin and radiotherapy. This combination offers the ‘double’ benefit since it is more effective in terms of survival and does not worsen the toxicity of any degree compared to cetuximab with radiotherapy. ”
Bystricky said the results agreed with the tentative findings of the RTOG 1016 trial of the National Cancer Institute of the United States and whose publication is scheduled for this month: “Now we have two studies that show that these patients should not be given cetuximab. Future studies should examine whether genotyping of the KRAS variant can select a group of patients who benefit from treatment with cetuximab with radiotherapy. ”
Distefar supports this study that supposes survival in this type of cancer, and shows the superiority of chemo-radiotherapy in patients with throat cancer.