MUNICH — Patients with recurrent or metastatic head and neck cancer with relatively high expression of the programmed cell death ligand 1 (PD-L1) could eventually be treated first-line with the immunotherapy pembrolizumab (Keytruda, Merck) rather than traditional chemotherapy.
This was the conclusion from experts discussing the results of KEYNOTE-048, the first study to look at immunotherapy use first-line in this patient population, presented here at the European Society of Medical Oncology 2018 annual meeting.
The new results show an improvement in overall survival (OS) over initial use of standard of care chemotherapy — the first time such a benefit has been seen in 10 years, they noted.
Immunotherapy is already used second-line in advanced head and neck cancer; pembrolizumab and the similar drug nivolumab (Opdivo, Bristol-Myers Squibb) are already approved for this indication.
The new finding concerns the use of pembrolizumab first-line in this patient population. The trial was conducted in nearly 900 patients and was split into two parts.
It compared pembrolizumab alone with standard of care cisplatin-based chemotherapy in patients stratified for PD-L1 expression.
In addition, it compared pembrolizumab plus carboplatin-based chemotherapy versus standard of care chemotherapy in all comers, regardless of PD-L1 expression.
The results show that pembrolizumab alone extended OS by 39% over standard of care chemotherapy in patients with PD-L1 expression ≥ 20% and extended OS by 22% in those with PD-L1 expression ≥ 1%.
However, immunotherapy was associated with a nonsignificant shorter progression-free survival (PFS) and substantially lower overall response rate than chemotherapy. But the duration of response, when it occurred, was almost five-times longer, and pembrolizumab was associated with fewer adverse events than chemotherapy.
In the other part of the trial, the combination of pembrolizumab plus chemotherapy that was tested in all comers, regardless of PD-L1 expression, was found to extend OS by a significant 23% compared with standard of care chemotherapy, but there was no PFS, overall response rate, or tolerability benefit.
Study lead Barbara Burtness, MD, Yale School of Medicine and Yale Cancer Center, New Haven, Connecticut, said in a press release the results show that "patients with PD-L1 expression live longer when they have initial treatment with pembrolizumab."
Noting, however, the lower overall response rate and shorter PFS with the PD-L1 inhibitor alone, she added that the drug "appears to prolong life even when the cancer continues to grow, suggesting that it should be a first-line therapy in recurrent and metastatic head and neck cancer."
"Whether pembrolizumab is given alone or with chemotherapy may depend on PD-L1 expression and we are conducting analyses to answer this question."
In a press conference for the study, Burtness said that this will include assessment of biomarker and clinical predictors, "and these may eventually optimally guide the choice of whether to administer pembrolizumab alone or in the novel combination."
In the meantime, she said that the findings could have a big impact on recurrent/metastatic patients who are not very symptomatic and are "PD-L1 rich."
"Patients are not enthusiastic about the toxicities of platinum-based chemotherapy," Burtness said. "I think they'll be delighted to be able to get pembrolizumab alone."
Survival Benefit Seen for First Time in 10 Years
Commenting for ESMO, Jean-Pascal Machiels, MD, PhD, head of the Department of Medical Oncology at the Cliniques Universitaires Saint-Luc, Brussels, Belgium, described the study as "very important."
"This is the first time in 10 years that we have shown an improvement in survival for this group of patients," he said.
"What is extremely important also is that, in a subgroup of patients with high expression of PD-L1, we can probably remove cisplatin and have a good outcome with immunotherapy alone," he added.
Machiels cautioned that "we still have some work to do to better characterize the group of patients that will benefit," adding that "we have to see how we can now bring this active drug to the curative treatment of the patient in combination with chemoradiation."
In the press release, Tanguy Seiwert, MD, head and neck cancer program director and assistant professor of medicine at University of Chicago Medicine, Illinois, also underlined that this is the first study to show a survival benefit over standard of care.
He noted that it also establishes PD-L1 scoring "as a valid marker for head and neck cancer that should be routinely measured."
"The challenge is that treatment benefit is not equally distributed but depends on a biomarker," he said, which means that it will be likely that PD-L1 scoring will be used to inform the choice of pembrolizumab alone or pembrolizumab plus chemotherapy.
"Higher PD-L1 expression is associated with more benefit but the exact cut points have to be determined, and individual patient characteristics will play an important role as well," he said. "Separate analyses are needed in patients who have tumors with low or absent PD-L1 expression, where there is potentially less benefit."
Despite these ongoing questions, Solange Peters, MD, PhD, ESMO scientific committee chair and Oncology Department, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, told Medscape Medical News before the ESMO 2018 congress that the results are among the "most exciting data" to be presented this year.
"It's interesting because it's paralleling what we had in lung cancer before, which is reassuring by the way, because they are very similar diseases, based on smoking habits, mutation burden, and so on," she commented.
"This is extremely exciting, and this could completely change the frontline strategy for these patients. Remember, frontline treatment for metastatic head and neck is very heavy, so it really could make management easier and more efficacious."
The KEYNOTE-048 study was designed to test three different treatment approaches:
Pembrolizumab monotherapy for up to 35 cycles.
Pembrolizumab plus carboplatin and 5-fluorouracil (5-FU) chemotherapy for 6 cycles, followed by pembrolizumab for a total of up to 35 cycles.
Standard of care chemotherapy, comprising cetuximab, cisplatin, and 5-FU for 6 cycles, followed by cetuximab once weekly (as used in the EXTREME trial).
Patients were required to have squamous cell carcinoma of the oropharynx, oral cavity, hypopharynx, or larynx that was incurable with local therapies and was recurrent or metastatic. They had an ECOG performance status of 0 or 1.
PD-L1 expression was measured using the combined positive score (CPS) and tumor proportion score (TPS), and patients were assessed for human papillomavirus virus (HPV) type 16 status.
In all, 882 patients were randomized to the three treatment arms in a 1:1:1 fashion between 2015 and 2017.
The researchers conducted two comparisons:
Pembrolizumab alone (n = 310) versus standard of care chemotherapy (n = 300); and
Pembrolizumab plus chemotherapy (n = 281) versus standard of care (n = 270).
The groups were well balanced in terms of baseline characteristics. The median age was approximately 61 years, and around 84% were men. Approximately 78% were current or former smokers, and around 21% were p16 positive.
In terms of PD-L1 expression, approximately 22% had a TPS ≥ 50%, around 42% had a CPS ≥ 20, and about 85% had a CPS ≥ 1.
Pembrolizumab Versus Chemotherapy in Stratified Patients
In the first comparison, in the subgroup of patients with CPS ≥ 20, pembrolizumab alone had a significantly better OS than standard of care chemotherapy, at a median OS of 14.9 months versus 10.7 months and a hazard ratio of 0.61 (P = .0007).
In the subgroup of patients with a CPS ≥ 1, pembrolizumab alone was associated with a lower, but still significant, improvement in OS over chemotherapy, at a median of 12.3 months versus 10.3 months and a hazard ratio of 0.78 (P = .0086).
However, it is notable that in neither the CPS ≥ 20 nor CPS ≥ 1 population was pembrolizumab alone associated with a significant improvement in PFS over standard of care chemotherapy, largely because of an increase in events in the first 6 months.
Pembrolizumab alone was associated with a lower overall response rate (ORR) than chemotherapy: in the CPS ≥ 20 group, the ORR was 23.3% vs 36.1%, and the in the CPS ≥ 1 population, the ORR was 19.1% vs 34.9%, respectively.
Burtness pointed out, however, that in those patients who responded, the duration of response with pembrolizumab alone was substantially longer than that see with chemotherapy, at 20.9 months versus 4.2 months in the CPS ≥ 20 group and 20.9 months versus 4.5 months in CPS ≥ 1 group.
Importantly, the rate of any grade treatment-related adverse events across the whole population was markedly less with pembrolizumab alone versus chemotherapy, at 58.3% versus 96.9%, a pattern that was repeated for grade 3-5 events, at 16.7% versus 69.0%.
All grade immune-mediated adverse events and infusion reactions were more common with immunotherapy, at 30.3% for pembrolizumab versus 23.7% for chemotherapy, although the opposite was seen for grade 3-5 events, at 6.7% versus 10.5%.
Pembrolizumab Plus Chemotherapy Versus Chemotherapy in All Comers
In the second comparison, conducted in all comers regardless of PD-L1 expression, pembrolizumab plus chemotherapy was associated with a significant increase in OS compared with chemotherapy, at a median of 13.0 months versus 10.7 months and a hazard ratio of 0.77 (P = .0034).
Again, PFS was not improved and there was no difference in the occurrence of progression events in the first 6 months of treatment.
The overall response rate was similar between the two treatment groups, at 35.6% for the combination and 36.3% for chemotherapy, as was the duration of response, at 6.7 months and 4.3 months, respectively.
The occurrence of any grade and grade 3-5 treatment-related adverse events was also comparable, at 96% for the combination and 70% for chemotherapy.
A similar pattern was seen for all grade immune-mediated adverse events and infusion reactions, at around 24% in both groups, although grade 3-5 events were more common with chemotherapy, at 10.5% versus 4.7% for the combination.
At the press conference, Burtness pointed out that all of the drugs used in the study are already available for use in the second-line setting.
"Obviously in different parts of the world it's easier or harder to prescribe outside of the approval but I'm very hopeful that these data will drive approvals in the first-line setting," she commented.
Discussing the potential for clinical markers to help further improve patient selection down the line, she said that tumor mutational burden "is of interest across a number of cancers, and we know that head and neck cancer has a high mutational load."
"What's a little complicated in head and neck cancer is that the mechanism of the mutations and the pattern of the mutations differs between HPV-related cancers and HPV-negative cancers, and I don't think we know whether or not we can translate the tumor mutational load in HPV-related disease to sensitivity to immune checkpoint inhibition," she commented.
Burtness noted that phase 1b data indicated an RNA-based interferon gene response expression signature "did seem to perform about equivalently to PD-L1," although it's not clear at this stage whether that would offer any additional clinically relevant information.
Speaking after presentation of the data as the invited discussant, Machiels discussed some of the study implications for clinicians.
He asked whether clinicians would be taking "any risk" giving pembrolizumab first-line to patients with PD-L1 expression ≥ 20%.
He pointed out that, despite the survival benefit, there is a lower overall response rate especially in the first few months, "so maybe if we need important tumor shrinkage for the patient at the beginning...we may chose a platinum regimen."
This is in contrast to the data in nonsmall cell lung cancer (NSCLC), where significant improvements in PFS were seen with pembrolizumab.
Machiels said that the results from the second part of the trial, comparing the combination of pembrolizumab with chemotherapy to chemotherapy alone, follow the same pattern seen in studies of unselected NSCLC patients.
However, he noted that PD-L1 expression is, overall, higher in patients with lung cancer, although the observation does raise some questions that remain to be addressed.
Machiels summarized that, for patients needing rapid tumor shrinkage and in whom PD-L1 assessment cannot be performed, the combination of pembrolizumab plus chemotherapy should be used first-line.
However, he urged clinicians to conduct PD-L1 testing as, for the 40% of patients with expression ≥ 20%, pembrolizumab alone is the new standard of care.
For the 15% of patients with no PD-L1 expression, "I will not be surprised if chemotherapy with cetuximab remains better."
In the 35% to 40% of patients with PD-L1 expression between 1% and 20%, the combination of pembrolizumab plus chemotherapy is "certainly a good treatment," he said, and those with low burden disease may be considered for pembrolizumab monotherapy.
Machiels concluded that questions remain, however, as to what to give patients once they have failed these novel treatment options.
The study was funded by Merck. Burtness has reported being an advisory board member for Merck, AstraZeneca, Bristol-Myers Squibb, Aduro, Amgen, and Genentech. She has received research funding from Merck, Advaxis, and Bristol-Myers Squibb, and honoraria from IDDI; and had travel expenses reimbursed by Boehringer Ingelheim. Machiels has reported being an advisory board member or speaker for Pfizer, Roche, AstraZeneca, Bayer, Innate, Merck Serono, Boehringer, Bristol-Myers Squibb, Novartis, Janssen, and Incyte. He reports having travel expenses reimbursed by Amgen, Bristol-Myers Squibb, Pfizer, MSD; being a member of data safety monitoring boards for Debio and Nanobiotix; and having an uncompensated advisory role for MSD.
European Society for Medical Oncology (ESMO) 2018 Congress. Abstract LBA8.
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Cite this: Chemo-Free Therapy for Head and Neck Cancer a Step Closer - Medscape - Oct 24, 2018.