Recurrent/metastatic head and neck carcinoma: Treatment sequencing in the era of immunotherapy
The introduction of two immunotherapy agents into the treatment armamentarium for recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) poses questions regarding optimal therapy sequencing. At the third Tri-Society Head and Neck Oncology Meeting co-organized by the Hong Kong Head & Neck Society, the Head & Neck Cancer Society, Singapore, and the Taiwan Head and Neck Society, Dr Ana Ferreira Castro of Lenitudes Medical Center & Research, Santa Maria da Feira, Portugal, discussed available treatment options for R/M SCCHN and highlighted the clinical evidence supporting first-line use of chemotherapy and cetuximab.
Changing treatment algorithms
The EXTREME regimen (cetuximab 400 mg/m2 intravenous [IV] initial dose, followed by 250 mg/m2 IV weekly; cisplatin 100 mg/m2 IV, day 1 or carboplatin area under the curve, 5 mg/mL*min IV, day 1; fluorouracil (5-FU) 1,000 mg/m2 IV, days 1–4) was approved in 2008 on the basis of the EXTREME trial and is the current first-line treatment of choice for patients with R/M SCCHN eligible for platinum-based therapy. Compared with chemotherapy alone, the EXTREME regimen extended overall survival (OS) (median, 10.1 months in EXTREME group vs 7.4 months in chemotherapy alone group; hazard ratio [HR], 0.80; 95 percent confidence interval [CI], 0.64 to 0.99; p=0.04), improved overall response rate (ORR) (36 percent vs 20 percent; odds ratio [OR], 2.33; 95 percent CI, 1.50 to 3.60; p<0.001), and prolonged progression-free survival (PFS) (median, 5.6 months vs 3.3; HR, 0.54; 95 percent CI, 0.43 to 0.67; p<0.001). [N Engl J Med 2008;359:1116-1127]
“Since the approval of EXTREME, for a number of years, there have been no improvements in the R/M SCCHN treatment algorithm,” said Castro. “The first bit of post-EXTREME news came from the field of immunotherapy, with the approval of nivolumab.”
The 2016 approval was based on the CheckMate 141 trial in patients with platinum-refractory, R/M SCCHN, where nivolumab improved OS vs standard single-agent therapy with methotrexate, docetaxel or cetuximab (1-year OS estimate: 36 percent vs 16.6 percent; HR for death, 0.70; 97.73 percent CI, 0.51 to 0.96; p=0.01). [N Engl J Med 2016;375:1856-1867]
Subsequently, single-agent pembrolizumab was approved by the US FDA in 2019 for the first-line treatment of patients with metastatic or unresectable, recurrent SCCHN whose tumours express PD-L1 (Combined Positive Score [CPS] ≥1) and as monotherapy for the treatment of patients with R/M SCCHN with disease progression on or after platinum-containing chemotherapy. At the same time, pembrolizumab in combination with platinum and 5-FU was approved for the first-line treatment of R/M SCCHN patients, regardless of PD-L1 expression status.
The approvals were based on the interim results of the KEYNOTE-048 trial, in which pembrolizumab improved OS vs EXTREME in patients with CPS ≥20 (median, 14.9 months vs 10.7 months; HR, 0.61; 95 percent CI, 0.45 to 0.83; p=0.0007) as well as in patients with CPS ≥1 (median, 12.3 months vs 10.3 months; HR, 0.78; 95 percent CI, 0.64 to 0.96; p=0.0086). [Burtness B, et al, ESMO 2018, abstract LBA8_PR] Final analysis revealed that pembrolizumab alone did not significantly improve OS vs EXTREME in the total population (HR, 0.83; 95 percent CI 0.70 to 0.99; p=0.0199; median 11.5 months vs 10.7 months). [Rischin D, et al, ASCO 2019, abstract 6000]
Pembrolizumab plus chemotherapy was noninferior and superior to EXTREME for OS in the total population (median OS, 13.0 months vs 10.7 months; HR, 0.77; 95 percent CI, 0.63 to 0.93; p=0.0034); PFS was not prolonged with pembrolizumab plus chemotherapy. [Burtness B, et al, ESMO 2018, abstract LBA8_PR]
“There is no clear rationale for combining immunotherapy with chemotherapy due to their opposing effects on the immune system,” noted Castro.
The KEYNOTE-048 trial showed that all-cause grade 3-5 adverse events (AEs) occurred in 54.7 percent of patients receiving pembrolizumab monotherapy, in 85.1 percent of patients receiving pembrolizumab plus chemotherapy and in 83.3 percent of patients receiving the EXTREME regimen. [Rischin D, et al, ASCO 2019, abstract 6000]
Careful selection of immunotherapy candidates
“In spite of the excellent results some patients achieve with immunotherapy, we should be very careful when choosing suitable SCCHN candidates for this treatment,” warned Castro. “Unlike melanoma and non-small-cell lung cancer patients, who can afford to experience pseudoprogression typical of immunotherapy, the disease site of SCCHN means that any tumour enlargement can be life-threatening, as this anatomical region is vital to breathing and feeding.”
SCCHN patients suitable for immunotherapy would be asymptomatic with a low tumour burden, while patients in need of rapid amelioration of symptoms should be offered another treatment with a faster tumour response, suggested Castro.
“Patients with open wounds should not be given immunotherapy, because their wound could become even more exposed and their skin will not grow quickly enough to cover it, leading to life-threatening fistulas in the oral cavity or trachea,” she added.
“Although the OS observed in patients with a CPS ≥20 on pembrolizumab was markedly improved compared with EXTREME in KEYNOTE-048, the survival curves show that approximately 30 percent of patients died in the first 6 months of immunotherapy,” noted Dr Castro. [Burtness B, et al, ESMO 2018, abstract LBA8_PR] “Unfortunately, at present, we have no way of reliably identifying and excluding those patients.”
TPEx: A new first-line regimen with clear subsequent-line options
The TPExtreme trial, whose results were presented at the American Society of Clinical Oncology (ASCO) 2019 Annual Meeting, was conceived 5 years ago, when the EXTREME regimen was the standard first-line treatment for R/M SCCHN, and was based on the promising results of the GORTEC TPEx phase II trial. [Ann Oncol 2015;9:1941-1947]
The TPExtreme trial assessed the use of a taxane instead of 5-FU in first-line chemotherapy for R/M SCCHN by comparing the TPEx and EXTREME regimens. The TPEx regimen consisted of cetuximab (400 mg/m2 IV loading dose, followed by 250 mg/m2 IV weekly), cisplatin (75 mg/m2 IV) and docetaxel (75 mg/m2 IV), delivered in four cycles over 3 weeks. The EXTREME regimen, using cisplatin, was delivered in six cycles every 3 weeks. Patients in both arms received cetuximab maintenance until progression or unacceptable toxicity. [Guigay J, et al, ASCO 2019, abstract 6002]
“While the TPExtreme trial showed comparable median OS [14.5 months vs 13.4 months; HR, 0.85; 95 percent CI, 0.71 to 1.05; p=0.15] and ORR [46 percent vs 40 percent at 12 weeks] for the TPEx and EXTREME regimens, TPEx was much better tolerated, with 34 percent of patients on TPEx vs 50 percent of patients on EXTREME experiencing grade ≥4 AEs [p<0.001]. Patients on TPEx had significantly better compliance [72 percent vs 44 percent in the EXTREME arm completed all planned treatment cycles] and a significantly higher rate of starting maintenance treatment [73 percent vs 53 percent],” commented Castro. (Table) [Guigay J, et al, ASCO 2019, abstract 6002]
“TPEx appears to be the optimal first-line treatment for R/M SCCHN. Firstly, it is less toxic than EXTREME. Secondly, compared with immunotherapy, there is a lower risk of losing patients in the first few months of treatment. Thirdly, immunotherapy can still be given following chemotherapy, while cetuximab in combination with chemotherapy is not approved for second-line use. At the same time, using nivolumab in the first line and pembrolizumab in the second line would not be appropriate due to their similar mechanism of action. Therefore, first-line use of immunotherapy would leave patients without a clear second-line option,” concluded Castro.