Given that up to three-quarters of our patients with squamous cell carcinoma of the head and neck present with locally advanced disease that can potentially be cured, this may be the place in which immunotherapy makes its greatest mark yet.— Lori J. Wirth, MD
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Most patients with squamous cell carcinoma of the head and neck present with locally advanced disease. With combined-modality approaches, the chance of cure ranges from < 50% to up to 80%, depending on the site, stage, and other risk factors, such as human papillomavirus (HPV) status. When patients do experience recurrent/metastatic disease, overall survival is short, and with the sequelae of the cancer and its treatment, the living is not easy. Curative salvage surgery and/or reirradiation are possible for only a handful of patients, and thus most patients are treated with palliative systemic therapy.
First-Line Treatment for Recurrent/Metastatic Disease
The phase III EXTREME trial was the first study to demonstrate an overall survival benefit in this patient population.1 In this study, cetuximab (Erbitux) added to platinum and fluorouracil (5-FU) was compared with platinum and 5-FU alone, leading to an overall survival improvement from 7.4 to 10.1 months (P = .04). However, this is an intensive three-drug regimen, resulting in grade 3/4 toxicities in 82% of patients and toxicity-mandated discontinuation of therapy in 20%. Thus, the EXTREME regimen, while perhaps aptly named, is not an appropriate regimen for all comers with recurrent/metastatic disease.
Beyond First-Line Setting
A number of cytotoxic chemotherapies have been employed in the second-line treatment of recurrent/metastatic squamous cell carcinoma of the head and neck, with modest activity at best. The frequent overexpression of epidermal growth factor receptor (EGFR) in squamous cell carcinoma of the head and neck and the success of cetuximab led to further study of anti-EGFR agents, including panitumumab (Vectibix), zalutumumab, erlotinib (Tarceva), and afatinib (Gilotrif).
Of these agents, the strongest signal was seen in the LUX-Head and Neck 1 phase III trial of afatinib vs methotrexate in platinum-refractory recurrent/metastatic squamous cell carcinoma of the head and neck.2 Although there was a statistically significant improvement in progression-free survival (2.6 vs 1.7 months, P = .03) and modest benefits were seen in patient-reported outcomes with afatinib, the progression-free survival benefit was small, and there was no improvement in overall survival.
Identifying and exploiting molecular drivers in squamous cell carcinoma of the head and neck are certainly an appealing approach for novel therapeutics in patients with recurrent/metastatic disease. Although comprehensive genetic, epigenetic, and transcriptional characterization of squamous cell carcinoma of the head and neck by several groups has yielded extensive insights its tumorigenesis, these data have yet to be translated into therapeutic advances.3-5 Alterations in the PI3K pathway are among the more readily druggable alterations found in squamous cell carcinomas of the head and neck, particularly in HPV-positive cases.6 Early trials targeting this pathway have been launched, although phase II trials incorporating temsirolimus (Torisel) and everolimus (Afinitor) have been disappointing.7,8
Another major hurdle to precision targeted therapy is the high frequency of inactivating mutations in tumor-suppressor genes, such as TP53, driving the majority of squamous cell carcinomas of the head and neck, particularly HPV-negative disease. Until therapeutic breakthroughs are made in restoring functional tumor-suppressor activity, the promise of precision targeting may remain unattainable for many patients with squamous cell carcinoma of the head and neck.
Basis of Immunotherapy in This Tumor Type
Until recently, the notion that immunotherapy could play a major role in squamous cell carcinoma of the head and neck treatment seemed a bit far-fetched; this is no longer the case. Abundant preclinical data have accumulated in support of the potential for immunotherapy in squamous cell carcinoma of the head and neck.9 For example, low lymphocyte counts are seen in patients with squamous cell carcinoma of the head and neck, whereas high levels of regulatory T cells are found. In fact, the presence of tumor-infiltrating lymphocytes correlates with better progression-free and overall survival in patients treated with chemoradiotherapy. Other inhibitory immune cells, including tumor-associated macrophages and myeloid-derived suppressor cells, further enrich the suppressive tumor microenvironment.
In addition, the expression of checkpoint programmed cell death ligands 1 and 2 (PD-L1, PD-L2) is frequent in squamous cell carcinoma of the head and neck tumor and immune cells, particularly in HPV-positive disease. Proinflammatory cytokines, such as transforming growth factor-beta (TGF-β) and interleukin-6 (IL-6), are another hallmark of squamous cell carcinomas of the head and neck. Although the high mutational burden of squamous cell carcinoma of the head and neck and expression of viral oncoproteins in HPV-positive squamous cell carcinomas of the head and neck should provide an ample source of neoantigens, immune evasion is promoted by the downregulation of components of the antigen-processing machinery and human leukocyte antigen (HLA) class I expression. Thus, the immunosuppressive microenvironment of squamous cell carcinoma of the head and neck, coupled with tumor immune-evasion strategies can allow disease progression unchecked by the immune system.
Immunotherapy Clinical Trials
This evidence, in part, prompted the first studies of checkpoint inhibitors in squamous cell carcinoma of the head and neck. It was clear from early experience in phase I recurrent/metastatic disease expansion cohorts with the anti–programmed cell death protein 1 (PD-1) antibody pembrolizumab (Keytruda) and the anti–PD-L1 antibody durvalumab that checkpoint inhibitors have promise.10,11 The phase I pembrolizumab experience led to KEYNOTE-055, a single-arm phase II study of pembrolizumab in 172 patients with recurrent/metastatic disease resistant to platinum and cetuximab.12 Treatment-related adverse events were manageable (only 12% of patients experienced grade 3 or higher events), and in this heavily pretreated population, the overall response rate was 16%. Of them, 82% of responders remained in response ≥ 6 months, and median overall survival was 8 months.
These results in a patient population with limited treatment options led to the U.S. Food and Drug Administration (FDA) accelerated approval of pembrolizumab in August 2016. KEYNOTE-040 and 048, both multicenter, randomized trials investigating pembrolizumab vs traditional therapy in patients with recurrent/metastatic disease, with a primary endpoint of overall survival, are ongoing.
Now, as reported by Ferris et al and summarized in this issue of The ASCO Post, the first randomized trial investigating checkpoint inhibition vs traditional therapy in recurrent/metastatic squamous cell carcinoma of the head and neck, CheckMate 141, is complete.13 This study randomized 361 patients with recurrent/metastatic disease whose disease had progressed within 6 months of platinum therapy with nivolumab (Opdivo) vs dealer’s choice single-agent standard therapy (methotrexate, docetaxel, or cetuximab). Patients were mostly men, with a median age of 60 years, and 76.5% were current or former smokers. Primary tumor sites included the oral cavity, oropharynx, larynx, and others, in that order, and a quarter of patients had p16-positive disease, used as a surrogate for HPV; 54.6% of patients had had at least 2 prior systemic therapies.
As in KEYNOTE-055, treatment-related adverse events with immunotherapy in CheckMate 141 were generally mild, with 13.1% of patients experiencing a grade 3 or higher event, compared with 35.1% of patients in the standard-therapy group. In addition, patient-reported outcomes were examined. Patients receiving standard therapy reported worsening physical and social functioning over time, as well as worsening pain, sensory, and social-contact problems. In the nivolumab group, however, these measures remained stable or showed slight improvements over time.
The overall response rate with nivolumab was 13.3%, and 2.5% of patients experienced a complete response. In patients on the standard-therapy arm, the overall response rate was 5.8%, with a single complete response. The median time to response was 2 months in both arms, but responses with nivolumab were more durable than those seen with standard therapy. Despite the difference in overall response rates, there was no difference between the two groups in terms of progression-free survival, with median progression-free survival in both groups of approximately 2.0 months. There was, however, a late separation of the progression-free survival curves, such that respective rates of progression-free survival at 6 months were 19.7% (95% confidence interval [CI] = 14.6%–25.4%) vs 9.9% (95% CI = 5.0%–16.9%), reflecting the durability of response seen with nivolumab.
Finally, overall survival was indeed improved with nivolumab; median overall survival was 7.5 months (95% CI = 5.5–9.1 months) vs 5.1 months (95% CI = 4.0–6.0 months). This overall survival benefit held up across all prespecified subgroups examined.
In addition, exploratory analyses investigated the relationship between PD-L1 and p16 status and overall survival. In all, 57.3% of tumors had ≥ 1% PD-L1 expression. In these patients, the hazard ratio for death with nivolumab vs standard therapy was 0.55 (95% CI = 0.36–0.83), as compared with that in patients with < 1% PD-L1 expression of 0.89 (95% CI = 0.54–1.45). Of the patients with p16-positive tumors, a similar hazard ratio for death with nivolumab vs standard therapy was seen, 0.56 (95% CI = 0.32–0.99), whereas the hazard ratio in patients with p16-negative disease was 0.73 (95% CI = 0.42–1.25). When PD-L1 expression was taken into account along with p16 status, hazard ratio trends most favored the combined ≥ 1% PD-L1/p16-positive group.
The authors indicated these exploratory data suggest that although nivolumab’s magnitude of effect may be greater in patients with tumors with ≥ 1% PD-L1 expression or p16 positivity, the interactions were not significant and not corrected for multiple comparisons. This finding, coupled with the fact that responses were seen in patients with both PD-L1 < 1% and p16-negative tumors, suggests that we should not at this point exclude these patients from treatment with nivolumab.
CheckMate 141 showed that nivolumab won out over standard therapy in platinum-resistant recurrent/metastatic squamous cell carcinoma of the head and neck, based not only on efficacy and overall survival, but also on tolerability and quality of life. It’s a win-win for all, and a second FDA approval for checkpoint inhibitor therapy in platinum-resistant disease has been granted. Numerous studies are now underway investigating combination approaches that will hopefully extend these initial immunotherapy successes to a larger percentage of patients. Many are working to decipher the determinants of response to checkpoint inhibitors, which should lead to new approaches to enhance efficacy. Phase III trials investigating immunotherapy in the first-line setting for recurrent/metastatic disease are also currently enrolling, and new efforts introducing immunotherapy into upfront combined-modality treatment approaches have been launched. Given that up to three-quarters of our patients with squamous cell carcinoma of the head and neck present with locally advanced disease that can potentially be cured, this may be the place in which immunotherapy makes its greatest mark yet. ■
Disclosure: Dr. Wirth has served as a consultant to Amgen, Blueprint Medicines, Eisai, Loxo Oncology, and Merck.
2. Machiels JP, Haddad RI, Fayette J, et al: Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): An open-label, randomised phase 3 trial. Lancet Oncol 16:583-594, 2015.
7. Bauman JE, Arias-Pulido H, Lee SJ, et al: A phase II study of temsirolimus and erlotinib in patients with recurrent and/or metastatic, platinum-refractory head and neck squamous cell carcinoma. Oral Oncol 49:461-467, 2013.
8. Geiger JL, Bauman JE, Gibson MK, et al: Phase II trial of everolimus in patients with previously treated recurrent or metastatic head and neck squamous cell carcinoma. Head Neck 38:1759-1764, 2016.
10. Seiwert TY, Burtness B, Mehra R, et al: Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): An open-label, multicentre, phase 1b trial. Lancet Oncol 17:956-965, 2016.
11. Fury M, Ou SI, Balmanoukian AS, et al: Clinical activity and safety of MEDI4736, an anti-PD-L1 antibody, in patients with head and neck cancer. 2014 ESMO Congress. Abstract 988PD. Presented September 28, 2014.
12. Bauml J, Seiwert TY, Pfister DG, et al: Preliminary results from KEYNOTE-055: Pembrolizumab after platinum and cetuximab failure in head and neck squamous cell carcinoma. 2016 ASCO Annual Meeting. Abstract 6011. Presented June 9, 2016.
Among patients with platinum-refractory, recurrent squamous-cell carcinoma of the head and neck, treatment with nivolumab resulted in longer overall survival than treatment with standard, single-agent therapy.!-->!-->— Robert L. Ferris, MD, PhD, and colleagues