Updates in Head and Neck Oncology – Current Knowledge and Future Horizons

Abstract

Treatment for head and neck recurrent/metastatic squamous cell carcinoma (HNSCC) with immune checkpoint inhibitors has now become the new therapeutic standard, primarily replacing the EXTREME and TPex protocols that included the EGFR inhibitor Cetuximab and chemotherapy. Even if there are considerable advances in therapeutic results, less than 20% of patients with this stage of the disease survive more than four years. These results demonstrate the need to identify more effective therapies beyond simple PD1/PD-L1 blockade. Antibody-drug conjugates (ADC), vaccines, bispecific kinase inhibitors and fusion proteins involving the modulation of the tumor microenvironment are strategies to be exploited in the future. Also, in locally advanced cancers, the results of combining immunotherapy with chemoradiation treatment did not give the expected results. The use of other therapeutic sequences, including immunotherapy in association with neo-adjuvant chemotherapy, but also the association with mTOR inhibitors are also evaluated in clinical trials. We propose to present some new directions in the therapies of locally advanced relapsed or metastatic HNSCC.

Keywords:: locally advanced HNSCC, recurrent/metastatic HNSCC, immunotherapy, PD1, PD-L1, CTLA-4, Nivolumab, Pembrolizumab, ADC, chemotherapy, mTOR.

INTRODUCTION

Currently, immunotherapy with programmed death-1 (PD1) inhibitors Pembrolizumab and Nivolumab is approved in the first line for recurrent or metastatic squamous cell carcinoma (SCC) of the head and neck (HNSCC) that has progressed after chemotherapy based on platinum salts. In locally advanced HNSCC, the results of immunotherapy have not demonstrated a significant benefit yet. We aimed to present some research directions and perspectives evaluated in clinical trials regarding systemic therapies in HNSCC (1).

Standard course in recurrent and metastatic HHSCC

Pembrolizumab has been approved by the Food and Drug Administration (FDA) for use in combination with platinum and fluorouracil in all cases of recurrent or metastatic HNSCC that has progressed after platinum-based therapy. When the combined positive score (CPS) ≥1, Pembrolizumab could be administered as a single therapy, in both cases the approval being supported by the results of the randomized trial KEYNOTE- 048 (NCT02358031). The median follow- up of patients in the study was 45.0 months, overall survival (OS) being improved for subjects with PD-L1 CPS ≥20 and PD-L1 CPS ≥1 with non-inferior results in the general population. If chemotherapy was added to Pembrolizumab, OS was superior in all study lots. In the later treatment lines, OS was higher when taxanes were added compared to other chemotherapeutic agents. Nivolumab has been approved by the FDA for the treatment of recurrent or metastatic HNSCC that has progressed after platinum-based therapy. A median OS of 7.5 months in the Nivolumab-treated group versus 5.1 months in the standard-of-care at that time group was recorded, with the OS rate being approximately 19% higher in the group with Nivolumab immunotherapy. A benefit was also obtained for immunotherapy in progression-free survival (PFS) (2.3 months versus two months). Previously, the therapeutic standard was established by the EXTREME protocol that combines Cetuximab (an epidermal growth factor receptor inhibitor) with chemotherapy (Cisplatin and 5-fluorouracil) and also by the TPex protocol, a modified regimen that includes taxanes (Docetaxel or Paclitaxel) in combination with Cetuximab and platinumbased chemotherapy (6-10).

Updates in recurrent and metastatic HNSCC

Therapeutic vaccines for head and neck cancer have been intensively studied in HNSCC since 2011, both as monotherapy and in combination with other agents. The human papillomavirus (HPV) is currently increasingly identified as the etiological agent of HNSCC, especially in oropharyngeal cancers diagnosed in young neversmoker patients. In these cases, HPV is the main target of vaccines aimed at viral proteins E6 and E7. ISA101, BNT113 and PDS0101 are currently evaluated independently or in combination with immunotherapy in phase II and III trials, the VERSATILE 002 study (ClinicTrials.gov: NCT04260126) being an example where the vaccine PDS0101 and Pembrolizumab are evaluated in the first line of recurrent HNSCC or metastatic for HPV-16 positive patients with a CPS .1. A response rate of 26.5%, a PFS and OS at one year of 10.4 months and 87.1%, respectively, justified the approval by the FDA even without the evidence from a phase III trial. PSD0101 is currently evaluated in neo-adjuvant settings, alone or combined with Pembrolizumab, before surgery. CUE-101 is a human leukocyte antigen that targets CD8+ lymphocytes in HPV+ HNSCC. INO-3112 is a DNA vaccine that contains three plasmids expressing HPV16/18 E6 and E7 together with a molecular booster (IL-12) of the immune response. HB-200 includes arenavirus vectors that express the E6/E7 fusion protein activating the CD8+ lymphocyte response in HPV+ HNSCC. Targets (hTERT, p53, MUC1, MAGE) for head and neck cancer vaccines that are not HPV-directed therapeutic vaccines are also being evaluated. Human telomerase reverse transcriptase (hTERT) is an enzyme with a significant role in cancer progression and its overexpression is associated with an unfavorable prognosis. The UV1 vaccine is composed of three synthetic peptides and is based on the identification of hTERT epitopes in the blood of cancer survivors. The FOCUS trial evaluates this vaccine in combination with Pembrolizumab in first-line therapy for cases with PD-L1.positive HNSCC. The results of the trial are expected at the end of 2024, while currently this vaccine in combination with PD-1/PD-L1 dual blockade and CTLA-4 provides benefit in pleural mesothelioma. The use of one's own tumor to develop neoantigens is used to generate vaccines that counteract the immunosuppressive tumor microenvironment (TME), the concept already being evaluated in phase II studies. The MVX-ONCO-1 vaccine is based on irradiated autologous tumor cells combined with a colony of macrophages and granulocytes, which have shown favorable results even in patients with HNSCC refractory to Nivolumab. Bispecific antibodies and multikinase inhibitors have the ability to dual target the tumor, but also to modulate the TME (11-23).

Even though cytotoxic chemotherapy has been the basis of systemic therapy in HNSCC for the last 30 years, the selectivity of chemotherapy against tumor cells is relatively low, the escalation of doses being associated with severe toxicity. Antibody drug conjugates (ADC) consist of a humanized monoclonal antibody (mAb), a linker and the cytotoxic agent. The cleavable or non-cleavable linker releases the cytotoxic charge into the extracellular environment or directly into the cell. The cytotoxic agent is usually a topoisomerase inhibitor, a DNA binder, or a microtubule inhibitor. MMAE (Vedotin) is the most frequently evaluated useful load in HNSCC, but until now ADCs are not approved by the FDA in the standard therapy of head and neck cancer. Bivatuzumab mertansine, Tisotumab vedotin, SGN-B6A, Enfortumab vedotin and Sacituzumab govitecan are currently being evaluated in clinical trials, with DM1, MMAE and SN-38 (the active metabolite of Irinotecan) being evaluated active agents (24-28).

Future perspectives in locally advanced HNSCC systemic therapy

The concept of using immunotherapy in combination with chemotherapy in the neo-adjuvant setting of locally advanced HNSCC was explored in a single-arm phase 2 monocentric trial that included cases of resectable HNSCC in stage III-IVB (29). Nab-Paclitaxel or Docetaxel and Cisplatin chemotherapy was combined with Carmelizumab immunotherapy. The latter was administered on day 1 of each 21-day cycle up to three cycles, followed by surgery and adjuvant radiotherapy. The endpoints of the 30-case study were pathologic complete response (pCR) rate and safety. An objective response was obtained in 29 of the 30 cases, and 27 subjects were operated on at the proposed time with 25 R0 resections. Down-staging was observed in all cases and pCR was obtained in 37% of cases. At 12 months after treatment, disease-free survival (DFS) was seen in 95.8% of cases. No grade 4 and 5 adverse events were recorded in the study, with skin rash and pruritus and thrombocytopenia being the most frequently reported. Delayed wound healing was reported in five cases. The results of Zhang’s study argue for the evaluation of chemotherapy combined with immunotherapy in phase III studies in the neo-adjuvant setting of locally advanced HNSCC (29).

It is considered that in 70% of HNSCC cases, the PI3K-AKT-mTOR pathway is dysregulated and the TME is also involved. These data justified the initiation of a study (CAPRA trial) aiming to evaluate the association of a treatment based on the double combination of chemotherapy (Carboplatin-Paclitaxel) with the mTOR inhibitor Everolimus. In the group of patients comprising 41 cases (out of the total number of 50 enrolled patients) who received a weekly dose of 50 mg Everolimus, the response rate was 75.6%. In all cases, nine sequences of chemotherapy and mTOR inhibitor were administered, after which patients were given chemo-radiotherapy. The study also had a translational component in which phosphorylation of downstream S6 kinase 1 (p-S6K), Ki67 and caspase 3 were evaluated from tumor tissue before and after exposure to therapy. A decrease in p-S6K, Ki67 and the release of pro-immunogenic cytokines (TNF-β Th1 IFN-γ and IL-2) was observed in the tumor tissue and peripheral blood, respectively. The authors noted the benefit of therapy and the modulation effect on the TME that could justify the decision to combine this protocol (the CAPRA regimen) with immunotherapy (30).

Future perspectives in recurrent/metastatic HNSCC systemic therapy

KESTREL phase III study evaluated the efficacy of the PD-1 inhibitor Durvalumab as mono-therapy or in combination with Tremelimumab, a cytotoxic T-lymphocyte associated protein 4 (CTLA-4) inhibitor, compared with the EXTREME protocol in patients with recurrent or metastatic HNSCC. Randomization included Durvalumab 1500 mg every four weeks (Q4W), Durvalumab 1500 mg Q4W plus Tremelimumab 75 mg Q4W, or the EXTREME protocol. Tremelimumab was administered up to a maximum of four doses. In the case of patients with high PD-L1 expression, the combination of double immunotherapy was not superior to the EXTREME regimen, but Durvalumab and Durvalumab plus Tremelimumab were associated with a longer duration of response at 12 months (49.3% and 48.1% compared to 9.8%). In cases where a favorable response was obtained, a benefit in OS was also observed. The authors also mention the possibility of using the combination of double immunotherapy in patients treated with the EXTREME regimen, without differences in OS between the study groups. The toxicity profile was in favor of immunotherapy, with grade 3/4 adverse events for Durvalumab, Durvalumab plus Tremelimumab and EXTREME being 8.9%, 19.1% and 53.1%, respectively. In conclusion, the authors noted the reduced rate of severe adverse events and similar results to EXTREME regimen in cases with high PD-L1 expression (31).

The CheckMate 651 trial (ClinicalTrials.gov identifier: NCT02741570) evaluated the double combination of Nivolumab and Ipilimumab in the first-line treatment of recurrent or metastatic HNSCC in relation to the EXTREME protocol. Its primary objective was OS in cases with PD-L1 CPS ≥20 and the secondary objectives included OS, PFS and objective response rate (ORR) in patients with CPS ≥1, but also duration of response in those with CPS ≥20. The study enrolled 947 patients, of whom 38.3% had CPS ≥20. In the randomly assigned group, there were no significant differences in OS between the combination of immunotherapy and EXTREME regimen (13.9 vs 13.5 months). In patients with CPS ≥20, the median OS was 17.6 vs 14.6 in favor of immunotherapy, while in those with CPS ≥1 the benefit was only 2.5 months in favor of Nivolumab plus Ipilimumab. Even though ORR and PFS were in favor of the group treated with the EXTREME regimen, the response duration was 32.7 vs seven months in favor of anti-PD-1 plus anti-CTLA-4 therapy. The rate of grade 3/4 treatment-related adverse events was only 28.2% in the group who received immunotherapy compared to 70,7% in that treated with the EXTREME protocol, but the Checkmate 651 trial did not reach its OS objective in the case randomly distributed population (32).

CONCLUSIONS

Chemoradiotherapy and immunotherapy with Nivolumab and Pembrolizumab remain the therapeutic standard in locally advanced and recurrent or metastatic HNSCC, respectively. Vaccines, bispecific kinases, ADCs but also mTOR inhibitors and the dual combination of anti-PD-1/PD-L1 and anti-CTLA-4 immunotherapy are all currently evaluated strategies in clinical trials, with TME modulation for limiting the immunosuppressive component being one of the most promising involved phenomenon. Also, neoadjuvant immuno-chemotherapy followed by surgery and radiotherapy seems to open new therapeutic horizons in HNSCC.

Conflicts of interest: none declared.

Financial support: none declared.