Sage Journals: Discover world-class research

Abstract

Immunotherapy with PD-1 inhibitors monotherapy or combined with chemotherapy comprises the first-line palliative treatment for patients with recurrent or metastatic head and neck squamous cell cancers (R/M HNSCC). The established survival advantage among responders is overshadowed by the high percentage of patients failing the standard PD-1 inhibitor-based treatments. Salvage therapies are direly needed. However, no current standards are available. We present the case of a 65-year-old patient with heavily pretreated laryngeal squamous cell carcinoma who had an exceptional response to cetuximab monotherapy following the failure of immunotherapy with the PD-1 inhibitor nivolumab. We reviewed the literature for other cases of exceptional response to cetuximab, clinical studies investigating the combined or sequential administration of cetuximab and PD-1 inhibitors, and the mechanistic rationale for consideration of cetuximab as a potential salvage treatment after immunotherapy with PD-1 inhibitors. In addition to the specific epidermal growth factor receptor inhibitory effect, cetuximab, as an immunoglobulin G1 isotype, binds NK cells and elicits antibody-dependent cellular toxicity, triggering a domino of immunostimulatory, and immunoinhibitory effects that actually might decrease the cetuximab anticancer efficacy. However, in a tumor microenvironment exposed to previous treatment with a PD-1 inhibitor, the effects of the PD-1 inhibitor followed by cetuximab on innate and adaptative immune response appear to synergize. Specifically, persistent immune checkpoint inhibitors’ consequences may negate downstream immunosuppressive effects of cetuximab caused through PD-1/PD-L1 upregulation, making it a more potent treatment option. Besides the potential synergistic effect on antitumor immune response with previous immune checkpoint inhibitors therapy, cetuximab is the only targeted agent approved for treating R/M HNSCC, making it a most advantageous candidate for further treatment validation studies as salvage treatment post-immunotherapy.

Keywords

anti-PD-1 case report cetuximab checkpoint inhibitors exceptional response head and neck cancer

Introduction

Despite advances in the treatment of head and neck squamous cell carcinoma (HNSCC), more than 50% of patients with locoregionally advanced HNSCC experience local recurrence or distant metastases within 3 years of diagnosis.^1,2 Recurrent and/or metastatic HNSCC (R/M HNSCC) has a median survival of less than 1 year.^3,4 Until recently, the first-line treatment of R/M HNSCC was a combination of cetuximab, cisplatin, and 5-fluorouracil, known as the EXTREME regimen. However, the results of KEYNOTE-048 led to a change in practice, and immune checkpoint inhibitors (ICI) alone or combined with platinum and 5-fluorouracil were established as the first-line treatment of R/M HNSCC.^5–8 Prior data from CHECKPOINT 141, which showed the benefit of nivolumab in R/M HNSCC, further supported the more frequent use of ICIs.⁶ A recent publication outlining 4-year follow-up data from KEYNOTE-048 continues to show that ICIs have a survival benefit as first-line agents.⁹ The introduction of ICIs has improved survival for treatment responders. Disappointingly, the response rate to single-agent ICI remains only 13−19%, and the response rate to combination treatment is only 36%, with most patients demonstrating primary resistance and requiring salvage therapy.^7,8,10–15 Patients failing immunotherapy have a dismal prognosis. No standard treatment options exist, and there are no guidelines for the most appropriate salvage therapy. Some studies have evaluated the reintroduction of chemotherapy after ICI use, even if the chemotherapeutic agents had been used earlier in the patient’s treatment. This strategy was shown to be effective in several other metastatic cancers, including non-small-cell lung cancer, melanoma, B-cell lymphoma, gastric cancer, and urothelial carcinoma.^16–20 Scattered reports of R/M HNSCC being treated with regimens consisting of platins, taxanes, and cetuximab following initial treatment with ICI document promising results, including a few describing efficacy beyond what would be expected based on historical data for single-agent or combination treatments.^21–26

Ideally, a salvage therapeutic agent would work synergistically with previously used agents (e.g. ICIs in the case of R/M HNSCC). Cetuximab is a crucial part of existing HNSCC and R/M HNSCC treatment algorithms and may also be an effective salvage treatment agent.²⁷ The mechanistic rationale for investigating salvage cetuximab following previous ICI relates to the sequential and combined effect of the two agents on adaptive and innate immune responses against the tumor and the tumor microenvironment (TME).^28,29 Clinical data regarding the feasibility and efficacy of a cetuximab salvage therapy after treatment with ICI are currently lacking. We present the case of a patient with metastatic HNSCC who sustained an unexpectedly durable response to cetuximab monotherapy after failing treatment with the PD-1 inhibitor nivolumab. We review the scientific mechanisms supporting the use of cetuximab and ICIs in tandem or sequentially and the limited relevant clinical studies. Our case suggests that single-agent cetuximab warrants further evaluation as a potential salvage therapy after treatment with ICIs.

Case presentation

A 65-year-old White male with a history of heavy smoking was initially diagnosed with squamous cell cancer (SCC) of the epiglottis in 2003 and treated with radiotherapy. He developed a second primary SCC of the left false vocal cord in 2014, which was treated with laser therapy. One year later, he developed three synchronous SCCs in the left supraglottic area, epiglottis, and posterior hypopharyngeal wall. These cancers were treated with total laryngopharyngectomy, cervical esophagectomy with flap reconstruction, and bilateral neck dissection. Histopathologic evaluation of the surgical specimen showed negative margins around all three cancers, no lymphovascular or peri-neural invasion, and negative lymph nodes (LNs). A small new primary SCC at the tongue base was resected endoscopically in 2016. The patient developed another SCC in the left anterior floor of the mouth in 2018 and underwent surgical resection with marginal mandibulectomy and flap reconstruction. A preoperative CT scan showed multiple concerning lesions in the neopharynx, which were biopsied during surgery. The biopsies were positive for SCC, and the local recurrence was treated with radiation in addition to systemic weekly carboplatin and paclitaxel.

Four months later, in October 2018, PET/CT showed enlarged and hypermetabolic left axillary LNs, one of which measured 1.4 cm with SUVmax of 5.4 [Figure 1(a)]. Fine-needle aspiration of the left axillary LN confirmed SCC. PD-L1 by Tumor Proportion Score (TPS) (Dako 22C3 pharmaDx™) was negative. tDNA analysis by the FoundationOne platform (Figure 2) measured a tumor mutational burden of 4. CCND1 amplification was identified as the only targetable mutation for an off-label indication of CDK4/CDK6 inhibitors. Following a discussion of available treatment options, first-line palliative therapy with nivolumab 480 mg every 4 weeks was selected, and treatment started in November 2018.

Figure 1.

Axial CT (a, b and d–f) and axial PET/CT (c) images obtained before initiation of nivolumab (a), after six administrations of nivolumab and just before the initiation of treatment with cetuximab (b and c) and through treatment with cetuximab (d–f). Imaging acquired in October 2018 (a) before initiation of nivolumab demonstrates a metastatic left axillary node (arrow, a) measuring 1.4 cm. Imaging performed in April 2019 (b and c) shows interval development of multiple bilateral enlarged hypermetabolic axillary lymph nodes (circles, b and c) consistent with progressive metastatic disease. The left axillary lymph node measuring 1.4 cm in October 2018 measured 3.1 cm at this time. Following the initiation of cetuximab therapy in April 2019, follow-up imaging in June demonstrated a substantial decrease in the size of the metastatic bilateral axillary lymph nodes (circles, d), with the index left axillary lymph node measuring 1.6 cm. This treatment response was sustained through March 2020, when follow-up imaging demonstrated a continued decrease in axillary lymph node size (circles, e), including the index left axillary lymph node, which measured 1.0 cm at that time. However, follow-up imaging in July 2020 demonstrated enlarging left subpectoral (arrow, f) and left axillary (arrowhead, f) lymph nodes consistent with progression.

Figure 2.

tDNA alterations and PD-L1 tested in the metastatic left axillary lymph node specimen.

Follow-up PET/CT after four treatments with nivolumab demonstrated interval enlargement of multiple left axillary LNs (SUVmax 11.0) and interval development of hypermetabolic right axillary LNs (SUVmax 2.9). The patient was asymptomatic from these tumors and elected to continue immunotherapy with close follow-up. A repeat PET/CT performed in April 2019 after two more immunotherapy treatments showed a continued increase in the size of the hypermetabolic bilateral axillary lymph nodes [Figure 1(b) and (c)] and a new 1.8 cm hypermetabolic soft tissue nodule in the superficial anterior neck [Figure 3(c) and (d)]. The left axillary LNs were now painful, and the patient was troubled by the anterior neck metastasis, which was visible on physical examination as an exophytic growth.

Figure 3.

Axial PET/CT (a, c, and e) and axial CT (b, d, and f) images obtained before initiation of treatment with nivolumab (a and b) after six administrations of nivolumab (c and d), and after treatment with cetuximab (e and f). Imaging acquired in October 2018 (a and b) before initiating nivolumab demonstrates no evidence of head and neck disease. Imaging performed in April 2019 (c and d) shows interval development of a hypermetabolic, exophytic, cutaneous nodule in the anterior neck (arrows, c and d) consistent with metastasis. Following therapy with cetuximab initiated in April 2019, this metastasis completely resolved, and this response was sustained through October 2020 (e and f).

After further discussions regarding the treatment options, the plan was for chemotherapy with weekly carboplatin and taxol combined with cetuximab. The patient received the loading dose of cetuximab in April 2019 (i.e. 25 days from the last administration of nivolumab) as a lead-in with the intent to add carboplatin and taxol the following week. However, before treatment with carboplatin and taxol, the patient reported that the pain in the left axilla had resolved. Furthermore, physical examination revealed a substantial decrease in the bilateral axillary LNs and the exophytic anterior neck mass sizes. Given this rapid improvement, it was decided to proceed with maintenance cetuximab monotherapy and to add chemotherapy upon progression. The exophytic anterior neck lesion was no longer visible on physical examination after several weeks of cetuximab monotherapy and was confirmed to have resolved on follow-up imaging performed 10 weeks after the beginning of treatment. The patient’s axillary LNs also continued to decrease in size. Follow-up CT imaging [Figure 1(d) and (e)] showed axillary nodal disease stabilization for a total response duration of 455 days.

While receiving cetuximab, the patient developed a severe pustular skin rash on the face, chest, and scalp that partially responded to treatment with minocycline, topical cortisone, and moisturizers. He experienced no other toxicities attributable to the treatment with cetuximab. A follow-up CT [Figure 1(f)] in July 2020 showed enlarging left axillary and left subpectoral LNs; however, there was no progression of disease in the head, neck, or lungs, and the patient remained asymptomatic from his cancer. After discussing treatment options, the patient elected to continue cetuximab therapy and to receive palliative radiotherapy for the enlarging left axillary and left subpectoral LNs. The patient received 30 Gy of palliative radiotherapy in 10 fractions, and a follow-up CT showed decreased size of the left axillary and left subpectoral LNs with no new or enlarging lesions elsewhere. One month later, the patient presented with a new large, indurated, and erythematous plaque on his central chest and upper abdomen containing multiple coalescing skin nodules (Figure 4). This skin abnormality was biopsied and showed to represent SCC. Shortly after that, the patient suffered a stroke and elected to transition to hospice.

Figure 4.

Indurated and erythematous plaque on the central chest and upper abdomen containing multiple coalescing skin nodules. Biopsy confirmed SCC.

Discussion

This case illustrates an exceptional response to cetuximab after progression on ICI. A patient with heavily pretreated recurrent larynx cancer who developed metastases to axillary lymph nodes and skin achieved a nearly complete remission lasting 15 months (i.e. 455 days) on single-agent cetuximab that was started after he progressed on immunotherapy with nivolumab. The National Cancer Institute (NCI) launched an ‘Exceptional Responders Initiative’ in 2014 to advance the personalized treatment approach and the more efficacious use of drugs by accelerating the identification of predictors of response. This initiative requested the submission of cases of exceptional responses to drug therapy defined as (a) a complete response to a drug(s) where a complete response is seen in less than 10% of patients receiving similar treatment; (b) a partial response lasting at least 6 months where such a response is seen in less than 10% of patients receiving similar treatment; and (c) a complete or partial response that lasts longer than three times the median response duration in the literature for the treatment.³⁰ This case meets criteria C of the NCI definition of an exceptional responder, as the patient experienced progression-free survival (PFS) of 455 days, much longer than three times the median response duration of 70 days reported by Fury et al. and by Vermorken et al. in their clinical studies of cetuximab monotherapy among patients with R/M HNSCC.^30,31

We identified only three other cases of exceptional response to cetuximab monotherapy reported in the literature. A 50-year-old female with treated HIV was diagnosed with loco-regionally advanced HPV16-positive tonsillar SCC. She underwent surgical resection of her initial cancer and of her first recurrence. A second recurrence was considered surgically unresectable, and due to multiple comorbidities, she was treated with cetuximab monotherapy. She surprisingly achieved a complete remission maintained for at least 5 years.³² In this scenario, her antiretroviral therapy may have maximized the cetuximab’s effect as the first-line therapy on a tumor that was both HPV and HIV positive, as both viruses have been shown to amplify the epidermal growth factor receptor (EGFR) pathway by triggering EGFR hyperactivation and by preventing EGFR receptor downregulation.³² Another report described the case of a 56-year-old male diagnosed with loco-regionally advanced HPV-negative base of tongue SCC who, after treatment with cetuximab and radiotherapy, experienced a complete response. The patient had a biopsy-proven recurrence in bilateral kidneys 19 months later that was treated with a combination of right nephrectomy and intermitted cetuximab monotherapy, to which the left lesion responded. Comprehensive multiplatform biomarker analysis of the kidney lesion showed EGFR overexpression with PI3K and TP53 mutations and PD-L1 negative.³³ The authors theorize that the response to cetuximab was most likely mediated immunologically as the direct EGFR inhibitory effect appeared to be blocked by the activation of compensatory escape pathways.³³ A third case report describes a 61-year-old patient diagnosed with a stage IVA tonsillar SCC HPV negative treated with induction chemotherapy with docetaxel, cisplatin, and 5-fluorouracil, followed by chemoradiotherapy with weekly carboplatin, with a complete response. The patient had a local recurrence that was initially monitored, but after lung metastases were identified 5 months later, cetuximab monotherapy was initiated with a complete response. Treatment with cetuximab was stopped after 41 weeks. 3 months after discontinuing treatment with cetuximab, the patient developed a local recurrence on the tongue. The patient was rechallenged with cetuximab monotherapy with a partial response of the tongue lesion that lasted for 9 months. The treatment was switched to capecitabine monotherapy with partial disease response upon local cancer progression.³⁴ The authors discuss that this case supports rechallenging patients with cetuximab after disease recurrence/progression.³⁴ Although not directly reported, we noticed one patient in the Vermorken et al. study who appeared to have a PFS of 252 days and three patients in the Fury et al. study (that used high-dose cetuximab) who appeared to have a PFS longer than 210 days.^30,31 No biomarker analysis was reported in these phase II clinical studies.

The case presented in this report differs from the existing cases in the literature because only our case included cetuximab treatment preceded by immunotherapy with an ICI. In the review of the tumor genomics presented in Figure 2, none of the known biomarkers or genomic alterations account for the exceptional response to cetuximab or immunotherapy in patients with HNSCC. FGF19 is listed among the 399 immune-regulated genes identified in the samples from 527 HNSCC patients in the cancer genome atlas dataset. However, it is not listed among the 69 genes with prognostic significance.³⁵ Sporadic reports associate Cyclin D1 (CCND1) and TP53 in combination with APC with response to cetuximab in colorectal cancer.^36–39 No such reports were found for HNSCC. We hypothesize that changes in the immune response induced by previous treatment with a PD-1 inhibitor enhanced the immune component of the tumor response to cetuximab. Understanding why these results can occur requires a review of the mechanisms of both cetuximab and ICIs and the proposed synergism between them.

Cetuximab, an EGFR inhibiting immunoglobulin G1 chimeric human/mouse monoclonal antibody, has been a crucial part of R/M HNSCC treatment since its approval by the FDA in 2006.²⁷ Cetuximab was effective for its ability to inhibit a variety of signaling pathways that led to tumor cell motility, growth, differentiation, and survival.⁴⁰ For many years, the first-line treatment of R/M HNSCC had been a cetuximab-containing combination chemotherapy called the EXTREME regimen. Only recently have guidelines shifted to ICI-based therapies, although there are many studies still looking at regimens consisting of cetuximab and other chemotherapies such as cisplatin/paclitaxel and bevacizumab.^8,41,42 Despite cetuximab’s well-known stronghold as a pivotal agent for HNSCC and the over-expression of EGFR in up to 90% of HNSCC tumors, the response rate to cetuximab monotherapy in HNSCC patients is only about 13% with a median time to progression of 70 days.³¹ A proposed explanation for this poor response is the activation by cetuximab of immune-inhibitory pathways. In addition to inhibiting the EGFR signaling cascade, the cetuximab immunoglobulin G1 antibody also binds natural killer (NK) cells via its constant Fc component, which stimulates NK cells to attack the tumor cells in an immune effect called antibody-dependent cellular cytotoxicity (ADCC). The relationships between cetuximab efficacy and ADCC were supported by Lattanzio et al., who showed that patients with a high baseline of both ADCC and EGFR3+ activity had higher chances of having a complete response in addition to longer overall survival (OS).⁴³ NK stimulation also leads to the release of interferon, other cytokines, and tumor cell antigens, triggering both innate and adaptive immune responses.^28,44,45 This complex immunomodulatory effect, with multiple different feedback loops, changes the TME and intra-tumoral immune tone. Some of these changes have immunosuppressant effects, dampening cetuximab’s overall effectiveness.^27,37,38 Examples of such immune-suppressive loops include activation of PD-1 expression on immune cells, activation of PD-L1 expression on tumor cells through direct EGFR signaling and indirect interferon/STAT-1 pathway stimulation, and the intra-tumoral increase in the regulatory T (Treg) cells expressing CTLA-4 or PD-L1, known as one of the most immune-suppressive mechanisms.^29,46–48 Cetuximab is also known for its immune-stimulatory effects. Activation of both the innate and adaptive immune systems stimulates dendritic cells, macrophages, and other immune cells, which leads to the recruitment and priming of effector T cells in the TME.^49,50

ICIs are antibodies to the programmed death-1 (PD-1) receptor or programed death-1 ligand (PD-L1). These antibodies function by inhibiting the binding of the PD-L1 to PD-1 receptors, thus allowing tumor cells to be recognized as ‘other’ and eliminated by the patient’s immune system.⁵¹ The PD-1 inhibitors pembrolizumab and nivolumab are considered standard of care for the R/M HNSCC. Extensive clinical investigations have been dedicated to determining which patients may respond best to treatment with ICIs. Biomarkers, including PD-L1 expression, tumor mutational burden, HPV status, microbial signatures, and certain risk factors, such as smoking, have been analyzed. However, the data remain inclusive, without causative association, and often with conflicting results.⁵² Cancers resistant to ICIs display low innate and adaptative immune response within the TME with low CD8 T-cell numbers, low interferon production, and often a low PD-L1 level. Studies have shown that the advanced R/M HNSCC tumors are dominated by an immune-suppressive TME with increased Tregs, immune-inhibitory M2 macrophages, myeloid-derived suppressive cells, and immune-inhibitory cytokines and growth factors or by TME with low immune infiltrate referred to as a ‘cold immune phenotype’.^47–51 Patients with ‘hot’ TME, with high levels of CD8 T cells and NK cells, have improved response to ICIs and improved prognosis independent of HPV status.^53,54 Substantial research efforts have explored strategies to capitalize upon a ‘hot immune phenotype’ and to convert their ‘cold’ and immune-suppressive counterparts. Preclinical and clinical studies have described the complexity of immune players in the TME, hence the challenges of advancing antitumor efficacy with single-targeted immune therapeutic strategies.⁵⁴ Combination treatment with various concurrent or salvage therapies provides an avenue that has been incompletely mapped in HNSCC.

There is a convincing rationale for combining ICIs with cetuximab, and clinical data support the scientific foundation. Cetuximab and ICIs appear to have a synergistic effect on activating both innate and adaptive immune responses. Cetuximab immune-inhibitory effects mediated by activation of PD1, PD-L1, and CTLA-4 pathways with increased Tregs in the TME can be directly targeted and neutralized by ICIs that capitalize on the amplification of the PD-1/PD-L1 pathway. By ‘inhibiting the inhibitor’, the ICIs can amplify the cetuximab antitumor effect. At the same time, by amplifying the PD-1/PD-L1 pathway of communication between cancer and immune cells, cetuximab creates the prospect of a more efficient effect of the ICIs that specifically attack and neutralize this pathway, exposing the tumor cells to the immune attack. Expression of PD-L1 is the only predictor of response to ICIs currently utilized in clinical practice.⁸ The cetuximab immune-stimulatory effect on mounting and priming effector T cells in the TME, mediated by cytokines released by activated NK cells and by released tumor antigens, generates the ‘hotter’ TME needed for the optimization of ICIs’ anticancer activity. By amplifying the anticancer effect of the expanded population of effector T cells, the ICIs increase the cetuximab efficacy in return.

While cetuximab and ICI seemingly synergize in mobilizing the innate and adaptive immune responses against the tumor, the optimal sequence of administration of the two drugs to maximize these effects is undetermined. Similarly, several ongoing studies are looking at the optimal timing of ICI and chemoradiotherapy.⁵⁴

Concurrent administration of immunotherapy and cetuximab has shown clinical effects. Sacco et al. reported early results of a phase II study of a combination of pembrolizumab and cetuximab in patients with R/M HNSCC, and the response rate was 45%, which compares well with the 36% response rate reported by Keynote 048 for patients treated with pembrolizumab combined with chemotherapy.^8,55 A more modest response of 22% was reported by Chung et al., with the combination of cetuximab and nivolumab being given every 2 weeks.⁵⁶ The results of Chung et al. might be explained by the fact that 69% of patients had exposure to either ICIs or cetuximab before enrollment in the study. Interestingly, in a follow-up report of this same study, p16-negative immunostaining was associated with a significantly higher response rate, and in p16-positive patients, a lower level of tumor-tissue-modified human papillomavirus circulating DNA was associated with a significantly improved response rate and prolonged OS compared to a higher level.⁵⁷ Furthermore, a meta-analysis of 684 patients treated with a PD-1 inhibitor and 118 patients treated with the combination of a PD-1 inhibitor and cetuximab showed that adding cetuximab to a PD-1 inhibitor is more effective compared with PD-1 inhibitor monotherapy only in patients with HPV-negative HNSCC. The addition of cetuximab improved the overall response rate and 1-year OS in HPV-negative patients (15% versus 46%, p < 0.001 and 36 versus 59%, p < 0.001) but not in HPV-positive patients (17% versus 18%, p = 0.686 and 40% versus 55%, p = 0.252).⁴⁸ Motivated by these results, more clinical trials were initiated to evaluate the efficacy of ICI concurrent with cetuximab in R/M HNSCC (Table 1).

Table 1.

Summary of ongoing clinical protocols with concurrent cetuximab and ICI for R/M HNSCC.

ICI	ICI MOA	Prior ICI	Line of treatment	Clinicaltrial.gov number
Durvalumab	PD-L1 inhibitor	Yes*	At least second	NCT03691714
Pembrolizumab	PD-1 inhibitor	Yes^$	Any	NCT03082534
Penpulimab	PD-1 inhibitor	No	First Line	NCT05260671
Nivolumab	PD-1 inhibitor	Yes	At least second^‡	NCT03370276
Avelumab	PD-1 inhibitor	No	At least second	NCT03494322

Previous exposure to both ICI and cetuximab was excluded. Singular exposures to either were included.

4 Cohorts: PD-1/PD-L1 inhibitor naïve, cetuximab naïve; PD-1/PD-L1 inhibitor-refractory, cetuximab naïve; PD-1/PD-L1 inhibitor refractory, cetuximab refractory; cutaneous HNSCC.

‡

Unless the patient is likely to be intolerant of first-line therapy, then they can be enrolled for first-line therapy.

HLA-E, human leukocyte antigen E; ICI, immune checkpoint inhibitor; MOA, mechanism of action; PD-1, programmed cell death receptor 1; PD-L1, programed cell death ligand 1.

Sequential administration of cetuximab and ICIs has yielded mixed results in published reports. However, interfering factors, especially the time window between the two sequential treatments, likely affected these results. Because the precise time curve of the relevant immune events is not known for either of the two therapies, the timing of sequential treatments is arbitrarily selected and variable among existing studies.

Administration of cetuximab before immunotherapy yielded conflicting results. Lien et al. reported a study of 290 patients with R/M HNSCC treated with cetuximab and chemotherapy that showed similar OS when ICI was added to the cetuximab-containing regimen or was administered sequentially as a second-line salvage therapy.⁵⁸ Another study by Park et al. showed that of 113 patients analyzed, those who received cetuximab-based treatment prior to ICI had lower response rates, worse OS, and worse PFS than those who had not received prior cetuximab treatment.⁵⁹ No more precise information is provided in these studies regarding the time window between the two sequential treatments. The elimination half-life of cetuximab is approximately 112 h (range: 63–230 h). Considering cetuximab’s half-life, differences in the timing of ICI administration following cetuximab may contribute to different clinical outcomes based on whether ICI is administered when desirable cetuximab-mediated immune effects on the TME are present or not, a question worthy of future study. Park et al. also reported that cetuximab-based treatment was associated with higher response rates and more prolonged survival than non-cetuximab regimens among patients receiving salvage therapy after ICI. From this data, the authors concluded that ICI before cetuximab was superior to ICI after cetuximab, which likely, at least in part, relates to the fact that ICIs have half-lives of around 27 days.⁵⁹ Data suggest that even low levels of circulating ICI can cause enough PD-1 pathway inhibition to have detectable immune effects.^60,61 Persistent PD-1/PD-L1 inhibition could annihilate immune-inhibitory pathways triggered by NK cell-induced ADCC, leaving immune-stimulatory effects to dominate the response to the salvage treatment with cetuximab.

Other retrospective studies have also examined various combinations of salvage therapy after ICI use to treat R/M HNSCC. They have shown promising results with overall response rates (ORR) of 30−60%, disease control rates (DCR) of 57−90%, median PFS (mPFS) of 3.6–6.5 months, and mOS of 7.8–18.4 months, summarized in Table 2.^59,62–69 All of these studies included cetuximab with some focused on the influence of cetuximab versus other salvage therapies and whether cetuximab was given as part of a multidrug regimen or as a single agent. For example, Wakasaki et al. compared salvage post-ICI therapy with a combination of paclitaxel and cetuximab to an oral fluoropyrimidine and found that the ORR was 60% versus 21.4%.⁶⁷ Issa et al. showed that patients who received chemotherapy plus cetuximab after progression on an ICI had a significantly improved mPFS compared to those who received chemotherapy only.⁶⁹

Table 2.

Summary of results of retrospective studies regarding cetuximab-based Salvage Chemotherapy and ICI for treatment of R/M HNSCC.

Study	Inclusion criteria	Cetuximab combination	Cetuximab mono-therapy	N	ORR (%)	DCR (%)	mPFS (mo)	mOS (mo)
Cabeza-Camarero et al.*	R/M HNSCC Progression in PD-1 or PD-L1	Cetuximab + different chemotherapy Agents	No	23	56.5	78.3	6	12
Suzuki et al.*	R/M HNSCC Progression in ICI therapy	Cetuximab + paclitaxel	No	18	44.4	72.2	3.8	9.6
Park et al.	R/M HNSCC Received at least two doses of ICI therapy	Cetuximab-containing regimen	Yes – 6 pts No – 21 pts	27	37.5	NA	NA	11.3
		Non-cetuximab-containing regimen	No	21	19	NA	NA	8.0
Saleh et al.	R/M HNSCCProgression on ICI therapy	Cetuximab ± taxane ± platinum versus ± taxane ± platin	No	30 versus 82	The combination of cetuximab + taxane ± platinum was associated with higher ORR than other chemotherapies without cetuximab regimens (53% versus 25%, p = 0.024)
Pestana et al.*	R/M HNSCCProgression on ICI therapy	CetuximabMonotherapy	Yes	16	37.5%	NA	4.24	8.41
Wakasaki et al.*	R/M HNSCCProgression and/or AE on nivolumab therapy	Cetuximab + paclitaxel	No	25	60	96	6.5	13.4
Kurosaki et al.	R/M HNSCCProgression in ICI therapy	Cetuximab + paclitaxel	No	22^$	40.9	86.4	5.2	14.5
Issa et al.*	R/M HNSCCProgression on ICI therapy	Cetuximab + carboplatin and paclitaxel	No	28	32%	NA	5.6	10

Data for groups that received cetuximab-containing chemotherapy regimen only.

One of the 22 patients was treated with cetuximab + cisplatin and 5-fluorouracil.

AE, adverse event; DCR, disease control rate; ICI, immune checkpoint inhibitor; mOS, median OS; mPFS, median progression-free survival; (N), number of patients studied; NA, not available; ORR, overall response rate; R/M HNSCC, recurrent-metastatic head and neck squamous cell cancer.

A short retrospective series by Pestana et al. is one of very few that reports on cetuximab monotherapy following ICI treatment in R/M HNSCC. Patients received single-agent cetuximab (n = 16), other single-agent chemotherapy (n = 14), combination therapy including cetuximab (n = 8), or combination therapy without cetuximab (n = 5). The ORR, mPFS, and mOS did not significantly differ among groups, suggesting that cetuximab is at least as efficacious as multidrug regimens and may be an excellent option for sparing patients with the side effects of additional chemotherapies.⁶⁵ A retrospective chart review-based study reported a significant OS difference among patients with (N = 29) and without (N = 53) prior ICI in a cohort of patients treated with cetuximab (HR 1.81, 95% CI 1.02–3.16).⁵⁶ However, in the same study population, the patients treated with cetuximab monotherapy had similar OS to those treated with ICI alone (HR 0.94, 95% CI 0.70–1.29), raising concerns about the generalizability of this study’s results.⁵⁶ Taken together, these studies suggest an impressive potential benefit of cetuximab-based salvage therapy following ICI in R/M HNSCC.

Our case reporting an unexpectedly durable response to cetuximab following the failure of multiple lines of therapy, most recently nivolumab, aligns with several other retrospective case series and supports further investigation of the potential synergistic effects of sequential therapy with ICI followed by cetuximab in prospective studies. This would address a treatment gap with no current guidelines, offering patients who failed previous treatment with ICI a potentially effective therapy with limited toxicity. Notably, a prospective clinical trial is currently accruing patients with R/M HNSCC to be treated with salvage cetuximab monotherapy following treatment with the PD-1 inhibitor pembrolizumab (ClinicalTrials.gov NCT04375384).

Conclusion

The current case, previous studies, and prevailing immunomodulatory theories discussed in this review highlight novel potential uses of ICIs and cetuximab to achieve each therapy’s desirable individual effects while leveraging potentially advantageous synergistic modulation of the TME to attain better patient outcomes than previously seen. Our case, in particular, underscores the rationale, research efforts, and growing body of literature supporting the use of ICI in combination with cetuximab as salvage therapy for R/M HNSCC. Cetuximab may provide an effective and low-toxicity option to fill a critical therapeutic gap for many patients with R/M HNSCC who progress on ICIs. Considering the underlying mechanistic therapeutic rationale, future studies are warranted to elucidate the optimal sequence of combined ICI and cetuximab regimens and the most appropriate time window between sequential treatments.

Footnotes

Acknowledgements

None.

Declarations

ORCID iDs

Chance H. Bloomer

Kimberly M. Burcher

Mercedes Porosnicu

References

Licitra

Felip

. Squamous cell carcinoma of the head and neck: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 2009; 20(Suppl 4): 121–122.

Chen

Yen

Liu

, et al. Outcomes of induction chemotherapy for head and neck cancer patients a combined study of two national cohorts in Taiwan. Medicine 2016; 95: e2845.

Ferlay

Soerjomataram

Dikshit

, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015; 136: E359–E386.

Saleh

Eid

Haddad

, et al. New developments in the management of head and neck cancer – impact of pembrolizumab. Ther Clin Risk Manag 2018; 14: 295–303.

Vermorken

Mesia

Rivera

, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 2008; 359: 1116–1127.

Ferris

Blumenschein

Jr Fayette

, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 2016; 375: 1856–1867.

Cohen

EEW

Soulières

Tourneau

. Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. J Lancet 2019; 393: 156–167.

Burtness

Harrington

Greil

, et al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet 2019; 394: 1915–1928.

Harrington

Burtness

Greil

, et al. Pembrolizumab with or without chemotherapy in recurrent or metastatic head and neck squamous cell carcinoma: updated results of the Phase III KEYNOTE-048 Study. J Clin Oncol 2023; 41: 790–802.

10.

Szturz

Vermorken

. Immunotherapy in head and neck cancer: aiming at EXTREME precision. BMC Med 2017; 15: 110.

11.

Pfister

Spencer

Adelstein

. Head and neck cancers, version 2.2020. J Natl Compr Cancer Netw 2020; 18: 873–898.

12.

Bauml

Seiwert

Pfister

, et al. Pembrolizumab for platinum- and cetuximab-refractory head and neck cancer: results from a single-arm, phase II study. J Clin Oncol 2017; 35. DOI: 10.1200/JCO.2016.70.1524

13.

Ferris

Blumenschein

Jr Fayette

, et al. Nivolumab vs investigator’s choice in recurrent or metastatic squamous cell carcinoma of the head and neck: 2-year long-term survival update of checkmate 141 with analyses by tumor PD-L1 expression. Oral Oncol 2018; 81: 45–51.

14.

Zandberg

Algazi

Jimeno

, et al. Durvalumab for recurrent or metastatic head and neck squamous cell carcinoma: results from a single-arm, phase II study in patients with ⩾25% tumour cell PD-L1 expression who have progressed on platinum-based chemotherapy. Eur J Cancer 2019; 107: 142–152.

15.

Ferris

Spanos

Leidner

, et al. Neoadjuvant nivolumab for patients with resectable HPV-positive and HPV-negative squamous cell carcinomas of the head and neck in the CheckMate 358 trial. J Immunother Cancer 2021; 9: e002568.

16.

Tone

Izumo

Awano

, et al. Treatment effect and safety profile of salvage chemotherapy following immune checkpoint inhibitors in lung cancer. Lung Cancer Manag 2019; 4: LMT12.

17.

Soda

Ogawara

Fukuda

, et al. Dynamics of blood neutrophil-related indices during nivolumab treatment may be associated with response to salvage chemotherapy for non-small cell lung cancer: a hypothesis-generating study. Thorac Cancer 2019; 10: 341–346.

18.

Sathianathen

Regmi

Gupta

, et al. Immuno-oncology approaches to salvage treatment for non-muscle invasive bladder cancer. Urol Clin North Am 2020; 47: 103–110.

19.

Greally

Agarwal

El Dika

, et al. Maximizing response: a case report of salvage chemotherapy after immune checkpoint inhibition in a patient with previous chemo-refractory metastatic esophageal carcinoma. J Gastrointest Oncol 2019; 10: 367–372.

20.

Arigami

Matsushita

Okubo

, et al. Response rate and prognostic impact of salvage chemotherapy after nivolumab in patients with Advanced Gastric Cancer. Oncology 2020; 98: 630–636.

21.

Daste

De-Mones

Cochin

, et al. Progression beyond nivolumab: Stop or repeat? Dramatic responses with salvage chemotherapy. Oral Oncol 2018; 81: 116–118.

22.

Daste

de Mones

Digue

, et al. Immunotherapy in head and neck cancer: need for a new strategy? Rapid progression with nivolumab then unexpected response with next treatment. Oral Oncol 2017; 64: e1–e3.

23.

Dwary

Master

Patel

, et al. Excellent response to chemotherapy post immunotherapy. Oncotarget 2017; 8: 91795–91802.

24.

Larroquette

Domblides

Cousin

, et al. Dramatic response after anti PD1 treatment failure in a squamous cell carcinoma of the maxillary sinus. Oral Oncol 2018; 87: 207–209.

25.

Lasserre

Domblides

Gross-Goupil

, et al. The interest of sequential treatment with immune check point inhibitors followed chemotherapy: a case report. Oral Oncol 2019; 94: 125–127.

26.

Suzuki

Toyoma

Tomizawa

, et al. Efficacy of chemotherapy after progression with nivolumab in squamous cell carcinoma of the head and neck. Auris Nasus Larynx 2020; 47: 485–488.

27.

Taberna

Oliva

Mesía

. Cetuximab-containing combinations in locally advanced and recurrent or metastatic head and neck squamous cell carcinoma. Front Oncol 2019; 9: 383.

28.

Ferris

Lenz

Trotta

, et al. Rationale for combination of therapeutic antibodies targeting tumor cells and immune checkpoint receptors: harnessing innate and adaptive immunity through IgG1 isotype immune effector stimulation. Cancer Treat Rev 2018; 63: 48–60.

29.

Jie

Srivastava

Argiris

, et al. Increased PD-1+ and TIM-3+ TILs during cetuximab therapy inversely correlate with response in head and neck cancer patients. Cancer Immunol Res 2017; 5: 408–416.

30.

Fury

Sherman

Lisa

, et al. A randomized phase II study of cetuximab every 2 weeks at either 500 or 750 mg/m2 for patients with recurrent or metastatic head and neck squamous cell cancer. J Natl Compr Canc Netw 2012; 10: 1391–1398.

31.

Vermorken

Trigo

Hitt

, et al. Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. World J Clin Oncol 2007; 25: 2171–2177.

32.

Rubinstein

Lindgren

Setty

, et al. Durable complete remission induced by cetuximab monotherapy in a patient infected with HIV and diagnosed with recurrent squamous cell carcinoma of the head and neck. World J Clin Oncol 2011; 29: e222–e225.

33.

El-Osta

Peddi

Paryani

, et al. Exceptional response to cetuximab monotherapy in a patient with metastatic oropharyngeal squamous cell carcinoma: a molecular insight. OncoTargets Ther 2016; 9: 705.

34.

Knutzen

Subbiah

. Cetuximab rechallenge and monotherapy in patients with squamous cell carcinoma of the head and neck. Case Rep Oncol 2015; 8: 503–508.

35.

Wang

Lei

, et al. Comprehensive immunogenomic landscape analysis of prognosis-related genes in head and neck cancer. Sci Rep 2020; 10: 6395.

36.

Vallböhmer

Zhang

Gordon

, et al. Molecular determinants of cetuximab efficacy. World J Clin Oncol 2005; 23: 3536–3544.

37.

Zhang

Gordon

Press

, et al. Cyclin D1 and epidermal growth factor polymorphisms associated with survival in patients with advanced colorectal cancer treated with Cetuximab. Pharmacogenet Genomics 2006; 16: 475–483.

38.

Aujla

. Genetics: TP53 mutations predict response to cetuximab. Nat Rev Clin Oncol 2009; 6: 373. DOI: 10.1038/nrclinonc.2009.75

39.

Thota

Yang

Pflieger

, et al. Apc and tp53 mutations predict cetuximab sensitivity across consensus molecular subtypes. Cancers (Basel) 2021; 13. DOI: 10.3390/cancers13215394

40.

Khadela

Shah

Mistry

, et al. Immunomodulatory therapy in head and neck squamous cell carcinoma: recent advances and clinical prospects. Technol Cancer Res Treat 2023; 22: 15330338221150559.

41.

Khadela

Shah

Mistry

, et al. A review of efficacy and safety of cetuximab and bevacizumab-based monoclonal antibodies in head and neck cancer. Med Oncol 2023; 40. DOI: 10.1007/s12032-022-01939-x

42.

Khadela

Vyas

Mansuri

, et al. Impact of cetuximab plus cisplatin alone and cetuximab plus cisplatin and paclitaxel regimen on humanistic outcome in head and neck cancer. J Egypt Natl Canc Inst 2023; 35: 1.

43.

Lattanzio

Denaro

Vivenza

, et al. Elevated basal antibody-dependent cell-mediated cytotoxicity (ADCC) and high epidermal growth factor receptor (EGFR) expression predict favourable outcome in patients with locally advanced head and neck cancer treated with cetuximab and radiotherapy. Cancer Immunol Immunother 2017; 66: 573–579.

44.

Schoppy

Sunwoo

. Immunotherapy for head and neck squamous cell carcinoma. Hematol Oncol Clin North Am 2015; 29: 1033–1043.

45.

Bhat

Watzl

. Serial killing of tumor cells by human natural killer cells—enhancement by therapeutic antibodies. PLoS One 2007; 2: e326.

46.

Concha-Benavente

Srivastava

Trivedi

, et al. Identification of the cell-intrinsic and -extrinsic pathways downstream of EGFR and IFNγ that induce PD-L1 expression in head and neck cancer. Cancer Res 2016; 76: 1031–1043.

47.

Jie

Gildener-Leapman

, et al. Intratumoral regulatory T cells upregulate immunosuppressive molecules in head and neck cancer patients. Br J Cancer 2013; 109: 2629–2635.

48.

Zhang

Zheng

Nie

, et al. Efficacy of cetuximab plus PD-1 inhibitor differs by HPV status in head and neck squamous cell carcinoma: a systematic review and meta-analysis. J Immunother Cancer 2022; 10: e005158.

49.

Lee

Srivastava

López-Albaitero

, et al. Natural killer (NK):dendritic cell (DC) cross talk induced by therapeutic monoclonal antibody triggers tumor antigen-specific T cell immunity. Immunol Res 2011; 50: 248–254.

50.

Srivastava

Lee

Andrade Filho

, et al. Cetuximab-activated natural killer and dendritic cells collaborate to trigger tumor antigen-specific T-cell immunity in head and neck cancer patients. Clin Cancer Res 2013; 19: 1858–1872.

51.

Ferris

. Immunology and immunotherapy of head and neck cancer. World J Clin Oncol 2015; 33: 3293–3304.

52.

Oliva

Spreafico

Taberna

, et al. Immune biomarkers of response to immune-checkpoint inhibitors in head and neck squamous cell carcinoma. Ann Oncol 2019; 30: 57–67.

53.

Johnson

Burtness

Leemans

, et al. Head and neck squamous cell carcinoma. Nat Rev Dis Primers 2020; 6: 92.

54.

Ruffin

Vujanovic

, et al. Improving head and neck cancer therapies by immunomodulation of the tumour microenvironment. Nat Rev Cancer. 2023; 23: 173–188.

55.

Sacco

Chen

Worden

, et al. Pembrolizumab plus cetuximab in patients with recurrent or metastatic head and neck squamous cell carcinoma: an open-label, multi-arm, non-randomised, multicentre, phase 2 trial. Lancet Oncol 2021; 22: 883–892.

56.

Chung

Bonomi

Steuer

, et al. Concurrent cetuximab and nivolumab as a second-line or beyond treatment of patients with recurrent and/or metastatic head and neck squamous cell carcinoma: results of phase i/ii study. Cancers 2021; 13: 1180.

57.

Chung

Steuer

, et al. Phase II multi-institutional clinical trial result of concurrent cetuximab and nivolumab in recurrent and/or metastatic head and neck squamous cell carcinoma. Clin Cancer Res 2022; 28: 2329–2338.

58.

Lien

Wang

Hsieh

, et al. Both combined or sequential use with immune checkpoint inhibitors on cetuximab-treated patients with recurrent or metastatic head and neck squamous cell carcinoma improve the overall survival. Oral Oncol 2021; 119: 105380.

59.

Park

Durbeck

Clark

, et al. Treatment sequence of cetuximab and immune checkpoint inhibitor in head and neck squamous cell carcinoma differentially affects outcomes. Oral Oncol 2020; 111: 105024.

60.

Wang

Thudium

Han

, et al. In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human primates. Cancer Immunol Res 2014; 2: 846–856.

61.

Brahmer

Drake

Wollner

, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 2010; 28: 3167–3175.

62.

Cabezas-Camarero

Cabrera-Martín

Merino-Menéndez

, et al. Safety and efficacy of cetuximab-based salvage chemotherapy after checkpoint inhibitors in head and neck cancer. Oncologist 2021; 26: e1018–e1035.

63.

Suzuki

Toyoma

Kawasaki

, et al. Clinical outcomes of cetuximab and paclitaxel after progression on immune checkpoint inhibitors in recurrent or metastatic head and neck squamous cell carcinoma. Medicinar 2021; 57: 1151.

64.

Saleh

Daste

Martin

, et al. Response to salvage chemotherapy after progression on immune checkpoint inhibitors in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. Eur J Cancer 2019; 121: 123–129.

65.

Pestana

Becnel

Rubin

, et al. Response rates and survival to systemic therapy after immune checkpoint inhibitor failure in recurrent/metastatic head and neck squamous cell carcinoma. Oral Oncol 2020; 101: 104523.

66.

Wakasaki

Yasumatsu

Uchi

, et al. Outcome of chemotherapy following nivolumab treatment for recurrent and/or metastatic head and neck squamous cell carcinoma. Auris Nasus Larynx 2020; 47: 116–122.

67.

Wakasaki

Yasumatsu

Masuda

, et al. Prognostic biomarkers of salvage chemotherapy following nivolumab treatment for recurrent and/or metastatic head and neck squamous cell carcinoma. Cancers 2020; 12: 2299.

68.

Kurosaki

Mitani

Tanaka

, et al. Safety and efficacy of cetuximab-containing chemotherapy after immune checkpoint inhibitors for patients with squamous cell carcinoma of the head and neck: a single-center retrospective study. Anticancer Drugs 2021; 32: 95–101.

69.

Issa

Klamer

Karivedu

, et al. Use of cetuximab added to weekly chemotherapy to improve progression-free survival in patients with recurrent metastatic head and neck squamous cell carcinoma after progression on immune checkpoint inhibitors. World J Clin Oncol 2021; 39: 6038–6038.

Exceptional response to cetuximab monotherapy after failure of immunotherapy with a checkpoint inhibitor in a patient with metastatic head and neck squamous cell cancer: case report and review of the literature

Abstract

Keywords

Introduction

Case presentation

Discussion

Conclusion

Footnotes

Acknowledgements

Declarations

ORCID iDs

References