Metastatic Head And Neck Squamous Cell Cancer Research Articles

Abstract 5503: Ultrahigh-plex spatial phenotyping of head and neck cancer tissue uncovers multiomic signatures of immunotherapy response

Abstract Background Targeted immune checkpoint inhibitors (ICI) with anti-PD-1/PD-L1 therapy offer durable treatment of mucosal head and neck squamous cell cancer (HNSCC), in both human papillomavirus-positive (HPV+) and negative (HPV-) patients. However, currently available biomarker signatures for targeted ICI therapies have limited predictive value. Our recent ultrahigh-plex profiling of HNSCC tissue with 100+ cancer hallmarks of tumor and immunobiology uncovered distinct spatial domains that serve as defining factors for clinical response and resistance. Methods Our unbiased analysis of whole-slide metastatic HNSCC tumors is from a clinical cohort of patients treated with Pembrolizumab/Nivolumab. The cohort consisted of patients with a range of outcomes from complete vs partial vs progressive disease responses to ICI therapy. We first characterized the tumor microenvironment using our ultrahigh-plex protein panel with 100+ antibodies on the PhenoCycler®-Fusion platform. To expand upon our biomarker discovery, we included multiomic cancer hallmarks with a multimodal protein/RNA detection panel. Targeted spatial RNA detection was performed to complement and augment the microenvironment characterization achieved by our protein panel. To further consolidate the multiomic data, we leveraged MaxFuse, a state-of-the art computational framework that integrates multimodal spatial and single-cell expression data. Results Our multiomic spatial phenotyping uncovered diverse tumor regions, each with distinct biomarker expression that is reflected across modalities including protein, RNA, and metabolic activity, indicating regions likely associated with resistance to immunotherapy. Our multiomic data integration also revealed spatial signatures associated with different tissue compartments, such as the tumor and non-tumor associated tertiary lymphoid structures. Conclusions We demonstrate a multi-pronged approach that incorporated both novel experimental and computational techniques for elucidating tumor microenvironment in HNSCC tissue prior to ICI-based immunotherapy. Our multiomic approach provides deeper characterization of the HNSCC at the transcriptomic and proteomic level incorporating depth across the entire transcriptome and single-cell spatial resolution of key protein determinants for predicting and furthering our understanding of immunotherapy response to ICI therapy. Citation Format: Aditya Pratapa, Lydia Hernandez, Bassem Ben Cheikh, Niyati Jhaveri, Arutha Kulasinghe. Ultrahigh-plex spatial phenotyping of head and neck cancer tissue uncovers multiomic signatures of immunotherapy response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5503.

Clinical outcomes in patients with metastatic non-small cell lung cancer and head and neck squamous cell cancer treated with immune checkpoint inhibitors according to COVID-19 vaccination status.

e14696 Background: Immune checkpoint inhibitor (ICI) constitute the mainstay of therapy in metastatic non-small cell lung cancer (NSCLC) and head and neck squamous cell cancer (HNSCC). Infectious vaccines administered intratumorally or systemically have been suggested to enhance response to ICI and improve outcomes. No data is available on the effect of COVID-19 vaccines on clinical outcomes in patients treated with ICI. The aim of the study is to investigate overall survival (OS), progression-free survival (PFS), and immune related adverse events (IRAEs) according to mRNA COVID-19 vaccination status in patients with metastatic NSCLC and HNSCC who were treated with ICI. Methods: We performed retrospective analysis of clinical outcomes between a cohort of patients treated with ICI who received at least one dose of COVID-19 vaccine, and a historic control group of patients who did not receive COVID-19 vaccine and did not have documented COVID-19 infection. We included patients with metastatic NSCLC and HNSCC who had received at least one dose of ICI, either as monotherapy or in combination with chemotherapy or targeted therapy. Patients were stratified by age, gender, ethnicity, COVID-19 vaccination status, number of vaccinations, treatment type (monotherapy versus combined), treatment line, and PD-L1 status. Endpoints included IRAEs, PFS and OS. Results: A total of 151 patients met inclusion criteria (94 vaccinated and 57 control). Mean age at diagnosis was 62 years, the majority were female (51%), African American (58.3%), and received ICI monotherapy (57.6%). There was prolonged OS in patients who received COVID-19 vaccination versus control group ( p-value=0.04). In a multivariate analysis, patients in the COVID-19 vaccine arm had significantly reduced hazard of dying (HR:0.49, p =0.0446) when controlled for all of the above variables, and each additional received vaccine was associated with significant reduced hazard (HR=0.701, p-value = 0.0099). Race and type of cancer were statistically associated with PFS. Controlled for these factors, COVID arm patients had reduced hazard of disease progression (HR = 0.58, p-value = 0.0506), and each additional received mRNA vaccine was associated with a significantly reduced hazard of progression (HR = 0.74, p-value = 0.0046). There was no significant difference in the rate of IRAEs between vaccinated and non-vaccinated patients ( p=0.71). Conclusions: In this sample of patients with metastatic NSCLC and HNSCC who received ICI, there was significant improvement in OS between patients who received a COVID-19 vaccine compared patients who did not receive vaccination and did not have COVID-19 infection. There were no significant differences in IRAEs. Further studies are required to assess whether there is a synergistic effect between COVID-19 vaccination and ICI efficacy.

A phase 2 open-label study of conditionally active biologic ozuriftamab vedotin (BA3021) in failed PD-1/L1 treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck.

TPS6107 Background: Ozuriftamab vedotin (BA3021) is a conditionally active biologic (CAB) anti-receptor tyrosine kinase orphan receptor 2 (ROR2) humanized monoclonal antibody (IgG1) conjugated to monomethyl auristatin E (MMAE) using a cleavable linker (CAB ROR2 ADC) (Short, et al., 2014, Chang, et al. 2021). Conditional and reversible binding by CABs is designed to reduce off-tumor toxicity and immunogenicity, avoid tissue-mediated drug deposition, and improve pharmacokinetics (PK). ROR2 is a cell-surface transmembrane receptor protein tyrosine kinase highly expressed in several tumor types including head and neck squamous cell cancer (HNSCC). Increased ROR2 expression has been associated with tumor resistance to chemotherapy, programmed death-1 (PD-1) inhibitors, molecular targeted therapy, and radiation therapy. A pronounced unmet need exists as the majority of patients with recurrent or metastatic HNSCC experience disease progression with existing therapies (Chow 2020). Methods: BA3021-002 is a multi-center, open-label, single-arm Phase 2 study (n=40) designed to evaluate the efficacy and safety of BA3021 in patients previously treated with PD-(L)1 with ROR-2 expressing recurrent or metastatic HNSCC. Eligible patients include those with measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 criteria. Failure to prior treatment is defined as documented disease progression after no more than one PD-1/L1 inhibitor either administered as monotherapy or in combination therapy. Pharmacokinetic (PK), pharmacodynamic (PD), immunogenicity, and biomarker assessments will be performed. Enrollment is ongoing (NCT05271604)

Treatment patterns for patients with metastatic or recurrent head and neck cancer in a large integrated health-care system.

e18015 Background: Since publication of the landmark KEYNOTE-048 Trial, pembrolizumab alone or with platinum-based chemotherapy and 5-fluorouracil (5FU) was established as a standard of care for the frontline treatment of patients with recurrent or metastatic head and neck squamous cell cancer (HNSCC), replacing the EXTREME regimen of Cetuximab with platinum and 5FU. In clinical practice, some clinicians modify the KEYNOTE-048 regimen by substituting a taxane for 5FU (i.e., Paclitaxel + Carboplatin + Pembrolizumab, PCT). Within the Kaiser Permanente Northern California (KPNCAL) network, we identified a cohort of 123 patients who received palliative first-line therapy for metastatic HNSCC to identify practice patterns in a real-world setting within a large health care delivery system. Methods: This is a data-only cohort study of all adult KPNCAL members diagnosed with metastatic HNSCC treated with palliative combination chemotherapy and/or immunotherapy between January 1, 2018 and July 31, 2020. Results: Among a cohort of 123 patients, 28 patients received the EXTREME regimen (platinum + 5FU + cetuximab), 10 received modified EXTREME (platinum + taxane + cetuximab), 14 received platinum + 5FU + pembrolizumab, 9 received platinum + taxane + pembrolizumab and 62 received single agent immunotherapy. From 2018 through mid-2020, there was an apparent shift away from cetuximab based regimens and a concurrent rise in immunotherapy-based regimens. By mid-2020, the majority of patients received an immunotherapy-based regimen (28 patients), while only 5 patients received a cetuximab based regimen (Table). Conclusions: Data from our cohort reported clinical practice patterns within a large multispecialty integrated health-care system in Northern California. Our findings highlight the marked variability in practice patterns within a single health care system for first-line metastatic therapy. While we identified trends away from cetuximab based therapy and toward immunotherapy-based therapy in clinical practice there remained wide practice variations among clinical oncologist treating patients with newly diagnosed metastatic HNSCC. This further emphasizes the need for prospective clinical trials to identify the optimal regimen or to confirm clinical equipoise between regimens among patients with metastatic or recurrent head and neck cancer. [Table: see text]

Priming immunotherapy with radiotherapy (RT) in advanced non-small cell lung cancer (NSCLC) and head and neck squamous cell cancer (HNSCC): Interim analysis of phase II clinical trial.

2628 Background: Preclinical models demonstrate that combined RT with immune checkpoint inhibitor (ICI) results in specific CD8+ T-cell phenotype associated with a tumor-reactive population resulting in significant tumor response. Sequential treatment could allow radiation to release tumor antigens from immune inaccessible areas and provide robust anti-tumor immune response with ICI. We report an interim analysis of the phase II clinical trial evaluating the efficacy and safety of the combination. Methods: Advanced NSCLC and HNSCC patients who had initiated on FDA approved single-agent ICI were eligible. Patients were given SBRT (BED>100Gy) or 30 Gy fractionated RT delivered as a 3-dimensional dose to a single metastatic site within 14 days of the first ICI dose. Primary objective was 6-month PFS and secondary objectives were safety and tolerability, 1Y PFS and OS. This interim analysis was done after enrollment of 43 patients. Results: Between 10/2017 to 1/2021, 43 patients were enrolled, and 38 included in this analysis. Median age was 62 years; 26 patients were male. 9 patients received ICI for NSCLC as first-line, 7 for NSCLC second-line and 22 for HNSCC second-line. 24 patients received pembrolizumab and 14 nivolumab; 21 had SBRT and 17 fractionated RT. Median follow up duration was 11.8m (range: 2.7 - 31.4m) for patients without progressive disease (PD). 10 patients were off-study, 7 continuing treatment. 15 died and 26 had PD. 14 patients died of malignancy and cause of death for one patient was unknown. 6-month PFS was 49.19% with median PFS of 5.5 months. (table) Fifty-two grade-3-5 adverse events (AEs) were reported among 21 subjects. Most common were transaminitis (n=15), lymphopenia (n=8), and GI side effects (n=4). Treatment related AEs included 19 grade-3 events, and none were grade 4/5. Two grade-5 AEs were from PD (oral bleeding and unspecified). There were 20 grade-1/2 and 3 grade-3 immune related adverse events (IRAEs). No grade-4/5 IRAEs were reported. Two patients discontinued treatment due to grade 3 transaminitis. Conclusions: Interim analysis shows that 6m PFS was acceptable with majority of patients being second-line metastatic HNSCC who historically had mPFS of 2.1-2.3 months and mOS 7.7-8.4 months in Checkmate-141/KEYNOTE-040 trials. Hence, the combination is of further interest and accrual will continue to reach the goal. The combination therapy was tolerable without unexpected AEs. Majority of deaths were from disease progression. No treatment related grade 4/5 adverse events were reported. Two patients discontinued treatment due to grade-3 IRAE. Clinical trial information: NCT03313804. [Table: see text]

Nuclear entrapment of p33ING1b by inhibition of exportin-1: A trigger of apoptosis in head and neck squamous cell cancer

The effect of deregulation of nuclear export mediated by exportin-1, with consequent cellular mislocalization of p33ING1b, a member of the tumor suppressor gene family, has not been previously investigated in head and neck squamous cell cancer (HNSCC). We evaluated the effect of reversing cytoplasmic p33ING1b localization through inhibition of exportin-1 by leptomycin B (LMB) and the effect of nuclear entrapment of p33ING1b on molecular alterations in primary and metastatic HNSCC lines. The expression and location of exportin-1 and p33ING1b were analyzed by a quantitative real‑time reverse transcription polymerase chain reaction PCR (qRT-PCR), a Western blot, and immunostaining. Cell proliferation and migration assays were conducted to determine the effect of exportin-1 inhibition on the cell lines. Exportin-1 was overexpressed in metastatic HNSCC, whereas p33ING1b was poorly expressed. Exportin-1 inhibition induced nuclear entrapment and upregulation of p33ING1b, extensive apoptosis, and growth arrest. It also suppressed cell migration. Cytoplasmic p33ING1b-mediated regulation of cell growth and nuclear entrapment of p33ING1b via inhibition of exportin-1 may be a key mechanism for inducing HNSCC apoptosis.

P16(INK4a) status and survival benefit of EGFR inhibitors in head and neck squamous cell cancer: A systematic review and meta-analysis.

We conducted a systematic review and meta-analysis to investigate the impact of p16(INK4a) status on survival benefits in head and neck squamous cell cancer (HNSCC) after anti-epidermal growth factor receptor (EGFR) based treatments. We identified studies assessing anti-EGFR based versus non-anti-EGFR based regimens in patients with unresectable locoregionally advanced, recurrent or metastatic HNSCC. The primary endpoint was progression-free survival (PFS). We assessed the risk of bias in each included study. Random-effects models were used to estimate the efficacy of anti-EGFR based treatments for the p16-positive/p16-negative patients and prespecified subgroups defined by treatment modalities (chemotherapy or radiotherapy). Ten studies with 1929 patients were included. Adding an EGFR inhibitor did not significantly improve PFS or overall survival (OS) in either p16-negative or p16-positive disease. Subgroup analyses suggested a significant PFS benefit (hazard ratio [HR] 0.58; P < 0.001) of adding an EGFR inhibitor to chemotherapy versus chemotherapy for p16-negative disease. The p16-negativity was also associated with a significant OS benefit (HR 0.77; P = 0.003) when studies with high risk of bias were excluded. In contrast, adding an EGFR inhibitor to chemotherapy provided no benefit in either PFS or OS for p16-positive disease. No benefit was shown in either PFS or OS from adding an EGFR inhibitor to radiotherapy or chemoradiotherapy versus chemoradiotherapy regardless of p16 status. For the first time, our meta-analysis provides evidence that efficacy of anti-EGFR based treatments could be dependent on both p16 status and treatment modality. p16 status is likely to have a role in predicting survival to anti-EGFR based treatments in recurrent or metastatic HNSCC.

TWISTT analysis of open labeled multicentric study of BIOMAb- EGFR [Nimotuzumab] in head and neck cancers with chemotherapy and/or radiotherapy.

e17505 Background: Head and neck Squamous Cell Cancer (HNSCC) have poor prognosis in recurrent and metastatic setting with limited treatment options. The treatment decision are predominantly driven by quality of life (QOL) issues, pharmaco-economics besides the survival and response rates. Present TWISTT analysis was based on the earlier “open labeled multicentric study of Nimotuzumab in head and neck cancers with chemotherapy and/or radiotherapy”, to evaluate the QOL outcomes Methods: The active part study was conducted between Nov 2007 and Jan 2009 followed by long term follow up. Patients received Nimotuzumab w at 200 mg/m2 / week along with RT or chemotherapy Results: A total of 150 patients received therapy, who met the eligibility criteria [ Ref-CTRI/2007/95] Overall adverse event rate is 24% [ 36 subjects who experienced any AE]. Mucosal inflammation [ related to RT] was most frequent AE and three were only 4 [2.7%] serious adverse events [ all of them not related to IP]. Skin rash was not apredictor for the response to BIOMAB and was observed in 1.3%. The median TWISTT score in responding patients was 246 days vs 128 days for non responders. PFS and OS were not presented as the main focus of the study is to report the QOL and TWISTT score. Conclusions: Based on the results of this analysis, Nimotuzumab in combination with chemo +/- radiotherapy appears as an attractive regimen for patients with metastatic HNSCC. Clinical trial information: CTRI/2007/95.

Docetaxel plus cisplatin plus fluorouracil versus carboplatin plus fluorouracil-cetuximab in first-line setting in patients with recurrent or metastatic head and neck squamous cell cancer who did not previously receive neoadjuvant or adjuvant chemotherapy, which is standard?

The prognosis of recurrent or metastatic head and neck squamous cell cancer (HNSCC) is very poor. In the present retrospective study, we compared the impact of docetaxel plus cisplatin plus fluorouracil (TCF), and cisplatin plus fluorouracil plus cetuximab (CF-Ctx) regimens on the prognosis of patients with recurrent or metastatic HNSCC in first-line. A total of 70 patients were evaluated as two groups, according to treatment protocol: TCF (n: 47) and CF-Ctx (n: 23). The groups were compared regarding survival. The median progression-free survival was 7.3 and 8.3 months, TCF and CF-Ctx groups, respectively, (P = 0.280). The median overall survival (OS) was 15.6 and 9.3 months for TCF and CF-Ctx groups, respectively, (P = 0.029). The dose reduction and using of granulocyte colony stimulating factor were significantly higher in TCF group (P = 0.048 and P = 0.018, respectively). In first-line setting, TCF regimen is superior to CF-Ctx regimen in terms of OS in patients with recurrent or metastatic HNSCC, who did not previously receive neoadjuvant or adjuvant chemotherapy.

Neutrophil to lymphocyte ratio is an independent prognostic factor in patients with recurrent or metastatic head and neck squamous cell cancer.

The neutrophil to lymphocyte ratio (NLR) has been widely investigated for its prognostic significance in cancer. In the present study, we aimed to determine whether NLR is a prognostic factor in patients with recurrent or metastatic head and neck squamous cell cancer (HNSCC). A total of 79 patients from the Akdeniz University database were retrospectively analyzed. The cut-off NLR was set at 2.93; patients with NLR >2.93 had a median overall survival (OS) of 12.1 months, whereas the median OS was not reached for patients with NLR ≤2.93 (P=0.027). On multivariate analysis, NLR and recurrence or metastatic site were found to be independent prognostic factors for OS (P=0.014 and P=0.002, respectively). Therefore, NLR was identified as an independent prognostic factor for OS in patients with recurrent or metastatic HNSCC.

A randomized, phase II trial of cetuximab with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or metastatic head and neck squamous cell cancer

The phosphotidylinositol-3 kinase (PI3K)/serine-threonine kinase/mammalian target of rapamycin signaling pathway is frequently altered in head and neck squamous cell cancer (HNSCC). PX-866 is an oral, irreversible, pan-isoform inhibitor of PI3K. A phase I trial demonstrated tolerability of this combination. This randomized phase II study evaluated PX-866 combined with cetuximab in patients with advanced, refractory HNSCC. Patients with recurrent or metastatic HNSCC who had received at least one and no more than two prior systemic treatment regimens were randomized (1 : 1) to cetuximab with or without PX-866 (8 mg p.o. daily; arms A and B, respectively). The primary end point was progression-free survival (PFS). Secondary end points included objective response rate (ORR), overall survival (OS), toxicity, and correlation of key biomarkers with efficacy outcomes. Eighty-three patients were enrolled. There was a similar response rate between arms (10% versus 7%). Of patients for whom tissue was assessable, 57% were human papillomavirus (HPV) positive. Median PFS was 80 days in both arms and there was no difference in OS between the two arms (211 versus 256 days). Overall toxicity was higher in arm A compared with arm B, especially in terms of nausea (53% versus 23%), vomiting (45% versus 15%), fatigue (43% versus 23%), diarrhea (40% versus 21%), and hypokalemia (25% versus 10%). Grade 3 or higher adverse events were infrequent, but more common in the combination arm although without a specific pattern. PIK3CA mutations were observed in 17% of the cases assessed, and PTEN loss was infrequently observed. The addition of PX-866 to cetuximab did not improve PFS, RR, or OS in patients with advanced, refractory HNSCC enrolled without molecular preselection. In this contemporary cohort, HPV-positive patients comprised the majority, and neither HPV-positive nor HPV-negative patients derived clinical benefit for the addition of cetuximab plus PX-866.

A randomized, phase 2 trial of docetaxel with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or metastatic head and neck squamous cell cancer

The phosphotidylinositol-3 kinase (PI3K)/serine-threonine kinase (AKT)/mammalian target of rapamycin (mTOR) signaling pathway is frequently altered in head and neck squamous cell cancer (HNSCC). PX-866 is an oral, irreversible, pan-isoform inhibitor of PI3K. Preclinical models revealed synergy with docetaxel and a phase 1 trial demonstrated tolerability of this combination. This randomized phase 2 study evaluated PX-866 combined with docetaxel in patients with advanced, refractory HNSCC. Patients with locally advanced, recurrent or metastatic HNSCC who had received at least one and no more than two prior systemic treatment regimens were randomized (1:1) to a combination of docetaxel (75mg/m(2) IV every 21days) with or without PX-866 (8mg PO daily; Arms A and B, respectively). The primary endpoint was progression free survival (PFS). Secondary endpoints included objective response rate (RR), overall survival (OS), toxicity, and correlation of biomarker analyses with efficacy outcomes. 85 patients were enrolled. There was a non-significant improvement in response rate in the combination arm (14% vs. 5%; P=0.13). Median PFS was 92days in Arm A and 82days in Arm B (P=0.42). There was no difference in OS between the two arms (263 vs. 195days; P=0.62). Grade 3 or higher adverse events were infrequent, but more common in the combination arm with respect to diarrhea (17% vs. 2%), nausea (7% vs. 0%), and febrile neutropenia (21% vs. 5%); grade 3 or higher anemia was more frequent in arm B (7% vs. 27%). PIK3CA mutations or PTEN loss were infrequently observed. The addition of PX-866 to docetaxel did not improve PFS, RR, or OS in patients with advanced, refractory HNSCC without molecular pre-selection.

Palliative chemotherapy in head and neck squamous cell cancer - What is best in Indian population? A time without symptoms, treatment toxicity score based study

Background:Patients with recurrent and metastatic head and neck Squamous Cell Cancer (HNSCC) have poor prognosis with limited treatment options. In view of decimal prognosis, the treatment decision should include quality of life (QOL) issues, cost-effectiveness besides the response rates and survival.Aim:Present retrospective analysis was conducted to evaluate efficacy (disease-free survival), pharmacoeconomics, and toxicity profile of four (4) different regimens, viz. gefitinib alone, gefitinib with methotrexate, methotrexate alone, or 5-FU with cisplatin.Materials and Methods:Case records between 2007 September and 2008 September were analyzed, 68 patients were found suitable for analysis. Patients received gefitinib (250 mg/day), methotrexate as 50 mg intramuscular weekly or a combination of the same or 5-FU 750 mg/m2/day for 4 days along with cisplatin 75 mg/m2/day on day 1 in 21-day cycle.Results:A total of 68 patients received therapy. Fifty-one patients have clinically meaningful response (stable disease + complete + partial responses) (75%) and had symptomatic improvement. The median progression-free survival was significantly superior in responders (those who achieved partial or complete response) (8.4 months vs. 3.1 months, P=0.001). Methotrexate with gefitinib had maximum median survival and better overall QOL compared to the other treatment regimens. Weekly methotrexate is relatively cost-effective followed by methotrexate with gefitinib and gefitinib alone. 5-FU with cisplatin in our experience does not appear so attractive in view of high complication rates (when given in full doses) and prolonged hospital stay.Conclusion:Based on the results of this retrospective analysis, methotrexate weekly as single agent or in combination with gefitinib appears as an attractive alternative regimen for patients with metastatic HNSCC including those having poor performance status. A prospective study was planned and submitted to the local ethics committee based on above results to validate these results and compare methotrexate and gefitinib arm with 5-FU + cisplatin.

A Randomized Phase II Study of Cetuximab Every 2 Weeks at Either 500 or 750 mg/m2for Patients With Recurrent or Metastatic Head and Neck Squamous Cell Cancer

Cetuximab is typically administered on a weekly schedule for patients with recurrent or metastatic head and neck squamous cell cancer (HNSCC). This study explores cetuximab administered every 2 weeks (q2w). In this multicenter randomized prospective phase II study, eligible patients (≤2 prior cytotoxic chemotherapy regimens for recurrent or metastatic disease; ECOG performance status ≤2) were randomized to receive cetuximab q2w at 500 mg/m(2) (Group A) or 750 mg/m(2) (Group B). The primary end point was response rate (RECIST 1.0). Sixty-one patients were enrolled: 35 in Group A and 26 in Group B, which was closed early for lack of efficacy. Confirmed partial response rates were 11% for Group A (4/35) and 8% for Group B (2/26) according to intention to treat analysis. Partial responses occurred only among patients whose primary tumors were in the oral cavity or larynx. Median progression-free survival (PFS) and median overall survival (OS) were similar for both groups (PFS, 2.2 and 2.0 months; OS, 7.0 and 9.4 months; Groups A and B, respectively). The most common cetuximab-related adverse events (all grades) among treated subjects included rash, fatigue, and hypomagnesemia. Cetuximab, 500 mg/m(2), q2w achieves similar efficacy as conventional dosing for patients with recurrent or metastatic HNSCC. Escalating the dose to 750 mg/m(2) q2w offers no obvious therapeutic advantage.

Safety and feasibility of every‐other‐week maintenance cetuximab after first‐line chemotherapy in patients with recurrent or metastatic head and neck squamous cell cancer

In patients with recurrent and/or metastatic head and neck squamous cell cancer (HNSCC), there are no data about an every-other-week cetuximab maintenance schedule after chemotherapy plus cetuximab as first-line treatment. We reviewed the safety and feasibility of every-other-week maintenance cetuximab administered at 3 different European centers. Thirty-one patients with recurrent or metastatic HNSCC were treated from 2006 to 2010. Mean cetuximab dose intensity in the maintenance phase was 93%. The major toxicities reported during every-other-week maintenance cetuximab were skin rash (grade 3, 16%; grade 2, 23%), fatigue (grade 3, 3%; grade 2, 16%), diarrhea (grade 3, 7%; grade 2, 13%), hypomagnesemia (grade 4, 3%; grade 3, 3%; grade 2, 19%), and mucositis (grade 3, 3%; grade 2, 23%). Every-other-week maintenance cetuximab schedule was well tolerated and did not worsen toxicity that occurred during chemotherapy. In daily practice, this simplified schedule could improve compliance and possibly improve quality of life in patients with recurrent or metastatic HNSCC that showed no progression during first-line chemotherapy.

A phase 2 study of pemetrexed plus gemcitabine every 2 weeks for patients with recurrent or metastatic head and neck squamous cell cancer

Preclinical studies suggest that additive or synergistic effects are achieved with the combination of pemetrexed plus gemcitabine. A phase 1 study of pemetrexed plus gemcitabine given every 2 weeks demonstrated encouraging preliminary efficacy against head and neck squamous cell cancer (HNSCC). This was an open-label, single-institution, single-arm, phase 2 study for patients who had received no more than 2 cytotoxic regimens for recurrent and/or metastatic HNSCC. All patients received pemetrexed 500 mg/m² intravenously plus gemcitabine 1250 mg/m² intravenously every 2 weeks with vitamin B12 and folate support. The primary endpoint was the objective response rate according to Response Evaluation Criteria in Solid Tumors (RECIST); secondary endpoints were to estimate overall survival and to evaluate safety and tolerability. Twenty-five patients received therapy. All patients had received prior radiotherapy, and half had received prior cytotoxic chemotherapy for recurrent and/or metastatic disease. Neutropenia (grade ≥ 3) occurred in 24% of patients. Four patients (16%) had a partial response (PR) according to RECIST, and 5 additional patients (20%) had objective tumor reductions of > 20 but < 30% did not meet RECIST criteria for a PR. The median overall survival for all treated patients was 8.8 months. Treatment with pemetrexed plus gemcitabine every 2 weeks with vitamin support generally was well tolerated. The results of this study provided further evidence that pemetrexed may have significant palliative activity against advanced HNSCC.

A phase II study of pemetrexed (P) plus gemcitabine (G) in patients with recurrent or metastatic (R/M) head and neck squamous cell cancer (HNSCC).

5554 Background: Pemetrexed yielded an objective response rate of 26.5% in a phase II study for patients (pts) with locally advanced or metastatic HNSCC (Br J Ca 2001;85:649). Pemetrexed plus gemcitabine has demonstrated evidence of additive or synergistic antitumor effects in preclinical models, and encouraging efficacy against HNSCC (CCR 2008;14:6310) in a phase I study that evaluated an every two week schedule of these agents Methods: This was a single-institution, single-arm, open-label phase II study. Eligible pts had R/M HNSCC, Karnofsky score ≥70, and adequate hematologic, metabolic and renal function. No more than 2 prior cytotoxic regimens for R/M HNSCC were allowed. The study regimen was pemetrexed 500 mg/m2 intravenously (IV) plus gemcitabine 1,250 mg/m2 IV every two weeks, with vitamin B12 and folate support. Objective response rate by RECIST criteria was the primary endpoint (target response rate ≥30%); secondary endpoints were overall survival and safety/tolerability Results: 26 pts were enrolled: all had received prior radiotherapy; half prior cytotoxic chemotherapy for R/M disease. Among 25 pts who received therapy, there were no grade 5 events; ≥grade 3 toxicities occurring in >20% of pts included neutropenia (24%), lymphopenia (84% [64% grade 3]), and anemia (24%). The RECIST partial response (PR) rate was 16% (4/25); there were no complete responses. Five additional patients (20%) experienced objective tumor reductions of >20% but <30% (but <RECIST PR). Median overall survival was 8.8 months Conclusions: The outlined regimen of pemetrexed plus gemcitabine is feasible and has an acceptable side effect profile in pts with R/M HNSCC, but the observed response rate was less than our desired target. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Lilly

Phase I study of pemetrexed in recurrent/metastatic head and neck squamous cell cancer (HNSCC) and to assess the need for steroid premedication

e17009 Background: Pemetrexed is a novel antimetabolite that inhibits both purine and pyrimidine biosynthesis. Because its mechanism of action is similar to that of both methotrexate and 5-FU, it may also have activity in recurrent/metastatic HNSCC, a disease with limited treatment options and very poor median survival. Pemetrexed is traditionally prescribed with steroids due to skin toxicities observed in early studies; however vitamin supplementation (B12 and folic acid) was not standard at the time of those studies. No study to date has evaluated the optimal use of steroids with pemetrexed in the era of vitamin supplementation. Methods: All patients had metastatic or recurrent HNSCC, were treated with at least one prior chemotherapy regimen, and had ECOG PS of 0–2. The first cohort of patients received pemetrexed 500 mg/m2 every 3 weeks and the next receiving 600 mg/m2 based on a predefined standard dose escalation design. Within each dose level, patients were randomized to one of 3 premedication regimens: no dexamethasone, 20 mg IV on day 1, or standard 4 mg orally bid for 3 days. All patients received vitamin supplementation. The primary endpoint of the study was to determine the maximum tolerated dose of pemetrexed based on steroid premedication. Results: From October 2005 to March 2008, 36 patients were enrolled and 31 were available for evaluation. Median age was 57 years (range 42–82). 51.5% of patients had more than one prior chemotherapy regimens, 81.8% of patients had prior radiation therapy, and 48.5% of patients had prior surgery. Incidence of rash and combined skin toxicities were: 1/11 (9%) and 3/11 (27%) of patients without steroids, 1/11 (9%) and 3/11 (27%) with single IV dose, and 4/9 (44%) and 5/9 (55%) with oral steroids. No treatment-related grade 3 toxicities were observed. One patient initially received no steroid and required dose reduction and addition of steroid due to grade 2 rash. A partial response was observed in one patient (3.2%), and stable disease in 8 patients (25.8%) for a disease control rate of 29%. Conclusions: This is the first study to report the role of steroids as a premedication for pemetrexed. Our data suggests that no steroid premedication is needed with pemetrexed and vitamin supplementation. [Table: see text]

EGFR-Targeting Monoclonal Antibodies in Head and Neck Cancer

The epidermal growth factor (EGFR) and its receptor were discovered nearly 40 years ago. Over the past decade interruption of this pathway has been exploited in the treatment of various solid tumors. Antibodies that interfere with ligand binding to and dimerization of the EGFR (and small molecules that inhibit the EGFR tyrosine kinase) are anti-proliferative, profoundly radiosensitizing, and synergistic with DNA-damaging cytotoxic agents. Proposed mechanisms of radio- and chemosensitization include enhanced apoptosis, interference with DNA repair and angiogenesis, receptor depletion from the cell surface and antibody-dependent cell-mediated cytotoxicity. This article provides a reader with a comprehensive review of EGFR-targeting antibodies under development for the treatment of head and neck squamous cell cancer (HNSCC) and also summarizes relevant clinical data in this disease with small molecule EGFR inhibitors. One of the monoclonal antibodies, cetuximab, recently received full FDA approval for the treatment of patients with locally advanced (with radiation) or metastatic HNSCC (as a single agent). Regulatory approval followed reporting of a large international study in which the addition of cetuximab to definitive radiation therapy in HNSCC resulted in statistically significant improvements in locoregional control and overall survival. Results of the pivotal trial, other clinical data supporting the regulatory approval, and a preview of the next generation of clinical trials are presented. Considerable work remains to be done, particularly to enhance our understanding of factors that may predict for favorable response to EGFR inhibitor therapy and to evaluate the impact of integrating anti-EGFR therapies into complex chemoradiation programs delivered with curative intent.

A phase I dose escalation study of pemetrexed in patients with advanced head and neck squamous cell cancer (HNSCC)

6055 Background: Despite recent advances in therapy, patients (pts) with recurrent or metastatic HNSCC continue to demonstrate a poor median survival. In these pts, early trials with pemetrexed, a novel antimetabolite that acts upon several enzymes involved in pyrimidine and purine synthesis, have demonstrated promising efficacy and tolerability. Prior studies found that the administration of oral dexamethasone with pemetrexed reduced the incidence of skin rash. Later, vitamin supplementation (B12 and folic acid), given in addition to the dexamethasone, further diminished side effects. However, no trial has yet evaluated the appropriate steroid dose and its relation to the dosing of pemetrexed, in the setting of vitamin supplementation. We conducted a phase I trial to determine the maximum tolerated dose, toxicity, and preliminary efficacy of pemetrexed when given with different schedules of, or in the absence of, dexamethasone in pts with advanced HNSCC who had been treated with at least one or more chemotherapy regimens. Methods: Eligible pts had metastatic or recurrent HNSCC, prior treatment with one or more chemotherapy regimens, ECOG PS =2, and life expectancy &gt;3 months. A conventional algorithm-based dose escalation design was applied, with three predefined dose levels (DL) of pemetrexed (500 mg/m2, 600 mg/m2, and 700 mg/m2) within each schedule of dexamethasone (none, 20 mg IV on day 1, and 4 mg orally bid for 3 days). Results: A total of 23 pts have been enrolled; 18 pts were evaluable. Median age was 57 years (range 47–82). Median ECOG PS was 1 (range 0–2), and 75% of pts were male. Number of prior chemotherapy regimens were as follows: 1 (40%), 2 (35%), 3 (15%), and 4 (10%). Preliminary data demonstrated only 2 treatment-related adverse events that were grade 3 or greater: anemia (DL1) and pneumonia (DL 1). In all, 13 pts have received pemetrexed with less than standard recommended dexamethasone dosing (none or IV), including 7 pts who received no dexamethasone. Of the 18 evaluable pts, 1 pt had a partial response and 2 pts had stable disease. Conclusions: This represents the first study that demonstrates that steroids may not be required as premedication with pemetrexed. Due to the limited toxicity observed, trial enrollment continues with dose escalation. [Table: see text]