Hyper-late major response after 5†years of nivolumab: role of treatment beyond progression in head and neck cancer.

Patients with recurrent/metastatic (R/M) platinum-refractory squamous cell carcinoma of the head and neck (SCCHN) have fewer treatment options and harbor an especially poor prognosis. Maintaining treatment with anti-PD1 agents beyond response evaluation criteria in solid tumors-defined disease progression (TBP) has been shown to be efficacious in several solid tumors, including head and neck cancer. We present the case of a platinum-refractory locally recurrent, PD-L1-negative hypopharyngeal carcinoma, that received second-line nivolumab which was then maintained beyond progression under the following criteria: no Eastern Cooperative Oncology Group performance status deterioration, no rapidly progressive disease, no severe toxicity, and evidence of overall treatment benefit. The patient achieved a partial response 8 months after starting second-line nivolumab, with progressive disease at 26 months, then followed by the first TBP with nivolumab lasting for 15 months due to a new tumor progression. A second TBP with nivolumab lasting for 7 months, was followed by a third TBP with nivolumab for 12 months and achieving a major tumor response. Treatment is still ongoing 60 months after starting nivolumab, with excellent tolerance to therapy. Maintaining anti-PD1 agents beyond progression is an efficacious treatment option for patients with R/M SCCHN, that may achieve very durable disease control and even late major responses.

Plasma ctDNA Monitoring of a PTCH1-Mutant Metastatic Adult Medulloblastoma Showing a Durable Benefit With Vismodegib.

Adult medulloblastoma (MB) is a rare disease affecting 0.6 persons per million adults over 19 years of age. The SHH-activated/TP53-wild type is the most common subtype, accounting for 60% of adult MBs, being characterized by mutations in PTCH1, SMO, or the TERT promoter. Several small studies demonstrate objective but short-lived responses to SMO inhibitors such as vismodegib or sonidegib. Like other oncogene-addicted solid tumors, detection of the corresponding drivers through liquid biopsy could aid in the molecular diagnosis and monitoring of the disease through less invasive procedures. However, most studies have only evaluated cerebrospinal fluid as the ctDNA reservoir, and very limited evidence exists on the role of liquid biopsy in plasma in patients with primary central nervous system tumors, including MB. We present the case of a 26-year-old patient with a recurrent MB, in which next-generation sequencing (FoundationOne CDx) revealed a mutation in PTCH1, allowing the patient to be treated with vismodegib in second line, resulting in a durable benefit lasting for 1 year. Using an in-house digital PCR probe, the PTCH1 mutation could be tracked in ctDNA during treatment with first-line chemotherapy and while on treatment with vismodegib, demonstrating a precise correlation with the radiological and clinical behavior of the disease.

Major and durable responses to photon and electron-beam palliative radiotherapies after immune-checkpoint inhibitors in head and neck cancer.

BACKGROUND: The immuno-modulatory effects of ionizing radiation are well-known and preclinical studies suggest a synergistic effect of combining radiotherapy (RT) and IO. However, data regarding the clinical activity and safety of this approach are limited. METHODS: We present the cases of two patients with SCCHN primary progressing to PDL1-based IO within a clinical trial (NCT03383094), that received subsequent but not concurrent palliative RT using two different modalities (electron beam and photon beam therapies). RESULTS: Both patients achieved major and durable responses at 4 irradiated sites, with excellent tolerance and no grade ≥ 3 toxicities. Complete response occurred in 3 of the disease areas (all locoregional) and partial response in 1 metastatic lesion. CONCLUSION: Palliative radiotherapy after progression to IO was safe and demonstrated profound and durable responses in the cases presented.

Clinical Behavior, Mutational Profile and T-Cell Repertoire of High-Grade Neuroendocrine Tumors of the Head and Neck.

Neuroendocrine carcinomas (NECs) of the head and neck (HN) account for <1% of HN cancers (HNCs), with a 5-year overall survival (OS) <20%. This is a retrospective study of HN NECs diagnosed at our institution between 2005 and 2022. Immunohistochemistry and next-generation sequencing (NGS) were used to evaluate neuroendocrine markers, tumor mutational burden (TMB), mutational profiles and T-cell receptor repertoires. Eleven patients with high-grade HN NECs were identified (male:female ratio 6:5; median age 61 (Min-Max: 31-86)): nasoethmoidal (3), parotid gland (3), submaxillary gland (1), larynx (3) and base of tongue (1). Among n = 8 stage II/IVA/B, all received (chemo)radiotherapy with/without prior surgery or induction chemotherapy, with complete response in 7/8 (87.5%). Among n = 6 recurrent/metastatic patients, three received anti-PD1 (nivolumab (2), pembrolizumab (1)): two achieved partial responses lasting 24 and 10 months. After a median follow-up of 30 and 23.5 months since diagnosis and since recurrent/metastatic, median OS was not reached. Median TMB (n = 7) was 6.72 Mut/Mb. The most common pathogenic variants were TP53, HNF1A, SMARCB1, CDKN2A, PIK3CA, RB1 and MYC. There were 224 median TCR clones (n = 5 pts). In one patient, TCR clones increased from 59 to 1446 after nivolumab. HN NECs may achieve long-lasting survival with multimodality treatment. They harbor moderate-high TMBs and large TCR repertoires, which may explain responses to anti-PD1 agents in two patients and justify the study of immunotherapy in this disease.

Durable complete remission with local therapies after neoadjuvant and adjuvant nivolumab in recurrent/metastatic head and neck cancer.

Up to 10-15% of patients with first-line recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) present with platinum-refractory disease. The anti-PD1 nivolumab is the first therapeutic option in this setting achieving a 19.2% objective response rate and a 7.7-month median overall survival (OS). Given the poor prognosis of platinum-refractory patients, those showing slow progressive disease with no functional status deterioration should maintain nivolumab beyond progression in the absence of severe or unmanageable toxicities. Another strategy is to use local therapies such as radiotherapy and surgical tumor resection in cases of oligometastatic or oligoprogressive disease. Both strategies may significantly improve disease control and OS in these populations. We present the case of a patient with platinum-refractory disease treated with first-line nivolumab beyond progression who achieved a durable complete response after palliative radiation and surgical resection of five tumor lesions. To our knowledge, this is the first reported case of an R/M HNSCC treated with such a strategy outside a clinical trial and contributes to the evidence for combining anti-PD1 agents and local therapies in selected patients with R/M HNSCC.

Safety and preliminary activity of pembrolizumab-carboplatin-paclitaxel in heavily pretreated and/or fragile patients with PDL1-positive recurrent/metastatic head and neck cancer.

Novel chemo-immunotherapy (chemo-IO) combinations should be evaluated, which may be suitable for cisplatin-unfit or fluoropyrimide-ineligible patients with recurrent or metastatic squamous cell carcinoma of head and neck (R/M SCCHN) to guarantee higher and deeper responses than IO alone. The aim of the present study was to review our experience using pembrolizumab-carboplatin-paclitaxel (pembro + CP) in patients with R/M SCCHN. This was a retrospective study of patients with R/M SCCHN who received pembro + CP in any-line via a compassionate-use program. The present study evaluated safety using Common Terminology Criteria for Adverse Events v4.0, compliance, overall response rate (ORR) and disease control rate (DCR) using Response Evaluation Criteria in Solid Tumors 1.1, duration of treatment, progression-free survival (PFS) and overall survival (OS). Between March 2020 and August 2021, 10 patients were identified (median age, 64 years; female, 60%; Eastern Cooperative Oncology Group 2, 80%). A total of 8 patients received pembro + 3-weekly carboplatin-paclitaxel (3wkCP). A total of 2 patients received pembro + weekly carboplatin-paclitaxel (wkCP). Patients received a median of 3 lines (range, 0-6) of systemic therapy prior to pembro + CP and 80% received IO in previous lines. Grade 1-2 adverse events (AEs) occurred in 100% of patients. Grade 3-5 AEs occurred in 30% of patients [all grade 3 (anemia, neutropenia, thrombopenia, hypertension)]. The mean numbers of pembro + wkCP and pembro + 3wkCP cycles were 2.5 and 6. The ORR (n=7) was 14% (1/7) with one complete response. The DCR was 43% (3/7). The median PFS (n=7) and OS (n=10) times since pembro + CP were 5 months (95% CI, 1-9) and 6 months (95% CI, 0.5-14), respectively. In this small retrospective series of heavily pretreated patients, pembro + CP was well tolerated, and compliance was high. Studies should be conducted to prospectively evaluate the safety and efficacy of this combination in patients with R/M SCCHN.

Paclitaxel Plus Cetuximab as Induction Chemotherapy for Patients With Locoregionally Advanced Head and Neck Squamous Cell Carcinoma Unfit for Cisplatin-Based Chemotherapy.

Objectives: Induction chemotherapy (ICT) followed by definitive treatment is an accepted non-surgical approach for locoregionally advanced head and neck squamous cell carcinoma (LA-HNSCC). However, ICT remains a challenge for cisplatin-unfit patients. We evaluated paclitaxel and cetuximab (P-C) as ICT in a cohort of LA-HNSCC patients unfit for cisplatin. Materials and Methods: This is a retrospective analysis of patients with newly diagnosed LA-HNSCC considered unfit for cisplatin-based chemotherapy (age >70 and/or ECOG≥2 and/or comorbidities) treated with weekly P-C followed by definitive radiotherapy and cetuximab (RT-C) between 2010 and 2017. Toxicity and objective response rate (ORR) to ICT and RT-C were collected. Median overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Cox regression analysis was performed to determine baseline predictors of OS and PFS. Results: A total of 57 patients were included. Grade 3-4 toxicity rate to ICT was 54.4%, and there was a death deemed treatment-related (G5). P-C achieved an ORR of 66.7%, including 12.3% of complete responses (CR). After P-C, 45 patients (78.9%) continued with concomitant RT-C. Twenty-six patients (45.6%) achieved a CR after definitive treatment. With a median follow-up of 21.7 months (range 1.2-94.6), median OS and PFS were 22.9 months and 10.7 months, respectively. The estimated 2-year OS and PFS rates were 48.9% and 33.7%, respectively. Disease stage had a negative impact on OS (stage IVb vs. III-IVa: HR = 2.55 [1.08-6.04], p = 0.03), with a trend towards worse PFS (HR = 1.92 [0.91-4.05], p = 0.09). Primary tumor in the larynx was associated with improved PFS but not OS (HR = 0.45 [0.22-0.92], p = 0.03, and HR = 0.69 [0.32-1.54], p = 0.37, respectively). Conclusion: P-C was a well-tolerated and active ICT regimen in this cohort of LA-HNSCC patients unfit for cisplatin-based chemotherapy. P-C might represent a valid ICT option for unfit patients and may aid patient selection for definitive treatment.

Durable benefit and change in TCR clonality with nivolumab in a Lynch syndrome-associated glioma.

Germline replication-repair deficient (gRRD) gliomas are exceptional events, and only a few of them have been treated with immune checkpoint inhibitors (ICIs). Contrary to sporadic gliomas, where ICIs have failed to show any objective benefit, the very few patients with gRRD gliomas treated with ICIs to date seem to benefit from programmed-death-1 (PD-1) inhibitors, such as nivolumab or pembrolizumab, either in terms of durable responses or in terms of survival. T-cell immunohistochemistry (IHC) and T-cell receptor (TCR) repertoire using high-throughput next-generation sequencing (NGS) with the Oncomine TCR-Beta-SR assay (Thermo Fisher Scientific) were analyzed in pre- and post-nivolumab tumor biopsies obtained from a patient with a Lynch syndrome-associated glioma due to a germline pathogenic hMLH1 mutation. The aim was to describe changes in the T-cell quantity and clonality after treatment with nivolumab to better understand the role of acquired immunity in gRRD gliomas. The patient showed a slow disease progression and overall survival of 10 months since the start of anti-PD-1 therapy with excellent tolerance. A very scant T-cell infiltrate was observed both at initial diagnosis and after four cycles of nivolumab. The drastic change observed in TCR clonality in the post-nivolumab biopsy may be explained by the highly spatial and temporal heterogeneity of glioblastomas. Despite the durable benefit from nivolumab, the scant T-cell infiltrate possibly explains the lack of objective response to anti-PD-1 therapy. The major change in TCR clonality observed after nivolumab possibly reflects the evolving molecular heterogeneity in a highly pre-treated disease. An in-deep review of the available literature regarding the role of ICIs in both sporadic and gRRD gliomas was conducted.

Liquid Biopsy in Head and Neck Cancer: Current Evidence and Future Perspective on Squamous Cell, Salivary Gland, Paranasal Sinus and Nasopharyngeal Cancers.

Head and neck cancer (HNC) is currently the sixth most common solid malignancy, accounting for a 50% five-year mortality rate. In the past decade, substantial improvements in understanding its molecular biology have allowed for a growing development of new biomarkers. Among these, the field of liquid biopsy has seen a sustained growth in HNC, demonstrating the feasibility to detect different liquid biomarkers such as circulating tumor DNA (ctDNA), circulating tumor cells (CTC), extracellular vesicles and microRNAs. Liquid biopsy has been studied in HPV-negative squamous cell carcinoma of the head and neck (SCCHN) but also in other subentities such as HPV-related SCCHN, EBV-positive nasopharyngeal cancer and oncogene-driven salivary gland cancers. However, future studies should be internally and externally validated, and ideally, clinical trials should incorporate the use of liquid biomarkers as endpoints in order to prospectively demonstrate their role in HNC. A thorough review of the current evidence on liquid biopsy in HNC as well as its prospects will be conducted.

Detection of IDH1 Mutations in Plasma Using BEAMing Technology in Patients with Gliomas.

Molecular testing using blood-based liquid biopsy approaches has not been widely investigated in patients with glioma. A prospective single-center study enrolled patients with gliomas ranging from grade II to IV. Peripheral blood (PB) was drawn at different timepoints for circulating tumour DNA (ctDNA) monitoring. Next-generation sequencing (NGS) was used for the study of isocitrate dehydrogenase 1 (IDH1) mutations in the primary tumor. Beads, Emulsion, Amplification and Magnetics (BEAMing) was used for the study of IDH1 mutations in plasma and correlated with the NGS results in the tumor. Between February 2017 and July 2018, ten patients were enrolled, six with IDH1-mutant and four with IDH1 wild-type gliomas. Among the six IDH-mutant gliomas, three had the same IDH1 mutation detected in plasma (50%), and the IDH1-positive ctDNA result was obtained in patients either at diagnosis (no treatment) or during progressive disease. While the false-negative rate reached 86% (18/21), 15 out of the 18 (83%) plasma-negative results were from PB collected from the six IDH-mutant patients at times at which there was no accompanying evidence of tumor progression, as assessed by MRI. There were no false-positive cases in plasma collected from patients with IDH1 wild-type tumors. BEAMing detected IDH1 mutations in the plasma of patients with gliomas, with a modest clinical sensitivity (true positivity rate) but with 100% clinical specificity, with complete agreement between the mutant loci detected in tumor and plasma. Larger prospective studies should be conducted to expand on these findings, and further explore the clearance of mutations in PB from IDH1-positive patients in response to therapy.

Neoadjuvant immunotherapy in head and neck cancer: Rationale, current evidence and future perspective.

Immune-checkpoint inhibitors (ICIs) have shown to improve survival in the first- and second-line settings of recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN). In the past two years more than a dozen neoadjuvant IO studies have been reported in SCCHN, demonstrating the feasibility of one or a few doses of single agent or combination ICIs. This approach seems safe with no surgical delays due to toxicity in most of the studies with no new safety signals. Efficacy in terms of pathologic response appears promising both with single-agent ICIs and especially with chemo-IO combinations. The scientific rationale and current clinical evidence of neoadjuvant IO trials in SCCHN will be reviewed, including currently debated aspects such as the methodology for radiological and pathological evaluation as well as types and criteria for biomarker use in this setting. Finally, the future perspective of neoadjuvant IO in SCCHN will be approached.

Major pathological response and durable locoregional control after neoadjuvant pembrolizumab-carboplatin-paclitaxel in head and neck cancer.

Head and neck cancers are increasingly being diagnosed in elderly patients, where standard curative-intent, therapeutic options are often too aggressive for frail, malnourished and heavily comorbid patients. Since the incorporation of immune checkpoint inhibitors (ICIs) a few small studies have reported promising safety and efficacy with ICIs in the neoadjuvant locally-advaced setting. We present the case of an elderly, frail and comorbid patient, with a high-PDL1 expressing and very locally-advanced unresectable oral cavity cancer, that was treated with the combination of pembrolizumab and weekly carboplatin and paclitaxel, achieving a major pathological response, that permitted to de-escalate adjuvant therapy after surgery and is free of locoregional relapse 7 months after surgery. This is, to our knowledge, the first patient treated with neoadjuvant chemo-immunotherapy outside a clinical trial in SCCHN.

Immunotherapy in microsatellite instability metastatic colorectal cancer: Current status and future perspectives.

BACKGROUND: Colorectal cancer (CRC) is one of the most frequent and deadly malignancies worldwide. This specific pathology is composed of various molecular entities, with distinct immunological phenotypes. In addition to KRAS, NRAS, and BRAF mutation status, other druggable alterations such as those in HER2, MET, NTRK, ALK, and ROS1 have been identified in recent years offering new therapeutic options for some patients with CRC. AIM: This review will focus on the molecular biology, immunological fingerprints, and current clinical evidence for the use of immunotherapy in patients with CRC. RELEVANCE FOR PATIENTS: High microsatellite instability (MSI-H) and mutations in mismatch repair genes constitute a new molecular entity within CRC, which is characterized by a high mutational and neoantigen burden, frequent immune cell infiltration, and where immune checkpoint inhibitors have shown high response and survival rates compared to microsatellite stable (MSS) tumors. Indeed, the approval of pembrolizumab in MSI-H tumors was the first agnostic FDA approval in solid tumors. While monotherapy with anti-programmed cell death protein-1 agents achieves objective response rates (ORR) of around 30% and 1-year overall survival (OS) rates of 76%, anti-PD1, and anti-CTLA4 combinations achieve a 55% ORR and a 1-year OS rate of 85%. Several ongoing trials are evaluating the use of different immunotherapy combinations, both in the advanced and early settings and in MSI-h and MSS CRCs.

Safety and Efficacy of Cetuximab-Based Salvage Chemotherapy After Checkpoint Inhibitors in Head and Neck Cancer.

BACKGROUND: There are still few data on the activity and safety of cetuximab-based salvage chemotherapy after immunotherapy (SCAI) in patients with squamous cell cancer of the head and neck (SCCHN). MATERIALS AND METHODS: This was a retrospective study of patients with SCCHN who received cetuximab-based SCAI after programmed cell death protein 1 or programmed cell death ligand 1(PD[L]1) inhibitors. Overall response rate (ORR) and disease control rate (DCR) with SCAI and with last chemotherapy before immunotherapy (LCBI) by RECIST 1.1, percentage change from baseline in target lesions (PCTL), progression-free survival (PFS), overall survival (OS), treatment compliance, and toxicity were evaluated. RESULTS: Between March 2016 and November 2019, 23 patients were identified. SCAI consisted of cetuximab-based combinations (3-weekly cisplatin-5FU-cetuximab [n = 2], weekly paclitaxel-cetuximab [n = 17], weekly cisplatin-cetuximab [n = 2], weekly carboplatin-paclitaxel-cetuximab [n = 2]). ORR was 56.5% (11 partial response, 2 complete response). DCR was 78.3%. Among 13 objective responders, median best PCTL was -53.5% (range, -30% to -100%). Median OS and PFS were 12 months and 6 months, respectively. In 10 patients receiving LCBI, ORR to LCBI was 40%, whereas ORR to SCAI achieved 60%. In LCBI-treated patients, median PFS with LCBI was 8 months and median PFS and OS with SCAI were 7 months and 12 months, respectively. Reduced dose intensity of the chemotherapy and cetuximab components occurred in 82.6% and 52.2% of the patients. Grade 1 or 2 adverse events (AEs) occurred in all patients. Grade 3 or 4 AEs developed in 65%, being grade 3 in all of them except in one patient (grade 4 neutropenia). There were no treatment-related deaths. CONCLUSION: Cetuximab-based salvage chemotherapy after PD(L)1 inhibitors associated with high response rates and deep tumor reductions with a manageable safety profile. Subsequent lines of therapy may explain the long survival achieved in our series. These results invite to design studies to elucidate the best therapeutic sequence in patients with SCCHN in the immunotherapy era. IMPLICATIONS FOR PRACTICE: Cetuximab-based salvage chemotherapy (SCAI) achieved high response rates in patients with recurrent/metastatic squamous cell cancer of the head and neck (SCCHN) after progression to PD-1/PD-L1 inhibitors. Objective response rate was higher than and progression-free survival was comparable to that of chemotherapy administered before immunotherapy (IO). In most patients, SCAI consisted of weekly, well-tolerated regimens. These observations have implications for current practice because of the limited evidence to date in SCCHN and the scant therapeutic options in this disease and invite to elucidate which may be the best treatment sequence for patients with head and neck cancer in the IO era.

Major and durable response to second-line pembrolizumab-carboplatin-paclitaxel in an oral cavity cancer patient.

Many patients with recurrent/metastatic squamous cell cancer of the head and neck (SCCHN) are old or fragile and, despite deserving rapid and deep responses due to symptoms or a high tumor burden, they are not candidates for the current standard in the first-line setting of pembrolizumab plus platinum-5-FU. Other chemoimmunotherapy combinations substituting the 5-FU infusion by a taxane, may allow for less toxic effects without the need for a central venous catheter placement while maintaining efficacy. We present the case of an oral cavity cancer progressing with bulky disease to first-line cetuximab-paclitaxel in a frail and malnourished patient, where second-line treatment with pembrolizumab and reduced-dose 3-weekly carboplatin-paclitaxel achieved a deep and durable response. This is, to our knowledge, the first reported case of such combination being used in the R/M setting of SCCHN. Clinical trials should try to investigate the feasibility of this potentially less toxic and convenient combination in patients with SCCHN.

Personalizing first-line treatment in advanced colorectal cancer: Present status and future perspectives.

BACKGROUND: Colorectal cancer is one of the most frequent neoplasms worldwide, and the majority of patients are diagnosed in advanced stages. Metastatic colorectal cancer (mCRC) harbors several mutations with different prognostic and predictive values; KRAS, NRAS, and BRAF mutations are the best known. Indeed, RAS and BRAF molecular status are associated with a different response to monoclonal antibodies (Anti-epidermal growth factor receptor and anti-vascular endothelial growth factor receptor agents), which are usually added to chemotherapy in first-line, and thus allow to select the optimal therapy for patients with mCRC. Furthermore, sidedness is an important predictive and prognostic factor in mCRC, which is explained by the different molecular profile of left and right-sided tumors. Recently, microsatellite instability-high has emerged as a predictive factor of response and survival from immune checkpoint inhibitors in mCRC. Finally, several other alterations have been described in lower frequencies, such as human epidermal growth factor receptor-2 overexpression/amplification, PIK3CA pathway alterations, phosphatase and tension homolog loss, and hepatocyte growth factor/mesenchymal-epithelial transition factor pathway dysregulation, with several targeted therapies already demonstrating activity or being tested in currently ongoing clinical trials. AIM: To review the importance of studying the predictive and prognostic roles of the molecular profile of mCRC, the changes occurred in recent years and how they would potentially change in the near future, to guide physicians in treatment decisions. RELEVANCE FOR PATIENTS: Today, several different therapeutic options can be offered to patients in the first-line setting of mCRC. Therapies at present approved or under investigation in clinical trials will be thoroughly reviewed, with special emphasis on the molecular rationale behind them. Understanding the molecular status, resistance mechanisms and potential new druggable targets may allow physicians to choose the best therapeutic option in the first-line mCRC.