Patients with platinum-refractory head and neck cancer had significantly longer survival with nivolumab treatment than with standard, single-agent therapy. Response rates were also higher and quality ...of life maintained longer with nivolumab.
Squamous-cell carcinoma of the head and neck is a major cause of cancer-associated illness and death, with more than 600,000 cases diagnosed annually worldwide.
1
Most patients present with locoregionally advanced disease, and more than 50% have recurrence within 3 years.
2
–
4
Patients with squamous-cell carcinoma of the head and neck who have cancer progression within 6 months after platinum-based chemotherapy administered in the context of primary or recurrent disease have a median survival of 6 months or less.
5
No therapeutic options prolong survival among these patients.
5
,
6
The recurrence and metastasis of squamous-cell carcinoma of the head and neck are . . .
•SalvGlandDx includes 27 genes known to be involved in salivary gland neoplasms•Can be applied to FFPE histological and cytological (cell block) specimen•Solely RNA extraction is needed•Gene fusions, ...hotspot mutations and gene expression levels can be detected•Guides diagnosis in uncertain cases and can detect therapeutically relevant fusions
Diagnosis of salivary gland neoplasms is often challenging due to their high morphological diversity and overlaps. Several recurrent molecular alterations have been described recently, which can serve as powerful diagnostic tools and potential therapeutic targets (e.g. NTRK or RET fusions). However, current sequential molecular testing can be expensive and time consuming. In order to facilitate the diagnosis of salivary gland neoplasms, we designed an all-in-one RNA-based next generation sequencing panel suitable for the detection of mutations, fusions and gene expression levels (including NR4A3) of 27 genes involved in salivary gland neoplasms. Here we present the validation of the “SalvGlandDx” panel on FFPE histological specimen including fine needle aspiration (FNA) cell block material, against the standard methods currently used at our institution. In a second part we describe selected unique cases in which the SalvGlandDx panel allowed proper diagnosis and new insights into special molecular characteristics of selected salivary gland tumors. We characterize a unique salivary gland adenocarcinoma harboring a ZCCHC7-NTRK2 fusion, a highly uncommon spindle cell and pseudoangiomatoid adenoid-cystic carcinoma with MYBL1-NFIB fusion, and a purely oncocytic mucoepidermoid carcinoma, whereas diagnosis could be made by detection of a CRTC3-MAML2 rearrangement on the cell block specimen of the FNA. Further, a rare case of a SS18-ZBTB7A rearranged low-grade adenocarcinoma previously described as potential spectrum of microsecretory adenocarcinoma, is reported. In addition, features of six cases within the spectrum of polymorphous adenocarcinoma / cribriform adenocarcinoma of salivary gland including PRKD1 p.E710D mutations and novel fusions involving PRKAR2A-PRKD1, SNX9-PRKD1 and ATL2-PRKD3, are described.
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6505
Background: 1L P vs E improved OS in PD-L1 CPS ≥20 and CPS ≥1 populations, and led to noninferior OS in the total population, with favorable safety; 1L P+C vs E had superior OS in ...CPS ≥20, CPS ≥1, and total populations with comparable safety in the phase 3 KEYNOTE-048 study (NCT02358031) in patients with R/M HNSCC. Neither P vs E nor P+C vs E improved PFS in the PD-L1 CPS ≥20, CPS ≥1, or total populations. Here, we present the progression after the next line of therapy (PFS2) to assess the effect of 1L P or P+C and subsequent anticancer therapy on patient outcomes. Methods: Patients with locally incurable R/M HNSCC and no prior systemic therapy in the R/M setting were randomly assigned 1:1:1 to P, P+C, or E. PFS2 was defined as time from randomization to objective tumor progression on next-line therapy or death from any cause. PFS2 was estimated using the Kaplan-Meier method as an exploratory outcome confined to those receiving subsequent therapy after 1L P. HR and 95% CIs were based on a Cox regression model with Efron’s method of tie handling with treatment as a covariate (stratified by ECOG performance status PS, HPV status, and PD-L1 for CPS ≥1 and total populations; by ECOG PS and HPV status for CPS ≥20 population). Data cutoff: Feb 25, 2019. Results: Of 882 (301 P; 281 P+C; 300 E) treated patients,422 (P: 148 49.2%; P+C: 115 40.9%; E: 159 53.0%) received subsequent anticancer therapy after 1L P, most commonly C (P: 135 44.9%; P+C: 88 31.3%; E: 102 34.0%); EGFR inhibitor (P: 59 19.6%; P+C: 37 13.2%; E: 19 6.3%); and immune checkpoint inhibitor (P: 6 2.0%; P+C: 12 4.3%; E: 50 16.7%); patients may have received more than one type of subsequent therapy. Median PFS2 is reported in Table. Conclusions: In patients with R/M HNSCC, longer median PFS2 was observed in the CPS ≥20 and CPS ≥1 populations for P vs E, and in the CPS ≥20, CPS ≥1, and total populations for P+C vs E. These data further support use of 1L P or P+C in patients with R/M HNSCC. Clinical trial information: NCT02358031 . Table: see text
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6000
Background: KEYNOTE-048 is a phase 3 study of P or P + chemo (C) vs EXTREME (E) as 1L therapy for R/M HNSCC (NCT02358031). At the second interim analysis (IA2), P significantly ...improved OS in the PD-L1 combined positive score (CPS) ≥20 and ≥1 populations and had noninferior OS in the total population with favorable safety; P+C significantly improved OS in the total population with comparable safety. We present the protocol-specified final results. Methods: 882 pts with locally incurable R/M HNSCC and no prior systemic therapy in the R/M setting who provided a tumor sample for PD-L1 testing were randomized to P 200 mg Q3W for 24 mo (n = 301), P for 24 mo + 6 cycles of C (cisplatin 100 mg/m
2
or carboplatin AUC 5 Q3W + 5-FU 1000 mg/m
2
/d for 4 d Q3W) (n = 281), or E (cetuximab 400 mg/m
2
loading/250 mg/m
2
QW + 6 cycles of chemo) (n = 300). OS superiority was tested sequentially for P+C vs E in the CPS ≥20 population, then the CPS ≥1 population, and for P vs E in the total population (superiority thresholds: one-sided P = .0023, .0026, and .0059, respectively). Data cutoff was 25 Feb 2019 (~25 mo after last pt randomized). Results: P+C significantly improved OS vs E in the CPS ≥20 (HR 0.60, 95% CI 0.45-0.82, P = .0004; median 14.7 vs 11.0 mo) and CPS ≥1 (HR 0.65, 95% CI 0.53-0.80, P < .0001; median 13.6 vs 10.4 mo) populations. HR (95% CI) for PFS was 0.76 (0.58-1.01) for CPS ≥20 and 0.84 (0.69-1.02) for CPS ≥1. ORR (P+C vs E) was 42.9% vs 38.2% for CPS ≥20 and 36.4% vs 35.7% for CPS ≥1; median DOR was 7.1 vs 4.2 mo and 6.7 vs 4.3 mo, respectively. P did not significantly improve OS vs E in the total population (HR 0.83, 95% CI 0.70-0.99, P = .0199; median 11.5 vs 10.7 mo). HR (95% CI) for PFS was 1.29 (1.09-1.53). ORR (P vs E) was 16.9% vs 36.0%; median DOR was 22.6 vs 4.5 mo. All-cause gr 3-5 AE rates were 54.7% for P, 85.1% for P+C, and 83.3% for E. Conclusion: Overall, KEYNOTE-048 showed that compared with E, P+C had superior OS in the PD-L1 CPS ≥20, CPS ≥1, and total populations with comparable safety and P had superior OS in the CPS ≥20 and ≥1 populations, noninferior OS in the total population, and favorable safety. These results support pembrolizumab and pembrolizumab + platinum + 5-FU as new 1L standards of care for R/M HNSCC. Clinical trial information: NCT02358031.
Metastatic extramammary Paget’s disease is a rare adenocarcinoma with poor prognosis. Several reports of human epidermal growth factor receptor 2 alterations point to its pathogenic role in the ...disease. However, the occurrence of treatment resistance to anti-HER2 therapy demand the need for further knowledge. We report of a patient with metastatic penoscrotal extramammary Paget’s disease, with an
ERBB2
S310F
mutation, in which near complete response was achieved upon treatment with trastuzumab and carboplatin. However, after 10 cycles of trastuzumab and carboplatin, widespread metastasis re-occurred. Analysis of a newly developing metastasis revealed additional genomic alterations including ERBB3
A232V
and
PIK3CA
G106V
point mutations as well as
MET
and
CDK6
amplification, providing a potential mechanism of acquired treatment resistance. Therefore,
ERBB
family inhibitor afatinib was initiated. Unfortunately, the patient succumbed to disease-related complications shortly after treatment initiation. This is the first report of
ERBB2
S310F
mutated, metastatic extramammary Paget’s disease with secondary resistance to trastuzumab / carboplatin, potentially due to additional acquired genomic alterations. This case contributes to the growing evidence of HER2 in the pathogenesis of metastatic extramammary Paget’s disease and emphasizes the importance of repetitive, genomic analysis in rare diseases.
Pathologic response to neoadjuvant chemotherapy (neoCTX) is a prognostic factor in many cancer types, and early prediction would help to modify treatment. In patients with gastric and esophagogastric ...junction (AEG) cancer, the accuracy of FDG PET-CT to predict early pathologic response after neoadjuvant chemotherapy (neoCTX) is currently not known. From a consecutive cohort of 72 patients, 44 patients with resectable, locally-advanced gastric cancer or AEG Siewert type II and III received neoCTX after primary staging with endoscopic ultrasound, PET-CT and laparoscopy. Overall, 14 patients did not show FDG uptake, and the remaining 30 were restaged by PET-CT 14 days after the first cycle of neoCTX. Metabolic response was defined as decrease of tumor standardized uptake value (SUV) by greater than or equai to35%. Major pathologic regression was defined as less than 10% residual tumor cells. Metabolic response after neoCTX was detected in 20/30 (66.7%), and non-response in 10/30 (33.3%) patients. Among metabolic responders, n = 10 (50%) showed major and n = 10 (50%) minor pathologic regression. In non-responders, n = 9 (90%) had minor and 1 (10%) a major pathologic regression. This resulted in a sensitivity of 90.9%, specificity 47.3%, positive predictive value 50%, negative predictive value 90% and accuracy of 63.3%. Response PET-CT after the first cycle of neoCTX does not accurately predict overall pathologic response. However, PET-CT reliably detects non-responders, and identifies patients who should either immediately proceed to resection or receive a modified multimodality therapy.
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6019
Background: In CheckMate 141, a randomized, phase 3 trial, nivo demonstrated superior overall survival (OS) and better tolerability in patients (pts) with PR R/M SCCHN compared ...with IC. Pts with SCCHN progressing within 6 mos of platinum in the primary treatment setting have dismal prognosis. We report outcomes in pts who were PR in the primary or adjuvant setting, and updated results in the overall population. Methods: Pts (N = 361) with PR R/M SCCHN were randomized 2:1 to nivo 3 mg/kg every 2 weeks or weekly IC (methotrexate, docetaxel, or cetuximab). Primary endpoint was OS estimated by Kaplan-Meier method. Cox proportional hazards models were used to estimate hazard ratios (HRs) and confidence intervals (CIs). Additional endpoints include objective response rate (ORR) and safety. Outcomes were analyzed overall and post hoc in pts who were PR in the primary/adjuvant setting and received nivo/IC as 1L R/M therapy. Results: Characteristics of the 78 (21.6%) pts who received nivo (n = 52) or IC (n = 26) in the 1L R/M setting were similar to the overall population.Nivo significantly improved OS vs IC among 1L R/M pts (median 95% CI: 7.7 mo 3.1, 13.8 vs 3.3 mo 2.1, 6.4; HR 95% CI = 0.56 0.33, 0.95); 12-mo OS rate: 39.2% vs 15.4%. ORR was 19.2% for nivo vs 11.5% for IC in this subgroup. At 11.4-mo minimum follow-up, updated efficacy and safety in the overall population were similar to the primary analysis. Median OS (95% CI) was 7.7 mo (5.7, 8.8) for nivo vs 5.1 mo (4.0, 6.2) for IC; HR (95% CI) = 0.71 (0.55, 0.90); P = 0.0048. For nivo vs IC, the 18-mo OS rate was 21.5% vs 8.3% and ORR was 13.3% vs 5.8%. Nivo doubled the median duration of response vs IC (9.7 vs 4.0 mo). Grade 3–4 treatment-related adverse event rates for nivo vs IC were 15.3% vs 36.0% overall and 27.5% vs 32.0% for 1L R/M pts; there were no new deaths due to study drug toxicity. Conclusions: Nivo significantly improved OS and increased ORR vs IC in a 1L R/M subgroup, supporting its use as 1L therapy for pts with PR R/M SCCHN. Nivo continued to show a significant survival benefit and better tolerability vs IC in pts with PR R/M SCCHN. Clinical trial information: NCT02105636.
Abstract
Background: Patients (pts) with platinum-refractory R/M SCCHN have an extremely poor prognosis and no chemotherapy (CT) options to extend survival. Nivo, a fully human anti-programmed ...death-1 monoclonal antibody, is FDA-approved and improves survival in other tumor types.
Methods: A randomized, open-label, phase 3 trial (NCT02105636) assigned pts (stratified by prior cetuximab) with SCCHN who progressed within 6 mo of platinum-based CT in a 2:1 ratio to nivo 3 mg/kg Q2W or weekly single-agent IC (methotrexate 40-60 mg/m2, docetaxel 30-40 mg/m2, or cetuximab 400-mg/m2 loading dose followed by 250 mg/m2 weekly). Pts must not have received systemic therapy subsequent to biopsy and prior to screening. Pts could receive nivo beyond disease progression if there was evidence of clinical benefit. The primary endpoint was OS. Secondary endpoints were PFS and objective response rate (ORR) by RECIST 1.1. Additional endpoints included safety and outcomes by PD-L1 and HPV (p16 IHC) status. An interim analysis (IA) was planned after at least 195 deaths.
Results: Of 361 randomized pts, median age was 60.0 yr, 76.5% were current/former smokers, 54.8% had received ?2 prior lines of CT, 91.4% had prior radiotherapy, and 98.3% had ECOG score ?1. At IA, 133 of 240 pts (55.4%) on nivo and 85 of 121 pts (70.2%) on IC had died. Nivo-treated pts had a 30% reduction in risk of death (HR, 0.70; 97.73% CI, 0.51-0.96; P = 0.010); median OS was 7.5 mo (95% CI, 5.5-9.1) with nivo vs 5.1 mo (95% CI, 4.0-6.0) with IC. Tumor PD-L1 status was evaluable in 260 pts (72.0%). Median OS in pts with PD-L1 ?1% was 8.7 mo with nivo vs 4.6 mo with IC (HR, 0.55; 95% CI, 0.36-0.83) and, in pts with PD-L1 <1%, 5.7 vs 5.8 mo, respectively (HR, 0.89; 95% CI, 0.54-1.45). HPV status by IHC was available in 178 pts (49.3%). Median OS in HPV+ pts was 9.1 mo with nivo vs. 4.4 mo with IC (HR, 0.56; 95% CI, 0.32-0.99) and 7.5 mo vs. 5.8 mo, respectively, in HPV- pts (HR, 0.73; 95% CI, 0.42-1.25). Treatment-related adverse events (TRAEs) of any grade occurred in 58.9% of pts on nivo vs 77.5% of pts on IC; TRAEs Grade 3-4 were reported in 13.1% vs 35.1% of pts, respectively. Two treatment-related deaths on the nivo arm and one on the IC arm occurred.
Conclusions: Nivo improved OS in pts with platinum-refractory R/M SCCHN compared to single-agent IC therapy. Pts with PD-L1 ?1% and HPV+ pts had significantly longer median OS with nivo than with IC, but nivo was effective regardless of PD-L1 or HPV status. As the first immunotherapy agent to increase survival in a randomized phase 3 study in R/M SCCHN, nivo is a new standard of care option for these pts.
Citation Format: Maura L. Gillison, George Blumenschein, Jérôme Fayette, Joel Guigay, A. Dimitrios Colevas, Lisa Licitra, Kevin Harrington, Stefan Kasper, Everett E. Vokes, Caroline Even, Francis Worden, Nabil F. Saba, Lara Carmen Iglesias Docampo, Robert Haddad, Tamara Rordorf, Naomi Kiyota, Makoto Tahara, Manish Monga, Mark Lynch, William J. Geese, Mark Schactman, Justin Kopit, James W. Shaw, Robert L. Ferris. Nivolumab (nivo) vs investigator's choice (IC) for recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): CheckMate-141. abstract. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT099.
Former prospective analyses revealed gross tumor volume (GTV) as the most reliable parameter to statistically significantly predict disease control in head neck cancer (HNC) patients treated with ...definitive intensity modulated radiation therapy (IMRT) +/-concomitant systemic therapy. The most 'unfavourable' subgroup was characterized by total GTV (tGTV) of > 70 cc, translating in ~50 and 65% 3-year disease free (DFS) and overall survival (OAS, vs 68% and 88% in tGTV < 70 cc, p = 0.001 and 0.0001), and ~25% distant spread (vs 6% for tGTV < 70 cc, p < 0.0001).The aim of this report was to analyze whether there is a subgroup out of patients with tGTV > 70 cc, which only marginally benefits from intensive curative treatment.
Between 03/2002-03/2011, 112 HNC patients with tGTV > 70 cc were definitively irradiated with curative intention. Mean tGTV was 104 cc (71-251). 98/112 (88%) patients underwent systemic therapy. Parameters with potential impact on disease outcome were retrospectively tested. The 3-year local-regional control (LRC), DFS and OAS rates were 61%, 50%, and 58%. The used cut-off value of 130 cc revealed an inverse association between tGTV and outcome. Patients able to undergo any systemic therapy (n = 98, mean tGTV0 103 cc, mean age 60 years) showed a satisfying and significantly superior outcome compared to the subgroup with radiation alone (n = 14, mean tGTV 99 cc, mean age 73 years), with 53% vs 17% 3-year DFS (p = 0.01). Radiation alone for tGTV > 130 cc failed to aim its curative goal in 3/3 patients.
Patients with tGTV > 70 cc unable to undergo any systemic therapy represented a subgroup in which disease control was achievable in < 20% following curatively intended IMRT. Prospective testing of a larger sample size is needed to evaluate, if radiation alone for tGTV >~130 cc fails to meet its curative aim.
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