Purpose There are no approved treatments for recurrent/metastatic head and neck squamous cell carcinoma refractory to platinum and cetuximab. In the single-arm, phase II KEYNOTE-055 study, we ...evaluated pembrolizumab, an anti-programmed death 1 receptor antibody, in this platinum- and cetuximab-pretreated population with poor prognosis. Methods Eligibility stipulated disease progression within 6 months of platinum and cetuximab treatment. Patients received pembrolizumab 200 mg every 3 weeks. Imaging was performed every 6 to 9 weeks. Primary end points: overall response rate (Response Evaluation Criteria in Solid Tumors v1.1, central review) and safety. Efficacy was assessed in all dosed patients and in subgroups on the basis of programmed death ligand 1 (PD-L1) expression and human papillomavirus (HPV) status. Results Among 171 patients treated, 75% received two or more prior lines of therapy for metastatic disease, 82% were PD-L1 positive, and 22% were HPV positive. At the time of analysis, 109 patients (64%) experienced a treatment-related adverse event; 26 patients (15%) experienced a grade ≥ 3 event. Seven patients (4%) discontinued treatment, and one died of treatment-related adverse events. Overall response rate was 16% (95% CI, 11% to 23%), with a median duration of response of 8 months (range, 2+ to 12+ months); 75% of responses were ongoing at the time of analysis. Response rates were similar in all HPV and PD-L1 subgroups. Median progression-free survival was 2.1 months, and median overall survival was 8 months. Conclusion Pembrolizumab exhibited clinically meaningful antitumor activity and an acceptable safety profile in recurrent/metastatic head and neck squamous cell carcinoma previously treated with platinum and cetuximab.
•Mutations in Kirsten rat sarcoma viral oncogene homolog (KRAS) are common in cancer.•KRAS remains a challenging therapeutic target.•Recently, several novel compounds against individual KRAS ...alterations have emerged.•Initial activity of AMG 510 and MRTX 849 appears promising in KRAS G12C NSCLC.•Single agent and combination studies are ongoing to evaluate their safety and efficacy.
Mutations in Kirsten rat sarcoma viral oncogene homolog (KRAS) are among the most common aberrations in cancer, including non-small cell lung cancer (NSCLC). The lack of an ideal small molecule binding pocket in the KRAS protein and its high affinity towards the abundance of cellular guanosine triphosphate (GTP) renders the design of specific small molecule drugs challenging. Despite efforts, KRAS remains a challenging therapeutic target.
Among the different known mutations; the KRASG12C (glycine 12 to cysteine) mutation has been considered potentially druggable. Several novel covalent direct inhibitors targeting KRASG12C with similar covalent binding mechanisms are now in clinical trials. Both AMG 510 from Amgen and MRTX849 from Mirati Therapeutics covalently binds to KRASG12C at the cysteine at residue 12, keeping KRASG12C in its inactive GDP-bound state and inhibiting KRAS-dependent signaling. Both inhibitors are being studied as a single agent or as combination with other targets. In addition, two novel KRAS G12C inhibitors JNJ-74699157 and LY3499446 will have entered phase 1 studies by the end of 2019.
Given the rapid clinical development of 4 direct covalent KRAS G12C inhibitors within a short period of time, understanding the similarities and differences among these will be important to determine the best treatment option based on tumor specific response (NSCLC versus colorectal carcinoma), potential resistance mechanisms (i.e. anticipated acquired mutation at the cysteine 12 residue) and central nervous system (CNS) activity. Additionally, further investigation evaluating the efficacy and safety of combination therapies with agents such as immune checkpoint inhibitors will be important next steps.
Liquid biopsy is now considered a valuable diagnostic tool for advanced metastatic non-small cell lung cancer (NSCLC). In NSCLC, circulating tumor DNA (ctDNA) analysis has been shown to increase the ...chances of identifying the presence of targetable mutations and has been adopted by many clinicians owing to its low risk. Serial monitoring of ctDNA may also help assess the treatment response or for monitoring relapse. As the presence of detectable plasma ctDNA post-surgery likely indicates residual tumor burden, studies have been performed to quantify plasma ctDNA to assess minimal residual disease (MRD) in early-stage resected NSCLC. Most data on utilizing liquid biopsy for monitoring MRD in early-stage NSCLC are from small-scale studies using ctDNA. Here, we review the recent research on liquid biopsy in NSCLC, not limited to ctDNA, and focus on novel methods such as micro RNAs (miRNA) and long non-coding (lncRNA).
We examined the impact of treatment modality on gastrostomy tube dependence and patient‐reported outcomes in human papillomavirus‐associated oropharyngeal cancer (HPV‐OPSCC). We performed systematic ...review and meta‐analysis of functional outcomes 1–3 years after treatment. Twenty‐three studies were included, reporting on 3127 patients treated for HPV‐OPSCC. Gastrostomy tube dependence failed to show statistically significant difference between surgery with adjuvant therapy and chemoradiotherapy with cisplatin at 12 months (8.3% 95% CI: 3.1–15.9 vs. 4.2% 1.1–9.2, p = 0.37) and 24–36 months (10.5% 95% CI: 3.2–21.5 vs. 3.3% 2.0–4.9, p = 0.06). Surgery with adjuvant therapy was associated with worse University of Washington Quality of Life (UW‐QOL) Swallowing (84 95% CI: 80–88 vs. 89 87–90, p = 0.03) and UW‐QOL Overall scores (76 95% CI: 72–80 vs. 84 81–86, p = 0.001) compared to chemoradiotherapy with cisplatin at 12 months. Surgery with adjuvant therapy was associated with worse performance on certain measures of patient‐reported swallow and overall function compared to chemoradiotherapy with cisplatin. Further randomized controlled trials are needed to directly compare functional outcomes after treatment for HPV‐OPSCC.
Background
The standardization of quality measures has been key in advancing the aims of the National Quality Forum established to improve health outcomes.
Methods
The National Cancer Database was ...used to identify eligible patients. Two quality metrics were evaluated including time to treatment initiation (TTI) and chemotherapy in locoregionally head and neck squamous cell carcinoma (HNSCC).
Results
TTI was significantly associated with mortality reflected by a hazard ratio (HR) of 1.13 for 60–90 days of TTI (95% CI 1.08–1.17), 1.19 for >90 days of TTI (95% CI 1.13–1.26). Patients with locoregionally advanced HNSCC had an 87% adherence to chemotherapy, which correlated with reduced mortality (HR 0.57; 95% CI 0.55–0.59). Patients treated at high quality centers had a 9% increase in survival (HR 0.91; 95% CI 0.88–0.93).
Conclusion
We identified that both TTI and chemotherapy for locoregionally advanced HNSCC meet criteria for valid quality metrics potentially suitable for national adoption.
Objective
Definitive concurrent chemoradiotherapy (CRT) is considered the standard of care for organ preservation and is the only potentially curative therapy for surgically unresectable patients ...with stage III to IVb locally advanced squamous cell carcinoma of the head and neck. In patients with high risks for adverse events utilizing cisplatin, carboplatin has been empirically substituted. The objective of this study was to estimate the locoregional control rate, progression‐free survival, overall survival, and adverse events in locally advanced squamous cell carcinoma of the head and neck patients treated with CRT utilizing carboplatin.
Study Design
A retrospective single‐arm analysis.
Methods
Data on consecutive patients who fit the eligibility criteria were collected. Eligible patients were treated with 70 Gy of radiation therapy and at least two cycles of carboplatin (area of curve AUC of 5 between January 2007 to December 2013.
Results
Fifty‐four patients were identified. Overall locoregional control rate was 50% (95% confidence interval CI 37%–63%). Median progression‐free and overall survival were 21 (CI 11–33) and 40 (CI 33–NA) months, respectively. One‐, 3‐, and 5‐year overall survival were 81% (CI 67%–89%), 59% (CI 41%–73%), and 42% (CI 22%–61%), respectively. Stage III/IVa patients (n = 45) had a median survival of 62 (CI 37–NA months) and 3 years of 71% (CI 53%–84%), whereas stage IVb (n = 9) had a median survival of 31 (CI 4–NA) months and none survived to 3 years.
Conclusion
Definitive CRT with carboplatin for locally advanced squamous cell carcinoma of the head and neck was well tolerated and demonstrated comparable results to CRT with cisplatin.
Level of Evidence
4. Laryngoscope, 127:2260–2264, 2017
Acute kidney injury (AKI) is a well-known complication of cisplatin-based chemotherapy; however, its impact on long-term patient survival is unclear. We sought to determine the incidence and risk ...factors for development of cisplatin-associated AKI and its impact on long-term renal function and patient survival. We identified 233 patients who received 629 cycles of high-dose cisplatin (99±9mg/m2) for treatment of head and neck cancer between 2005 and 2011. These subjects were reviewed for development of AKI. Cisplatin nephrotoxicity (CN) was defined as persistent rise in serum creatinine, with a concomitant decline in serum magnesium and potassium, in absence of use of nephrotoxic agents and not reversed with hydration. All patients were hydrated per protocol and none had baseline glomerular filtration rate (GFR) via CKD-EPI<60mL/min/1.73m2. The patients were grouped based on development of AKI and were staged for levels of injury, per KDIGO-AKI definition. Renal function was assessed via serum creatinine and estimated glomerular filtration rate (eGFR) via CKD-EPI at baseline, 6- and 12-months. Patients with AKI were screened for the absence of nephrotoxic medication use and a temporal decline in serum potassium and magnesium levels. Logistic regression models were constructed to determine risk factors for cisplatin-associated AKI. Twelve-month renal function was compared among groups using ANOVA. Kaplan-Maier curves and Cox proportional hazard models were constructed to study its impact on patient survival. Of 233 patients, 158(68%) developed AKI; 77 (49%) developed stage I, 55 (35%) developed stage II, and 26 (16%) developed stage III AKI. Their serum potassium and magnesium levels correlated negatively with level of injury (p<0.05). African American race was a significant risk factor for cisplatin-associated AKI, OR 2.8 (95% CI 1.3 to 6.3) and 2.8 (95% CI 1.2 to 6.7) patients with stage III AKI had the lowest eGFR value at 12 months (p = 0.05) and long-term patient survival (HR 2.1; p<0.01) than patients with no or lower grades of AKI. Most common causes of death were recurrent cancer (44%) or secondary malignancy elsewhere (40%). Cisplatin-associated severe AKI occurs in 20% of the patients and has a negative impact on long-term renal function and patient survival. PEG tube placement may be protective and should be considered in high risk-patients.
Lenvatinib is a multitargeted tyrosine kinase inhibitor (TKI) that shows improved median progression-free survival (PFS) in patients with thyroid carcinomas. However, virtually all patients ...ultimately progress, indicating the need for a better understanding of the mechanisms of resistance. Here, we examined the molecular profile of anaplastic thyroid cancer cells (8505C) exposed to lenvatinib and found that long-term exposure to lenvatinib caused phenotypic changes. Consistent with change toward mesenchymal morphology, activation of pro-survival signaling, nuclear exporter protein exportin 1 (XPO1) and Rho GTPase effector p21 activated kinases (PAK) was also observed. RNA-seq analysis showed that prolonged lenvatinib treatment caused alterations in numerous cellular pathways and several oncogenes such as
(carcinoembryonic antigen-related cell adhesion molecule) and
(Nuclear protein 1) were also upregulated. Further, we evaluated the impact of XPO1 and PAK4 inhibition in the presence or absence of lenvatinib. Targeted inhibition of XPO1 and PAK4 could sensitize the 8505C cells to lenvatinib. Both XPO1 and PAK4 inhibitors, when combined with lenvatinib, showed superior anti-tumor activity in 8505C sub-cutaneous xenograft. These studies bring forward novel drug combinations to complement lenvatinib for treating anaplastic thyroid cancer. Such combinations may possibly reduce the chances of lenvatinib resistance in thyroid cancer patients.
Vorinostat is a histone deacetylase inhibitor (HDACi). Based on a confirmed partial response (PR) in an adenoid cystic carcinoma (ACC) patient treated with vorinostat in a prior phase 1 trial, we ...initiated this phase 2 trial.
Vorinostat was administered orally 400 mg daily, 28 day cycles. The primary objective was to evaluate response rate (RR). Exploratory studies included whole exome sequencing (WES) of selected patients.
Thirty patients were enrolled. Median age of patients was 53 years (range 21-73). Median number of cycles was 5 (range 1-66). Lymphopenia (n = 5), hypertension (n = 3), oral pain (n = 2), thromboembolic events (n = 2) and fatigue (n = 2) were the only grade 3 adverse events (AEs) that occurred in more than 1 patient. Eleven patients were dose reduced secondary to drug-related AEs. Two patients had a partial response (PR), with response durations of 53 and 7.2 months. One patient had a minor response with a decrease in ascites (for 19 cycles). Stable disease was the best response in 27 patients. Targeted and WES of 8 patients in this trial identified mutations in chromatin remodeling genes highlighting the role of the epigenome in ACC.
Vorinostat demonstrated efficacy in patients with ACC supporting the inclusion of HDACi in future studies to treat ACC.
Key Clinical Message
While immunotherapy with programmed cell death protein 1 (PD1) checkpoint inhibition has shown promising activity against many tumor types, adverse events are common. ...Hypophysitis is a rare but serious immune‐related event known to occur with anti‐PD1 inhibition. It will become more prevalent as the usage of checkpoint inhibitors increases.
While immunotherapy with programmed cell death protein 1 (PD1) checkpoint inhibition has shown promising activity against many tumor types, adverse events are common. Hypophysitis is a rare but serious immune‐related event known to occur with anti‐PD1 inhibition. It will become more prevalent as the usage of checkpoint inhibitors increases.
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