Pembrolizumab versus methotrexate, docetaxel, or cetuximab in recurrent or metastatic head and neck squamous cell carcinoma (KEYNOTE-040): Subgroup analysis by pattern of disease recurrence.

BACKGROUND: In the phase 3 KEYNOTE-040 study, pembrolizumab prolonged OS versus chemotherapy in previously treated recurrent or metastatic (R/M) HNSCC. We present a post hoc subgroup analysis by disease recurrence pattern: recurrent-only, recurrent and metastatic (recurrent-metastatic), and metastatic-only HNSCC. MATERIALS AND METHODS: Patients had HNSCC that progressed during or after platinum-containing treatment for R/M disease or had recurrence or progression within 3-6 months of previous platinum-containing definitive therapy for locally advanced disease. Patients were randomly assigned (1:1) to pembrolizumab 200 mg Q3W or investigator's choice of standards of care (SOC): methotrexate, docetaxel, or cetuximab. Outcomes included OS, PFS, ORR, and DOR. The data cutoff was May 15, 2017. RESULTS: There were 125 patients (pembrolizumab, 53; SOC, 72) in the recurrent-only subgroup, 204 in the recurrent-metastatic subgroup (pembrolizumab, 108; SOC, 96), and 166 in the metastatic-only subgroup (pembrolizumab, 86; SOC, 80). The hazard ratio (95% CI) for death for pembrolizumab versus SOC was 0.83 (0.55-1.25) in the recurrent-only, 0.78 (0.58-1.06) in the recurrent-metastatic, and 0.74 (0.52-1.05) in the metastatic-only subgroups. PFS was similar between treatment arms in all subgroups. ORR was 22.6% for pembrolizumab versus 16.7% for SOC in the recurrent-only, 10.2% versus 6.3% in the recurrent-metastatic, and 15.1% versus 8.8% in the metastatic-only subgroups. DOR was numerically longer with pembrolizumab in all subgroups. CONCLUSION: Pembrolizumab provided numerically longer OS and durable responses in all subgroups compared with SOC, suggesting that patients with previously treated R/M HNSCC benefit from pembrolizumab regardless of recurrence pattern.

Renal cell carcinoma in the Canadian Indigenous population.

Background: Diagnosis and treatment of renal cell carcinoma (rcc) might be different in Indigenous Canadians than in non-Indigenous Canadians. In this cohort study, we compared rcc presentation and treatments in Indigenous and non-Indigenous Canadians. Methods: Patients registered in the Canadian Kidney Cancer Information System treated at 16 institutions between 2011 and 2018 were included. Baseline patient, tumour, and treatment characteristics were compared between Indigenous and non-Indigenous Canadians. The primary objective was to determine if differences in rcc stage at diagnosis were evident between the groups. The secondary objective was to determine if treatments and outcomes were different between the groups. Results: During the study period, 105 of the 4529 registered patients self-identified as Indigenous. Those patients were significantly younger at the time of clinical diagnosis (57.9 ± 11.3 years vs. 62.0 ± 12.1 years, p = 0.0006) and had a family history prevalence of rcc that was double the prevalence in the non-Indigenous patients (14% vs. 7%, p = 0.004). Clinical stage at diagnosis was similar in the two groups (p = 0.61). The disease was metastatic at presentation in 11 Indigenous Canadians (10%) and in 355 non-Indigenous Canadians (8%). Comorbid conditions that could affect the management of rcc-such as obesity, renal disease, diabetes mellitus, and smoking-were more common in Indigenous Canadians (p < 0.05). Indigenous Canadians experienced a lower rate of active surveillance (p = 0.01). Treatments and median time to treatments were similar in the two groups. Conclusions: Compared with their non-Indigenous counterparts, Indigenous Canadian patients with rcc are diagnosed at an earlier age and at a similar clinical stage. Despite higher baseline comorbid conditions, clinical outcomes are not worse for Indigenous Canadians than for non-Indigenous Canadians.

Use of targeted therapy in patients with metastatic renal cell carcinoma: clinical and economic impact in a Canadian real-life setting.

Introduction: Outside of randomized controlled clinical trials, the understanding of the effectiveness and costs associated with targeted therapies for metastatic renal cell carcinoma (mrcc) is limited in Canada. The purpose of the present study was to use real-world prospective data to assess the effectiveness and cost of targeted therapies for patients with mrcc. Methods: The Canadian Kidney Cancer Information System, a pan-Canadian database, was used to identify prospectively collected data relating to patients with mrcc. First- and subsequent-line time to treatment termination (ttt) was determined from therapy initiation time (sunitinib or pazopanib) to discontinuation of therapy. Kaplan-Meier survival curves were used to estimate the unadjusted and adjusted overall survival (os) by treatment. Unit treatment cost was used to estimate the cost by line of treatment and the total cost of therapy for the management of patients with mrcc. Results: The study included 475 patients receiving sunitinib or pazopanib in the first-line setting. Patients were treated mostly with sunitinib (81%); 19% of patients were treated with pazopanib. The median ttt in the first line was 7.7 months for patients receiving sunitinib and 4.6 months for those receiving pazopanib (p < 0.001). The adjusted os was 32 months with sunitinib and 21 months with pazopanib (hazard ratio: 1.61; p < 0.01). The total median cost of first- and second-line treatments was $56,476 (interquartile range: $23,738-$130,447) for patients in the sunitinib group and $46,251 (interquartile range: $28,167-$91,394) for those in the pazopanib group. Conclusions: For the two therapies, os differed significantly, with a higher median os being observed in the sunitinib group. The cost of treatment was higher in the sunitinib group, which is to be expected with longer survival.

HPV Prevalence and Prognostic Value in a Prospective Cohort of 255 Patients with Locally Advanced HNSCC: A Single-Centre Experience.

Background. HPV is a positive prognostic factor in HNSCC. We studied the prevalence and prognostic impact of HPV on survival parameters and treatment toxicity in patients with locally advanced HNSCC treated with concomitant chemoradiation therapy. Methods. Data on efficacy and toxicity were available for 560 patients. HPV was detected by PCR. Analysis was performed using Kaplan-Meier survival curves, Fisher's test for categorical data, and log-rank statistics for failure times. Results. Median follow-up was 4.7 years. DNA extraction was successful in 255 cases. HPV prevalence was 68.6%, and 53.3% for HPV 16. For HPV+ and HPV-, median LRC was 8.9 and 2.2 years (P = 0.0002), median DFS was 8.9 and 2.1 years (P = 0.0014), and median OS was 8.9 and 3.1 years (P = 0.0002). Survival was different based on HPV genotype, stage, treatment period, and chemotherapy regimen. COX adjusted analysis for T, N, age, and treatment remained significant (P = 0.004). Conclusions. Oropharyngeal cancer is increasingly linked to HPV. This study confirms that HPV status is associated with improved prognosis among H&N cancer patients receiving CRT and should be a stratification factor for clinical trials including H&N cases. Toxicity of CRT is not modified for the HPV population.

A phase II trial of dacomitinib, an oral pan-human EGF receptor (HER) inhibitor, as first-line treatment in recurrent and/or metastatic squamous-cell carcinoma of the head and neck.

BACKGROUND: An open-label, multicenter, single-arm phase II trial was conducted to investigate the clinical activity of dacomitinib in recurrent/metastatic squamous-cell carcinoma of the head and neck (RM-SCCHN). PATIENTS AND METHODS: Eligible patients were administered dacomitinib at 45 mg orally daily, in 21-day cycles. Primary end point was objective response rate. RESULTS: Sixty-nine patients were enrolled with a median age of 62 years. Among response-evaluable patients, 8 [12.7%, 95% confidence interval (CI) 5.6% to 23.5%] achieved a partial response and 36 (57.1%) had stable disease, lasting ≥24 weeks in 9 patients (14.3%). The median progression-free survival (PFS) was 12.1 weeks and the median overall survival (OS) was 34.6 weeks. Most adverse events (AEs) were tolerable. The most common grade 3 or higher treatment-related AEs were diarrhea (15.9%), acneiform dermatitis (8.7%), and fatigue (8.7%). Treatment-related AEs led to at least one dose interruption in 28 (40.6%) patients and dose reductions in 26 (37.7%). Permanent treatment discontinuation occurred in 8 (11.6%) patients due to treatment-related AEs. CONCLUSIONS: Dacomitinib demonstrated clinical activity in RM-SCCHN, and the primary end point of this study was met. The toxicity profile of this agent was generally manageable with dose interruptions and adjustments.

Association between treatment effects on disease progression end points and overall survival in clinical studies of patients with metastatic renal cell carcinoma.

BACKGROUND: The relationship between progression-free survival and time to progression (PFS/TTP) and overall survival (OS) has been demonstrated in a variety of solid tumours but not in metastatic renal cell carcinoma (mRCC). METHODS: A systematic literature search was conducted to identify controlled trials of cytokine or targeted therapies for mRCC reporting information on treatment effects on PFS/TTP and OS for one or more comparison. The associations between treatment effects on PFS/TTP and OS were analysed using linear regression. RESULTS: Thirty-one studies representing 10943 patients, 75 treatment groups, and 41 comparisons were identified. The correlation coefficient between the negative log of the hazard ratio (HR) for PFS/TTP (-ln HR(PFS/TTP)) vs the negative log of the HR for OS (-ln HR(OS)) was 0.80 (P<0.0001). In linear regression, the coefficient on -ln HR(PFS/TTP) vs -ln HR(OS) was 0.64 (95% confidence interval (CI): 0.470.81; R(2)=0.63), suggesting each 10% relative risk reduction (RRR) for PFS/TTP was associated with a 6% RRR for OS. A 1-month gain in median PFS/TTP was associated with a 1.17-month gain in median OS (95% CI: 0.59,1.76; R(2)=0.28). CONCLUSION: In trials of treatments for mRCC, treatment effects on PFS/TTP are strongly associated with treatment effects on OS.

EGFR tyrosine kinase mutation testing in the treatment of non-small-cell lung cancer.

BACKGROUND: Non-small-cell lung cancer (nsclc) tumours with activating mutations of the epidermal growth factor receptor (efgr) tyrosine kinase are highly sensitized to the effects of oral tyrosine kinase inhibitors such as gefitinib and erlotinib, suggesting the possibility of targeted treatment of nsclc based on EFGR mutation status. However, no standardized method exists for assessing the EGFR mutation status of tumours. Also, it is not known if available methods are feasible for routine screening. To address that question, we conducted a validation study of methods used for detecting EGFR mutations in exons 19 and 21 at molecular laboratories located in five specialized Canadian cancer centres. METHODS: The screening methods were first optimized using cell lines harbouring the mutations in question. A validation phase using anonymized patient samples followed. RESULTS: The methods used at the sites were highly specific and sensitive in detecting both mutations in cell-line dna (specificity of 100% and sensitivity of at least 1% across all centres). In the validation phase, we observed excellent concordance between the laboratories for detecting mutations in the patient samples. Concordant results were obtained in 26 of 30 samples (approximately 87%). In general, the samples for which results were discordant were also less optimal, containing small amounts of tumour. CONCLUSIONS: Our results suggest that currently available methods are capable of reliably detecting exon 19 and exon 21 mutations of EFGR in tumour samples (provided that sufficient tumour material is available) and that routine screening for those mutations is feasible in clinical practice.

Progression-free survival as a clinical trial endpoint in advanced renal cell carcinoma.

Traditionally, overall survival (os) has been considered the "gold standard" for evaluating new systemic oncologic therapies, because death is easy to define, is easily compared across disease sites, and is not subject to investigator bias. However, as the available options for continuing therapy increase, the use of os as a clinical trial endpoint has become problematic because of the increasing crossover and contamination of trials. As a result, the approval of promising new therapies may be delayed.Many clinicians believe that progression-free survival (pfs) is a more viable option for evaluating new therapies in metastatic and advanced renal cell carcinoma. As with all endpoints, pfs has inherent biases, and those biases must be addressed to ensure that trial results are not compromised and that they will be accepted by regulatory authorities. In this paper, we examine the issues surrounding the use of pfs as a clinical trial endpoint, and we suggest solutions to ensure that data integrity is maintained.

Canadian Expert Group consensus recommendations: KRAS testing in colorectal cancer.

Monoclonal antibodies against the epidermal growth factor receptor (anti-egfr) when used in the treatment of metastatic colorectal cancer are associated with improved survival. Patients whose tumours harbor a KRAS mutation in codon 12 or 13 have been shown not to benefit from anti-egfr antibodies. The importance of KRAS mutation status in the management of patients with metastatic colorectal cancer has led to the elaboration of Canadian consensus recommendations on KRAS testing, with the aim of standardizing practice across Canada and reconciling testing access with the clinical demand for testing. The present guidelines were developed at a Canadian consensus meeting held in Montreal in April 2010. The best available evidence and expertise were used to develop recommendations for various aspects of KRAS testing, including indications and timing for testing, sample requirements, recommendations for reporting requirements, and acceptable turnaround times.

KRAS mutation testing in the treatment of metastatic colorectal cancer with anti-EGFR therapies.

Survival of patients with metastatic CRC (mCRC) has improved steadily over the past several decades, due largely to the development of new combinations of standard chemotherapy, as well as to the introduction of new targeted therapies. Among the available targeted therapies are two monoclonal antibodies that target the epidermal growth factor receptor (EGFR) - cetuximab and panitumumab - which have demonstrated efficacy in the treatment of mCRC. These therapies are associated with a unique set of toxicities and costs, prompting the need for tools to select patients who are most likely to derive a benefit from them. Mutations in the KRAS oncogene have consistently been shown to predict non-response to cetuximab and panitumumab. The role of KRAS as a marker of efficacy of anti-EGFR therapies is reviewed.

Review of guidelines on the treatment of metastatic renal cell carcinoma.

Guidelines on the management of metastatic renal cell carcinoma (RCC) have emerged over the last couple of years because of the introduction of effective new targeted therapies. However, current guidelines are not always contemporary because of older data whose relevance is unclear in the context of the new therapies. Moreover, many of the relevant trials were interrupted prematurely because of significant advantages in progression-free survival. These circumstances sometimes make interpretation of the data and characterization of subgroups rather difficult. The current paper reviews the major guidelines available on the management of metastatic rcc and tries to put them into context.

The role of the epidermal growth factor receptor tyrosine kinase inhibitors as therapy for advanced, metastatic, and recurrent non-small-cell lung cancer: a Canadian national consensus statement.

PURPOSE: To provide consensus recommendations on the use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIS) in patients with advanced or meta-static non-small-cell lung cancer (NSCLC). METHODS: Using a systematic literature search, phase II trials, randomized phase III trials, and meta-analyses were identified for inclusion. RESULTS: A total of forty-six trials were included. Clear evidence is available that EGFR-TKIS should not be administered concurrently with platinum-based chemotherapy as first-line therapy in advanced or metastatic nsclc. Evidence is currently insufficient to recommend single-agent EGFR-TKIS as first-line therapy either in unselected populations or in populations selected on the basis of molecular or clinical characteristics. Following failure of platinum-based chemotherapy, the evidence suggests that second-line EGFR-TKIS or second-line chemotherapy result in similar survival. Quality of life and symptom improvement for patients treated with an EGFR-TKI appear better than they do for patients treated with second-line docetaxel. Sequence of therapy may not appear to be important, but if survival is the outcome of interest, the goal should be to optimize the number of patients receiving three lines of therapy. Based on available data, molecular markers and clinical characteristics do not appear to be predictive of a differential survival benefit from an EGFR-TKI and therefore those factors should not be used to select patients for EGFR-TKI therapy. CONCLUSIONS: The EGFR-TKIS represent an additional therapy in the treatment of advanced or metastatic NSCLC. The results of ongoing clinical trials may define the optimal role for these agents and the effectiveness of combinations of these agents with other targeted agents.

Sunitinib therapy for metastatic renal cell carcinoma: recommendations for management of side effects.

Sunitinib, a new vascular endothelial growth factor receptor inhibitor, has demonstrated high activity in renal cell carcinoma (RCC) and is now widely used for patients with metastatic disease. Although generally well tolerated and associated with a low incidence of common toxicity criteria grade 3 or 4 toxicities, sunitinib exhibits a distinct pattern of novel side effects that require monitoring and management. This article summarizes the most important side effects and proposes recommendations for their monitoring, prevention and treatment, based on the existing literature and on suggestions made by an expert group of Canadian oncologists. Fatigue, diarrhea, anorexia, oral changes, skin toxicity and hypertension seem to be the most clinically relevant toxicities of sunitinib. Fatigue may be partly related to the development of hypothyroidism during sunitinib therapy for which patients should be observed and, if necessary, treated. Hypertension can be treated with standard antihypertensive therapy and rarely requires treatment discontinuation. Neutropenia and thrombocytopenia usually do not require intervention, in particular no episodes of neutropenic fever have been reported to date. A decrease in left ventricular ejection fraction is a rare, but potentially life-threatening side effect. Because of its metabolism by cytochrome P450 3A4 a number of drugs can potentially interact with sunitinib. Clinical response and toxicity should be carefully observed when sunitinib is combined with either a cytochrome P450 3A4 inducer or inhibitor and doses adjusted as necessary. Knowledge about side effects, as well as the proactive assessment and consistent management of sunitinib-related side effects, is critical to ensure optimal benefit from sunitinib treatment.

Phase I study of Aplidine in a dailyx5 one-hour infusion every 3 weeks in patients with solid tumors refractory to standard therapy. A National Cancer Institute of Canada Clinical Trials Group study: NCIC CTG IND 115.

BACKGROUND: Aplidine is a cyclic depsipeptide isolated from the marine tunicate Aplidium albicans. METHODS: This phase I study of Aplidine given as a 1-hour i.v. infusion daily for 5 days every 3 weeks was conducted in patients with refractory solid tumors. Objectives were to define the dose limiting toxicities, the maximal tolerated dose, and the recommended phase II dose. RESULTS: Thirty-seven patients were accrued on study. Doses ranged from 80 microg/m(2) to 1500 microg/m(2)/day. Eleven patients received more than three cycles of Aplidine. Dose-limiting toxicities occurred at 1500 microg/m(2) and 1350 microg/m(2)/day and consisted of nausea, vomiting, myalgia, fatigue, skin rash and diarrhea. Mild to moderate muscular pain and weakness was noted in patients treated with multiple cycles with no significant drug related neurotoxicity. Bone marrow toxicity was not observed. The recommended dose for phase II studies was 1200 microg/m(2) daily for 5 days, every 3 weeks. Pharmacokinetic studies performed during the first cycle demonstrated that therapeutic plasma levels of Aplidine are reachable well below the recommended dose. Nine patients with progressive disease at study entry had stable disease and two had minor responses, one in non-small cell lung cancer and one in colorectal cancer. CONCLUSIONS: Aplidine given at a dose of 1200 microg/m(2) daily for 5 days, every 3 weeks is well tolerated with few severe adverse events. This schedule of Aplidine is under evaluation in phase II studies in hematological malignancies and solid tumors.

Phase II study of troxacitabine (BCH-4556) in patients with advanced non-small-cell lung cancer.

Troxacitabine. a promising new L-nucleoside, inhibits DNA polymerase and leads to complete DNA chain termination. The National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) conducted a phase II study to assess the efficacy and toxicity of troxacitabine in untreated patients with advanced non-small-cell lung cancer (NSCLC). Previously untreated patients were eligible if they had inoperable stage IIIB or IV NSCLC, ECOG PS < or = 2, adequate hematology and biochemistry, and at least one bidimensionally measurable lesion. Patients with prior malignancy or brain metastases were excluded. Troxacitabine (10 mg/m(2)) was administered intravenously over 30 minutes every 3 weeks. Between June 1999 and May 2000, 17 eligible patients received treatment. Patient characteristics included: median age 64 years; female 41%; stage IV (94%); PS 0 (12%), 1 (59%), and 2 (29 %), 3 or more disease sites (59%). In 17 patients, there were 8 stable disease, 9 disease progression, and no objective responses. Median duration of stable disease was 3.6 months (range = 2.0-7.1). A total of 56 cycles were administered (median = 3), and 88% of patients received 90% or more of the planned dose intensity. The majority (82%) of patients experienced skin rash. Hematologic and biochemical toxicities, grade 3/4 (%) were: granulocytopenia (41), anemia (12), thrombocytopenia (6), and hyperglycemia (6). Troxacitabine appears to have little activity in NSCLC in the dose and schedule tested.

Gangliosides in human uveal melanoma metastatic process.

The inability of current therapy to prevent metastases arising from uveal melanoma often results in patient mortality. With the goal of developing a treatment for metastasis, gangliosides were studied as potential tumor-associated antigens. Our report describes the production of a metastatic liver variant (MH) from a human uveal melanoma cell line (SP6.5). Cells were injected into nude mouse spleens and liver metastases collected 2 months later. After 21 days of in vitro subculture, the cells were re-injected into normal nude mice spleen; 10 cycles (MH10) were performed. Gangliosides were extracted, purified, chromatographed on HPTLC plates and sprayed with a resorcinol-HCl reagent, the sialic acid spots being quantified by densitometry. Gangliosides were analyzed in each metastatic liver variant and compared with the SP6.5 s.c. tumor. The results showed a significant increase in GM3 and a significant decrease in GD3 and GD2 in the last metastatic variants obtained (MH5, MH8, MH9 and MH1O) compared with the primary s.c. tumor, SP6.5. Such evolution in the ganglioside pattern was maintained throughout the progression of the different liver variants. Our results indicate that precursor ganglioside GM3 and gangliosides GD3 and GD2 could be associated with neoplastic evolution of malignancy of human uveal melanoma in nude mice.

The radiosensitivity of uveal melanoma cells and the cell survival curve.

BACKGROUND: No study of the radiosensitivity of uveal melanoma cells and their survival curve has been published. The purpose of this study was to investigate the sensitivity to different single radiation doses of SP6.5, a human uveal melanoma cell line. METHODS: Cells were irradiated with cobalt-60 at doses from 0 to 1200 cGy. Radiosensitivity was measured by three methods: soft-agar bilayer assay, tritiated thymidine incorporation, and bromodeoxyuridine (BrdU) incorporation. RESULTS: The soft-agar bilayer assay, by assessing the colony-forming units, showed that the D1 value was 470 cGy, the Dq value was 400 cGy, and the n value exceeded 10, thus indicating a broad, shoulder and relative radioresistance. The doubling time as estimated by [3H]thymidine incorporation was unaffected at doses below 600 cGy, another indication of radioresistance. BrdU incorporation revealed no significant increase between 0 and 1000 cGy, indicating that the cell cycle was not interrupted. CONCLUSION: Cell survival, doubling time, and cell phases are parameters of growth kinetics, and the results suggest that SP6.5 is radioresistant and virtually unaffected by single radiation doses lower than 600 cGy. Our data parallel published data for cutaneous melanomas.

Characterization of gangliosides in human uveal melanoma cells.

We have evaluated the ganglioside composition of 20 primary uveal melanomas, of 2 cell lines derived from 2 uveal melanomas, of a liver metastasis from an uveal melanoma, and of 8 normal choroids. The results show that normal choroid tissue has a ganglioside content similar to the primary tumors of uveal melanoma except for GD1a, GD1b, and GT1b, which are present only on normal choroid tissues. On the other hand, the uveal melanomas have similarities with cutaneous melanomas, since GM3 (74%) and GD3 (25%) are found in both tissues and are present in about the same amounts. However, GM1 was found in 50%, GM2 in 20% and GD2 in none of the uveal melanomas. According to data published by others, cutaneous melanoma biopsies have no GM1, whereas GM2 is present in 100% and GD2 in 71% of tumor tissues. Transplantation of the 2 cell lines subcutaneously into nude mice resulted in the growth of tumors which had a ganglioside profile larger than that of the primary tumors. GM3 was significantly diminished and GD3 significantly increased in the primary uveal melanoma from patients who had received radiotherapy before enucleation compared with those who did not have radiotherapy. These results show that uveal melanomas contain gangliosides that could be used as targets for monoclonal antibody therapy.