Survival in Young-Onset Metastatic Colorectal Cancer: Findings From Cancer and Leukemia Group B (Alliance)/SWOG 80405.

BACKGROUND: The incidence of young-onset colorectal cancer (yoCRC) is increasing. It is unknown if there are survival differences between young and older patients with metastatic colorectal cancer (mCRC). METHODS: We studied the association of age with survival in 2326 mCRC patients enrolled in the Cancer and Leukemia Group B and SWOG 80405 trial, a multicenter, randomized trial of first-line chemotherapy plus biologics. The primary and secondary outcomes of this study were overall survival (OS) and progression-free survival (PFS), respectively, which were assessed by Kaplan-Meier method and compared among younger vs older patients with the log-rank test. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated based on Cox proportional hazards modeling, adjusting for known prognostic variables. All statistical tests were 2-sided. RESULTS: Of 2326 eligible subjects, 514 (22.1%) were younger than age 50 years at study entry (yoCRC cohort). The median age of yoCRC patients was 44.3 vs 62.5 years in patients aged 50 years and older. There was no statistically significant difference in OS between yoCRC vs older-onset patients (median = 27.07 vs 26.12 months; adjusted HR = 0.98, 95% CI = 0.88 to 1.10; P = .78). The median PFS was also similar in yoCRC vs older patients (10.87 vs 10.55 months) with an adjusted hazard ratio of 1.02 (95% CI = 0.92 to 1.13; P = .67). Patients younger than age 35 years had the shortest OS with median OS of 21.95 vs 26.12 months in older-onset patients with an adjusted hazard ratio of 1.08 (95% CI = 0.81 to 1.44; Ptrend = .93). CONCLUSION: In this large study of mCRC patients, there were no statistically significant differences in survival between patients with yoCRC and CRC patients aged 50 years and older.

A phase 2 clinical trial of the heat shock protein 90 (HSP 90) inhibitor ganetespib in patients with refractory advanced esophagogastric cancer.

Subsets of esophagogastric (EG) cancers harbor genetic abnormalities, including amplification of HER2, MET, or FGFR2 or mutations in PIK3CA, EGFR, or BRAF. Ganetespib which is a novel triazolone heterocyclic inhibitor of HSP90, is a potentially biologically rational treatment strategy for advanced EG cancers with these gene amplification. This multicenter, single-arm phase 2 trial enrolled patients with histologically confirmed advanced EG cancer with progression on at least one line of systemic therapy. Patients received Ganetespib 200 mg/m2 IV on Days 1, 8, and 15 of a 28-day cycle. The primary endpoint was overall response rate (ORR). Secondary endpoints included: Progression Free Survival (PFS); to correlate the presence of HSP clients with ORR and PFS; evaluating the safety, tolerability and adverse events profile. In this study 26 eligible patients mainly: male 77%, median age 64 years were enrolled. The most common drug-related adverse events were diarrhea (77%), fatigue (65%), elevated ALKP (42%), and elevated AST (38%). The most common grade 3/4 AEs included: leucopenia (12%), fatigue (12%), diarrhea (8%), and elevated ALKP (8%). The ORR of 4% reflects the single patient of 26 who had a complete response and stayed on treatment for more than seventy (70) months. Median PFS and OS was 61 days (2.0 months), 94 days (3.1 months) respectively. Ganetespib showed manageable toxicity. While the study was terminated early due to insufficient evidence of single-agent activity, the durable CR and 2 minor responses suggest that there may be a subset of EG patients who could benefit from this drug.

FOLFOX plus ziv-aflibercept or placebo in first-line metastatic esophagogastric adenocarcinoma: A double-blind, randomized, multicenter phase 2 trial.

BACKGROUND: Antiangiogenic therapy is a proven therapeutic modality for refractory gastric and gastroesophageal junction adenocarcinoma. This trial assessed whether the addition of a high affinity angiogenesis inhibitor, ziv-aflibercept, could improve the efficacy of first-line mFOLFOX6 (oxaliplatin, leucovorin, and bolus plus infusional 5- fluorouracil) in metastatic esophagogastric adenocarcinoma. METHODS: Patients with treatment-naive metastatic esophagogastric adenocarcinoma were randomly assigned (in a 2:1 ratio) in a multicenter, placebo-controlled, double-blind trial to receive first-line mFOLFOX6 with or without ziv-aflibercept (4 mg/kg) every 2 weeks. The primary endpoint was 6-month progression-free survival (PFS). RESULTS: Sixty-four patients were randomized to receive mFOLFOX6 and ziv-aflibercept (43 patients) or mFOLFOX6 and a placebo (21 patients). There was no difference in the PFS, overall survival, or response rate. Patients treated with mFOLFOX6/ziv-aflibercept tended to be more likely to discontinue study treatment for reasons other than progressive disease (P = .06). The relative dose intensity of oxaliplatin and 5-fluorouracil was lower in the mFOLFOX6/ziv-aflibercept arm during the first 12 and 24 weeks of the trial. There were 2 treatment-related deaths due to cerebral hemorrhage and bowel perforation in the mFOLFOX6/ziv-aflibercept cohort. CONCLUSIONS: Ziv-aflibercept did not increase the anti-tumor activity of first-line mFOLFOX6 in metastatic esophagogastric cancer, potentially because of decreased dose intensity of FOLFOX. Further evaluation of ziv-aflibercept in unselected, chemotherapy-naive patients with metastatic esophagogastric adenocarcinoma is not warranted.

Efficacy of PD-1 & PD-L1 inhibitors in older adults: a meta-analysis.

BACKGROUND: Immune checkpoint inhibitors targeting PD-1/PD-L1 pathway demonstrated promising activities in variety of malignancies, however little is known regarding their efficacy in adults aged ≥65 years. METHODS: We conducted a systematic review and a study-level meta-analysis to explore efficacy of ICIs based on age, younger vs older than 65 years. We included in this analysis randomized controlled phase II or III studies in patients with metastatic solid tumors that compared efficacy of PD-1 or PD-L1 inhibitors to a non-PD-1/PD-L1 inhibitor. Aggregated estimates of overall survival (OS) and progression-free survival (PFS) are based on random/mixed effects (RE) models to allow for heterogeneity between the studies. RESULTS: Initial search identified 53 articles, 17 were randomized controlled trials that compared nivolumab, pembrolizumab or atezolizumab to chemotherapy or targeted therapy. Only 9 trials reported hazard ratiios (HR) for OS based on age and were included in this meta-analysis. Out of those studies seven reported HR for PFS but only 4 studies included subgroup-analysis based on age for PFS. The overall estimated random-effects HR for death was 0.64 with 95% CI of 0.54-0.76 in patients ≥65 years vs. 0.68 with 95% CI of 0.61-0.75 in patients < 65 years. The overall estimated random-effects for HR for progression was 0.74 with 95% CI of 0.60-0.92 in patients ≥65 years vs. 0.73 with 95% CI of 0.61-0.88 in patients < 65 years. CONCLUSIONS: PD-1 (nivolumab and pembrolizumab) and PD-L1 (atezolizumab) inhibitors had comparable efficacy in adults younger vs ≥ 65 years.

Personalizing Adjuvant Therapy for Stage II/III Colorectal Cancer.

This review focuses on three areas of interest with respect to the treatment of stage II and III colon and rectal cancer, including (1) tailoring adjuvant therapy for the geriatric population, (2) the controversy as to the optimal adjuvant therapy strategy for patients with locoregional rectal cancer and for patients with colorectal resectable metastatic disease, and (3) discussion of the microenvironment, molecular profiling, and the future of adjuvant therapy. It has become evident that age is the strongest predictive factor for receipt of adjuvant chemotherapy, duration of treatment, and risk of treatment-related toxicity. Although incorporating adjuvant chemotherapy for patients who have received neoadjuvant chemoradiation and surgery would appear to be a reasonable strategy to improve survivorship as an extrapolation from stage III colon cancer adjuvant trials, attempts at defining the optimal rectal cancer population that would benefit from adjuvant therapy remain elusive. Similarly, the role of adjuvant chemotherapy for patients after resection of metastatic colorectal cancer has not been clearly defined because of very limited data to provide guidance. An understanding of the biologic hallmarks and drivers of metastatic spread as well as the micrometastatic environment is expected to translate into therapeutic strategies tailored to select patients. The identification of actionable targets in mesenchymal tumors is of major interest.

A phase I and pharmacokinetic study of ganetespib (STA-9090) in advanced hepatocellular carcinoma.

BACKGROUND: Ganetespib (STA-9090) is an Hsp90 inhibitor that downregulates VEGFR, c-MET, HER2, IGF-IR, EGFR, and other Hsp90 client proteins involved in hepatocarcinogenesis, thereby making it an attractive therapy for HCC. This Phase I study was performed to establish the safety, tolerability, recommended Phase 2 dose (RP2D), and preliminary clinical activity of ganetespib in previously treated patients with advanced HCC. METHODS: Patients with advanced HCC, Child-Pugh A cirrhosis, progression on or intolerance to sorafenib, and ECOG PS ≤ 1 were enrolled in a standard 3x3 dose escalation study at doses of 100 mg/m(2), 150 mg/m(2), and 200 mg/m(2) IV given on days 1, 8, and 15 of each 28-day cycle. Objective response by RECIST version 1.1 criteria was evaluated by CT/MRI every 8 weeks. RESULTS: Fourteen patients were enrolled in this trial and received at least one dose of the study drug. Of the 14 patients: median age, 57 years old; male 71 %; Asian 36 %; HCC etiology (HBV 36 %, HCV 43 %, Hemachromatosis 7 %, unknown 21 %); Child Pugh Class (A 93 %, B 7 %); median number of prior treatments 2; median baseline AFP 70.1 ng/mL. The RP2D was determined to be 200 mg/m(2). The most commonly seen AEs were diarrhea (93 %), fatigue (71 %), AST elevation (64 %), and hyperglycemia (64 %). The most common Gr 3/4 AEs were hyperglycemia (21 %) and lipasemia (21 %). One (7 %) patient had a fatal AE, septic shock, within 30 days of receiving the study drug. One dose-limiting toxicity, grade 3 lipasemia, was observed at the 100 mg/m(2) dose. Pharmacokinetics studies showed a t1/2, CL, Tmax, and Vss of 6.45 h, 48.28 L/h (25.56 L/h/m(2)), 0.76 h, and 191 L (100.4 L/m(2)), respectively. No objective responses were seen; one patient (7 %) had stable disease at 16 weeks. Median time to progression was 1.8 months, and median overall survival was 7.2 months. CONCLUSION: Ganetespib had a manageable safety profile in patients with advanced HCC who had progressed on at least one line of systemic therapy. The pharmacokinetic profile showed that ganetespib exposure in patients with mild hepatic dysfunction is similar to that seen in patients with normal liver function. Ganetespib showed limited clinical benefit in patients with advanced HCC in this phase I trial.

Multi-drug inhibition of the HER pathway in metastatic colorectal cancer: results of a phase I study of pertuzumab plus cetuximab in cetuximab-refractory patients.

PURPOSE: Resistance to cetuximab, a monoclonal antibody against the epithelial growth factor receptor (EGFR), in colorectal cancer (CRC) may result from compensatory signaling through ErbB receptors, ErbB2/neu/HER2 (HER2) and ErbB3/HER3 (HER3). Pertuzumab is a monoclonal antibody that blocks HER2 hetero-dimerization; thus the combination of pertuzumab and cetuximab could possibly overcome cetuximab resistance. PATIENTS AND METHODS: This single-arm, open-label, multicenter phase I/II study was designed to assess the safety and efficacy of pertuzumab and cetuximab in patients with cetuximab-resistant KRAS wild type metastatic CRC. Thirteen patients were enrolled and received cetuximab in combination with pertuzumab at several dose levels in a 3 + 3 design. Patients were assessed for dose-limiting toxicity (DLT) during the first cycle. A phase II portion was planned, but not initiated due to toxicity. RESULTS: Six of the thirteen patients (46 %) experienced DLTs, therefore the study was terminated early. Grade 3 or higher DLTs included dermatitis with desquamation and/or acneiform rash (n = 6), mucositis or stomatitis (n = 5), and diarrhea (n = 2). There was one Grade 5 event (myocardial infarction) attributed to underlying disease. Among the 13 patients, seven (54 %) were evaluable for response. The objective response rate was 14 %: one patient had a partial response lasting 6 months. Two patients had stable disease (29 %), and four had progressive disease (57 %). Median progression free survival was 2.1 months (95 % CI, 1.5-4.9) and median overall survival was 3.7 months (95 % CI, 1.6-7.9). CONCLUSION: Combination pertuzumab and cetuximab in refractory CRC was associated with potential antitumor activity; however, the combination was not tolerable due to overlapping toxicities.

Efficacy, safety, pharmacokinetics, and biomarkers of cediranib monotherapy in advanced hepatocellular carcinoma: a phase II study.

PURPOSE: We conducted a single-arm phase II study of cediranib, a pan-VEGFR tyrosine kinase inhibitor, in patients with advanced hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN: Patients with histologically confirmed measurable advanced HCC and adequate hematologic, hepatic, and renal functions received cediranib 30-mg orally once daily (4 weeks/cycle). The primary endpoint was progression-free survival (PFS) rate at 3 months. Other endpoints included response rates, overall survival (OS), pharmacokinetics (PK), and biomarkers for cediranib. RESULTS: Cediranib treatment resulted in an estimated 3-month PFS rate of 77% (60%, 99%). Median PFS was 5.3 (3.5,9.7) months, stable disease was seen in 5/17 patients (29%), and median OS was 11.7 (7.5-13.6) months. Grade 3 toxicities included hypertension (29%), hyponatremia (29%), and hyperbilirubinemia (18%). Cediranib PK were comparable to those seen in cancer patients with normal hepatic function. Plasma levels of VEGF and PlGF increased and sVEGFR1, sVEGFR2, and Ang-2 decreased after cediranib treatment. PFS was inversely correlated with baseline levels of VEGF, sVEGFR2, and bFGF and with on-treatment levels of bFGF and IGF-1, and directly associated with on-treatment levels of IFN-γ. OS was inversely correlated with baseline levels of sVEGFR1, Ang-2, TNF-α, CAIX, and CD34(+)CD133(+)CD45(dim) circulating progenitor cells and on-treatment levels of sVEGFR2. CONCLUSIONS: Despite the limitations of primary endpoint selection, cediranib at 30-mg daily showed a high incidence of toxicity and preliminary evidence of antitumor activity in advanced HCC. Hepatic dysfunction did not seem to affect the steady-state PK of cediranib. Exploratory studies suggested proangiogenic and inflammatory factors as potential biomarkers of anti-VEGF therapy in HCC.

Safety and effectiveness of oxaliplatin-based chemotherapy regimens in adults 75 years and older with colorectal cancer.

UNLABELLED: Although the safety and efficacy of oxaliplatin-based chemotherapy regimens for colorectal cancer (CRC) have been demonstrated in adults > 75 years of age enrolled in clinical trials, safety and effectiveness outside the trial setting are less established. In this comparative effectiveness study, we note that older adults with stage III and metastatic CRC treated outside of a clinical trial experienced safety and effectiveness of oxaliplatin-based chemotherapy regimens comparable to that of younger adults. BACKGROUND: Although the safety and efficacy of oxaliplatin-based chemotherapy regimens for colorectal cancer (CRC) have been demonstrated in adults ≥ 75 years of age who are enrolled in clinical trials, safety and effectiveness outside the trial setting are less established. METHODS: We retrospectively collected cases of patients ≥ 75 years of age who were diagnosed with stage III and metastatic CRC and initiated treatment between January 2000 and January 2007 at 2 academic hospitals in Boston, MA. Cases were matched in a 1:2 ratio to controls who were < 75 years of age by hospital site, stage of disease (stage III vs. metastatic) and line of therapy (first- or second-line or beyond). The primary study endpoints were grade ≥ 3 treatment-associated toxicities and intolerance (number of dose delays/reductions and hospital/facility admissions during treatment). The secondary endpoint was overall survival. RESULTS: We identified 84 patients ≥ 75 years of age (25% ≥ 80 years) and 168 controls. In the cohort, 77% had colon cancer, 75% had metastatic disease, and 60% were receiving oxaliplatin as first-line therapy. There was no significant difference in grade ≥ 3 treatment-associated toxicities between the patients and the controls (71.4% vs. 68.5%, respectively; P = .63). Further there was no statistically significant difference between patients and controls for combined endpoints of any grade ≥ 3 toxicity or hospital/facility admission (P = .92). With a median follow-up of 52 months, 2-year overall survival was similar between patients and controls (43% vs. 52%, respectively; P = .87). CONCLUSION: Older adults with stage III and metastatic CRC treated outside of a clinical trial experienced safety and effectiveness of oxaliplatin-based chemotherapy regimens that was comparable to that of younger adults.

Effect of adjuvant chemotherapy on survival of patients with stage III colon cancer diagnosed after age 75 years.

PURPOSE: Few patients 75 years of age and older participate in clinical trials, thus whether adjuvant chemotherapy for stage III colon cancer (CC) benefits this group is unknown. METHODS: A total of 5,489 patients ≥ 75 years of age with resected stage III CC, diagnosed between 2004 and 2007, were selected from four data sets containing demographic, stage, treatment, and survival information. These data sets included SEER-Medicare, a linkage between the New York State Cancer Registry (NYSCR) and its Medicare programs, and prospective cohort studies Cancer Care Outcomes Research and Surveillance Consortium (CanCORS) and the National Comprehensive Cancer Network. Data sets were analyzed in parallel using covariate adjusted and propensity score (PS) matched proportional hazards models to evaluate the effect of treatment on survival. PS trimming was used to mitigate the effects of selection bias. RESULTS: Use of adjuvant therapy declined with age and comorbidity. Chemotherapy receipt was associated with a survival benefit of comparable magnitude to clinical trials results (SEER-Medicare PS-matched mortality, hazard ratio [HR], 0.60; 95% CI, 0.53 to 0.68). The incremental benefit of oxaliplatin over non-oxaliplatin-containing regimens was also of similar magnitude to clinical trial results (SEER-Medicare, HR, 0.84; 95% CI, 0.69 to 1.04; NYSCR-Medicare, HR, 0.82, 95% CI, 0.51 to 1.33) in two of three examined data sources. However, statistical significance was inconsistent. The beneficial effect of chemotherapy and oxaliplatin did not seem solely attributable to confounding. CONCLUSION: The noninvestigational experience suggests patients with stage III CC ≥ 75 years of age may anticipate a survival benefit from adjuvant chemotherapy. Oxaliplatin offers no more than a small incremental benefit. Use of adjuvant chemotherapy after the age of 75 years merits consideration in discussions that weigh individual risks and preferences.

New developments in the adjuvant therapy of stage II colon cancer. Risk assessments in the older patient.

While adjuvant chemotherapy has proven benefit in stage III colon cancer, its role for stage II colon cancer remains unclear. This article reviews data regarding adjuvant therapy in stage II colon cancer. We will discuss factors to consider in assessing the risk of recurrence in stage II disease. We will also outline considerations regarding adjuvant therapy in older patients.

Impact of smoking on patients with stage III colon cancer: results from Cancer and Leukemia Group B 89803.

BACKGROUND: Cigarette smoking has been shown to increase the risk of developing colorectal cancer, particularly smoking early in life. Little is known about the impact of tobacco use on colon cancer recurrence among colon cancer survivors. METHODS: The authors prospectively collected lifetime smoking history from stage III colon cancer patients enrolled in a phase 3 trial via self-report questionnaires during and 6 months after completion of adjuvant chemotherapy. Smoking status was defined as never, current, or past. Lifetime pack-years were defined as number of lifetime packs of cigarettes. Patients were followed for recurrence or death. RESULTS: Data on smoking history were captured on 1045 patients with stage III colon cancer receiving adjuvant therapy (46% never smokers; 44% past; 10% current). The adjusted hazard ratio (HR) for disease-free survival (DFS) was 0.99 (95% confidence interval [CI], 0.70-1.41), 1.17 (95% CI 0.89-1.55), and 1.22 (95% CI 0.92-1.61) for lifetime pack-years 0-10, 10-20, and 20+, respectively, compared with never smoking (P = .16). In a preplanned exploratory analysis of smoking intensity early in life, the adjusted HR for 12+ pack-years before age 30 years for DFS was 1.37 (95% CI, 1.02-1.84) compared with never smoking (P = .04). The adjusted HR for DFS was 1.18 (95% CI, 0.92-1.50) for past smokers and 1.10 (95% CI, 0.73-1.64) for current smokers, compared with never smokers. CONCLUSIONS: Total tobacco usage early in life may be an important, independent prognostic factor of cancer recurrences and mortality in patients with stage III colon cancer.