Dual human epidermal growth factor receptor 2 (HER2) targeting can increase pathologic complete response rates (pCRs) to neoadjuvant therapy and improve progression-free survival in metastatic ...disease. CALGB 40601 examined the impact of dual HER2 blockade consisting of trastuzumab and lapatinib added to paclitaxel, considering tumor and microenvironment molecular features.
Patients with stage II to III HER2-positive breast cancer underwent tumor biopsy followed by random assignment to paclitaxel plus trastuzumab alone (TH) or with the addition of lapatinib (THL) for 16 weeks before surgery. An investigational arm of paclitaxel plus lapatinib (TL) was closed early. The primary end point was pCR in the breast; correlative end points focused on molecular features identified by gene expression-based assays.
Among 305 randomly assigned patients (THL, n = 118; TH, n = 120; TL, n = 67), the pCR rate was 56% (95% CI, 47% to 65%) with THL and 46% (95% CI, 37% to 55%) with TH (P = .13), with no effect of dual therapy in the hormone receptor-positive subset but a significant increase in pCR with dual therapy in those with hormone receptor-negative disease (P = .01). The tumors were molecularly heterogeneous by gene expression analysis using mRNA sequencing (mRNAseq). pCR rates significantly differed by intrinsic subtype (HER2 enriched, 70%; luminal A, 34%; luminal B, 36%; P < .001). In multivariable analysis treatment arm, intrinsic subtype, HER2 amplicon gene expression, p53 mutation signature, and immune cell signatures were independently associated with pCR. Post-treatment residual disease was largely luminal A (69%).
pCR to dual HER2-targeted therapy was not significantly higher than single HER2 targeting. Tissue analysis demonstrated a high degree of intertumoral heterogeneity with respect to both tumor genomics and tumor microenvironment that significantly affected pCR rates. These factors should be considered when interpreting and designing trials in HER2-positive disease.
Factors captured in a geriatric assessment can predict morbidity and mortality in older adults, but are not routinely measured in cancer clinical trials. This study evaluated the implementation of a ...geriatric assessment tool in the cooperative group setting.
Patients age ≥ 65 with cancer, who enrolled on cooperative group cancer trials, were eligible to enroll on Cancer and Leukemia Group B (CALGB) 360401. They completed a geriatric assessment tool before initiation of protocol therapy, consisting of valid and reliable geriatric assessment measures which are primarily self-administered and require minimal resources and time by healthcare providers. The assessment measures functional status, comorbidity, cognitive function, psychological state, social support, and nutritional status. The protocol specified criteria for incorporation of the tool in future cooperative group trials was based on the time to completion and percent of patients who could complete their portion without assistance. Patient satisfaction with the tool was captured.
Of the 93 patients who enrolled in this study, five (5%) met criteria for cognitive impairment and three did not complete the cognitive screen, leaving 85 assessable patients (median age, 72 years). The median time to complete the geriatric assessment tool was 22 minutes, 87% of patients (n = 74) completed their portion without assistance, 92% (n = 78) were satisfied with the questionnaire length, 95% (n = 81) reported no difficult questions, and 96% (n = 82) reported no upsetting questions. One hundred percent of health care professionals completed their portion.
This brief, primarily self-administered geriatric assessment tool met the protocol specified criteria for inclusion in future cooperative group clinical trials.
In cancer clinical trials, symptomatic adverse events (AEs), such as nausea, are reported by investigators rather than by patients. There is increasing interest to collect symptomatic AE data via ...patient-reported outcome (PRO) questionnaires, but it is unclear whether it is feasible to implement this approach in multicenter trials.
To examine whether patients are willing and able to report their symptomatic AEs in multicenter trials.
A total of 361 consecutive patients enrolled in any 1 of 9 US multicenter cancer treatment trials were invited to self-report 13 common symptomatic AEs using a PRO adaptation of the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) via tablet computers at 5 successive clinic visits. Patient adherence was tracked with reasons for missed self-reports. Agreement with clinician AE reports was analyzed with weighted κ statistics. Patient and investigator perspectives were elicited by survey. The study was conducted from March 15, 2007, to August 11, 2011. Data analysis was performed from August 9, 2013, to March 21, 2014.
Of the 361 patients invited to participate, 285 individuals enrolled, with a median age of 57 years (range, 24-88), 202 (74.3%) female, 241 (85.5%) white, 73 (26.8%) with a high school education or less, and 176 (64.7%) who reported regular internet use (denominators varied owing to missing data). Across all patients and trials, there were 1280 visits during which patients had an opportunity to self-report (ie, patients were alive and enrolled in a treatment trial at the time of the visit). Self-reports were completed at 1202 visits (93.9% overall adherence). Adherence was highest at baseline and declined over time (visit 1, 100%; visit 2, 96%; visit 3, 95%; visit 4, 91%; and visit 5, 85%). Reasons for missing PROs included institutional errors in 27 of 48 (56.3%) of the cases (eg, staff forgetting to bring computers to patients at visits), patients feeling "too ill" in 8 (16.7%), patient refusal in 8 (16.7%), and internet connectivity problems in 5 (10.4%). Patient-investigator CTCAE agreement was moderate or worse for most symptoms (most κ < 0.05), with investigators reporting fewer AEs than patients across symptoms. Most patients believed that the system was easy to use (234 93.2%) and useful (230 93.1%), and investigators thought that the patient-reported AEs were useful (133 94.3%) and accurate (119 83.2%).
Participants in multicenter cancer trials are willing and able to report their own symptomatic AEs at most clinic visits and report more AEs than investigators. This approach may improve the precision of AE reporting in cancer trials.
Combination irinotecan and cetuximab is approved for irinotecan-refractory metastatic colorectal cancer (mCRC). It is unknown if adding bevacizumab improves outcomes.
In this multicenter, randomized, ...double-blind, placebo-controlled phase II trial, patients with irinotecan-refractory RAS-wildtype mCRC and no prior anti-EGFR therapy were randomized to cetuximab 500 mg/m2, bevacizumab 5 mg/kg, and irinotecan 180 mg/m2 (or previously tolerated dose) (CBI) versus cetuximab, irinotecan, and placebo (CI) every 2 weeks until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and adverse events (AEs).
The study closed early after the accrual of 36 out of a planned 120 patients due to changes in funding. Nineteen patients were randomized to CBI and 17 to CI. Baseline characteristics were similar between arms. Median PFS was 9.7 versus 5.5 months for CBI and CI, respectively (1-sided log-rank P = .38; adjusted hazard ratio HR = 0.64; 95% confidence interval CI, 0.25-1.66). Median OS was 19.7 versus 10.2 months for CBI and CI (1-sided log-rank P = .02; adjusted HR = 0.41; 95% CI, 0.15-1.09). ORR was 36.8% for CBI versus 11.8% for CI (P = .13). Grade 3 or higher AEs occurred in 47% of patients receiving CBI versus 35% for CI (P = .46).
In this prematurely discontinued trial, there was no significant difference in the primary endpoint of PFS between CBI and CI. There was a statistically significant improvement in OS in favor of CBI compared with CI. Further investigation of CBI for the treatment of irinotecan-refractory mCRC is warranted.Clinical Trial Registration: NCT02292758.
In observational studies, higher plasma 25-hydroxyvitamin D (25OHD) levels have been associated with improved survival in metastatic colorectal cancer (CRC).
To determine if high-dose vitamin D3 ...added to standard chemotherapy improves outcomes in patients with metastatic CRC.
Double-blind phase 2 randomized clinical trial of 139 patients with advanced or metastatic CRC conducted at 11 US academic and community cancer centers from March 2012 through November 2016 (database lock: September 2018).
mFOLFOX6 plus bevacizumab chemotherapy every 2 weeks and either high-dose vitamin D3 (n = 69) or standard-dose vitamin D3 (n = 70) daily until disease progression, intolerable toxicity, or withdrawal of consent.
The primary end point was progression-free survival (PFS) assessed by the log-rank test and a supportive Cox proportional hazards model. Testing was 1-sided. Secondary end points included tumor objective response rate (ORR), overall survival (OS), and change in plasma 25(OH)D level.
Among 139 patients (mean age, 56 years; 60 43% women) who completed or discontinued chemotherapy and vitamin D3 (median follow-up, 22.9 months), the median PFS for high-dose vitamin D3 was 13.0 months (95% CI, 10.1 to 14.7; 49 PFS events) vs 11.0 months (95% CI, 9.5 to 14.0; 62 PFS events) for standard-dose vitamin D3 (log-rank P = .07); multivariable hazard ratio for PFS or death was 0.64 (1-sided 95% CI, 0 to 0.90; P = .02). There were no significant differences between high-dose and standard-dose vitamin D3 for tumor ORR (58% vs 63%, respectively; difference, -5% 95% CI, -20% to 100%, P = .27) or OS (median, 24.3 months vs 24.3 months; log-rank P = .43). The median 25(OH)D level at baseline for high-dose vitamin D3 was 16.1 ng/mL vs 18.7 ng/mL for standard-dose vitamin D3 (difference, -2.6 ng/mL 95% CI, -6.6 to 1.4, P = .30); at first restaging, 32.0 ng/mL vs 18.7 ng/mL (difference, 12.8 ng/mL 95% CI, 9.0 to 16.6, P < .001); at second restaging, 35.2 ng/mL vs 18.5 ng/mL (difference, 16.7 ng/mL 95% CI, 10.9 to 22.5, P < .001); and at treatment discontinuation, 34.8 ng/mL vs 18.7 ng/mL (difference, 16.2 ng/mL 95% CI, 9.9 to 22.4, P < .001). The most common grade 3 and higher adverse events for chemotherapy plus high-dose vs standard-dose vitamin D3 were neutropenia (n = 24 35% vs n = 21 31%, respectively) and hypertension (n = 9 13% vs n = 11 16%).
Among patients with metastatic CRC, addition of high-dose vitamin D3, vs standard-dose vitamin D3, to standard chemotherapy resulted in a difference in median PFS that was not statistically significant, but with a significantly improved supportive hazard ratio. These findings warrant further evaluation in a larger multicenter randomized clinical trial.
ClinicalTrials.gov Identifier: NCT01516216.
Study Type – Therapy (cohort)
Level of Evidence 2a
What's known on the subject? and What does the study add?
Despite expanding treatment options for castration‐resistant prostate cancer (CRPC), ...therapies with long response duration remain intangible due to prostate cancer cells’ natural ability to develop iterative resistance. Androgen receptor (AR) signaling has been shown to play a critical role in CRPC and its expression is regulated by the PI3K‐Akt pathway. Thus inhibition of AR signalling and PI3K‐Akt‐mTOR (a downstream mediator of the PI3K‐Akt pathway) pathway is a logical combination in CRPC and we report a phase II trial of RAD001 and bicalutamide.
Our study is the first clinical trial report of an AR inhibitor of PI3K‐Akt‐mTOR. The AR pathway and the PI3K‐Akt‐mTOR pathway are two of the most relevant growth pathway for CRPC. Despite low efficacy results from our trial there will be significant interest in the field for these data (dose, schedule, response, toxicity, trial design) as newer generations of both AR inhibitors and PI3K‐Akt‐mTOR inhibitors are in development and likely will be tested in combination in CRPC.
OBJECTIVES
•
To determine best overall response and duration of response of RAD001, a selective inhibitor of mammalian target of rapamycin, in combination with bicalutamide in castration‐resistant prostate cancer (CRPC).
•
To characterize the toxicity profile of RAD001 in combination with bicalutamide in patients with CRPC.
PATIENTS AND METHODS
•
A phase II study was conducted to explore the efficacy and tolerability of RAD001 (10 mg daily) in combination with bicalutamide (50 mg daily) in men with progressive CRPC.
•
The primary endpoint was a composite of prostate‐specific antigen (PSA) level and measurable disease response by standard criteria.
•
This single‐stage trial with a sample size of 38 eligible patients provided 90% power to differentiate a response rate of ≥40% from a response rate of ≤20%, as expected for bicalutamide alone (α= 0.10, power = 0.90).
RESULTS
•
In total, 36 men were enrolled, with a median (range) age of 68 (60–72) years and median (range) baseline PSA level of 22.2 (8.4–121.3) ng/mL, and 89% had metastatic disease.
•
There were 31 (86%) patients had previously used bicalutamide for a median duration of 7.4 months.
•
There were two patients with a confirmed PSA level decline ≥50%.
•
The median (interquartile range) time to progression was 8.7 (7.9–15.9) weeks.
•
The most common toxicity was grade 1/2 mucositis, which was observed in 20 (56%) patients.
CONCLUSION
•
The combination of RAD001 and bicalutamide in men with CRPC was well tolerated but had low activity and failed to achieve the primary endpoint of improved response compared to the results previously achieved for bicalutamide alone in this population.
Skeletal muscle and adipose tissue express the vitamin D receptor and may be a mechanism through which vitamin D supplementation slows cancer progression and reduces cancer death. In this exploratory ...analysis of a double-blind, multicenter, randomized phase II clinical trial, 105 patients with advanced or metastatic colorectal cancer who were receiving chemotherapy were randomized to either high-dose vitamin D
(4000 IU) or standard-dose (400 IU) vitamin D
. Body composition was measured with abdominal computed tomography at enrollment (baseline) and after cycle 8 of chemotherapy (16 weeks). As compared with standard-dose vitamin D
, high-dose vitamin D
did not significantly change body weight -0.7 kg; (95% CI: -3.5, 2.0), body mass index -0.2 kg/m
; (95% CI: -1.2, 0.7), muscle area -1.7 cm
; (95% CI: -9.6, 6.3), muscle attenuation -0.4 HU; (95% CI: -4.2, 3.2), visceral adipose tissue area -7.5 cm
; (95% CI: -24.5, 9.6), or subcutaneous adipose tissue area -8.3 cm
; (95% CI: -35.5, 18.9) over the first 8 cycles of chemotherapy. Among patients with advanced or metastatic colorectal cancer, the addition of high-dose vitamin D
, vs standard-dose vitamin D
, to standard chemotherapy did not result in any changes in body composition.
Skeletal muscle and adipose tissue express the vitamin D receptor and may be a mechanism through which vitamin D supplementation slows cancer progression and reduces cancer death. In this exploratory ...analysis of a double-blind, multicenter, randomized phase II clinical trial, 105 patients with advanced or metastatic colorectal cancer who were receiving chemotherapy were randomized to either high-dose vitamin D3 (4000 IU) or standard-dose (400 IU) vitamin D3. Body composition was measured with abdominal computed tomography at enrollment (baseline) and after cycle 8 of chemotherapy (16 weeks). As compared with standard-dose vitamin D3, high-dose vitamin D3 did not significantly change body weight −0.7 kg; (95% CI: −3.5, 2.0), body mass index −0.2 kg/m2; (95% CI: −1.2, 0.7), muscle area −1.7 cm2; (95% CI: −9.6, 6.3), muscle attenuation −0.4 HU; (95% CI: −4.2, 3.2), visceral adipose tissue area −7.5 cm2; (95% CI: −24.5, 9.6), or subcutaneous adipose tissue area −8.3 cm2; (95% CI: −35.5, 18.9) over the first 8 cycles of chemotherapy. Among patients with advanced or metastatic colorectal cancer, the addition of high-dose vitamin D3, vs standard-dose vitamin D3, to standard chemotherapy did not result in any changes in body composition.
Zoledronic acid, a third-generation aminobisphosphonate, reduces the incidence of skeletal-related events and pain in patients with bone metastases. The optimal dosing interval for zoledronic acid is ...uncertain.
To determine whether zoledronic acid administered every 12 weeks is noninferior to zoledronic acid administered every 4 weeks.
Randomized, open-label clinical trial conducted at 269 academic and community sites in the United States. Patients (n = 1822) with metastatic breast cancer, metastatic prostate cancer, or multiple myeloma who had at least 1 site of bone involvement were enrolled between May 2009 and April 2012; follow-up concluded in April 2014.
Patients were randomized to receive zoledronic acid administered intravenously every 4 weeks (n = 911) vs every 12 weeks (n = 911) for 2 years.
The primary end point was the proportion of patients having at least 1 skeletal-related event (defined as clinical fracture, spinal cord compression, radiation to bone, or surgery involving bone) within 2 years after randomization and a between-group absolute difference of 7% as the noninferiority margin. Secondary end points included the proportion of patients with at least 1 skeletal-related event by disease type, pain as assessed by the Brief Pain Inventory (range, 0-10; higher scores indicate worse pain), Eastern Cooperative Oncology Group performance status (range, 0-4; higher scores indicate worse disability), incidence of osteonecrosis of the jaw, kidney dysfunction, skeletal morbidity rate (mean number of skeletal-related events per year), and, in a subset of 553 patients, suppression of bone turnover (assessed by C-terminal telopeptide levels).
Among 1822 patients who were randomized (median age, 65 years; 980 53.8% women; 855 with breast cancer, 689 with prostate cancer, and 278 with multiple myeloma), 795 completed the study at 2 years. A total of 260 patients (29.5%) in the zoledronic acid every 4-week dosing group and 253 patients (28.6%) in the every 12-week dosing group experienced at least 1 skeletal-related event within 2 years of randomization (risk difference of -0.3% 1-sided 95% CI, -4% to ∞; P < .001 for noninferiority). The proportions of skeletal-related events did not differ significantly between the every 4-week dosing group vs the every 12-week dosing group for patients with breast cancer, prostate cancer, or multiple myeloma. Pain scores, performance status scores, incidence of jaw osteonecrosis, and kidney dysfunction did not differ significantly between the treatment groups. Skeletal morbidity rates were numerically identical in both groups, but bone turnover was greater (C-terminal telopeptide levels were higher) among patients who received zoledronic acid every 12 weeks.
Among patients with bone metastases due to breast cancer, prostate cancer, or multiple myeloma, the use of zoledronic acid every 12 weeks compared with the standard dosing interval of every 4 weeks did not result in an increased risk of skeletal events over 2 years. This longer interval may be an acceptable treatment option.
clinicaltrials.gov Identifier: NCT00869206.
The ATEMPT trial was designed to determine if treatment with trastuzumab emtansine (T-DM1) caused less toxicity than paclitaxel plus trastuzumab (TH) and yielded clinically acceptable invasive ...disease-free survival (iDFS) among patients with stage I human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC).
Patients with stage I centrally confirmed HER2+ BC were randomly assigned 3:1 to T-DM1 or TH and received T-DM1 3.6 mg/kg IV every 3 weeks for 17 cycles or T 80 mg/m
IV with H once every week × 12 weeks (4 mg/kg load →2 mg/kg), followed by H × 39 weeks (6 mg/kg once every 3 weeks). The co-primary objectives were to compare the incidence of clinically relevant toxicities (CRTs) in patients treated with T-DM1 versus TH and to evaluate iDFS in patients receiving T-DM1.
The analysis population includes all 497 patients who initiated protocol therapy (383 T-DM1 and 114 TH). CRTs were experienced by 46% of patients on T-DM1 and 47% of patients on TH (
= .83). The 3-year iDFS for T-DM1 was 97.8% (95% CI, 96.3 to 99.3), which rejected the null hypothesis (
< .0001). Serially collected patient-reported outcomes indicated that patients treated with T-DM1 had less neuropathy and alopecia and better work productivity compared with patients on TH.
Among patients with stage I HER2+ BC, one year of adjuvant T-DM1 was associated with excellent 3-year iDFS, but was not associated with fewer CRT compared with TH.
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