scholarly journals Efficacy of BRAF and MEK Inhibition in Patients with BRAF-Mutant Advanced Melanoma and Germline CDKN2A Pathogenic Variants

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2440
Author(s):  
Francesco Spagnolo ◽  
Bruna Dalmasso ◽  
Enrica Tanda ◽  
Miriam Potrony ◽  
Susana Puig ◽  
...  
Keyword(s):  
Real World ◽  
Response Rate ◽  
Suppressor Gene ◽  
Phase Iii ◽  
Clinical Activity ◽  
P Value ◽  
Pathogenic Variants ◽  
Phase Iii Trials ◽  
The Difference ◽  
First Time

Inherited pathogenic variants (PVs) in the CDKN2A tumor suppressor gene are among the strongest risk factors for cutaneous melanoma. Dysregulation of the p16/RB1 pathway may intrinsically limit the activity of MAPK-directed therapy due to the interplay between the two pathways. In our study, we assessed, for the first time, whether patients with germline CDKN2A PVs achieve suboptimal results with BRAF inhibitors (BRAFi)+/−MEK inhibitors (MEKi). We compared the response rate of nineteen CDKN2A PVs carriers who received first-line treatment with BRAFi+/−MEKi with an expected rate derived from phase III trials and “real-world” studies. We observed partial response in 16/19 patients (84%), and no complete responses. The overall response rate was higher than that expected from phase III trials (66%), although not statistically significant (p-value = 0.143; 95% CI = 0.60–0.97); the difference was statistically significant (p-value = 0.019; 95% CI = 0.62–0.97) in the comparison with real-world studies (57%). The clinical activity of BRAFi+/−MEKi in patients with germline CDKN2A PV was not inferior to that of clinical trials and real-world studies, which is of primary importance for clinical management and genetic counseling of this subgroup of patients.

Cabozantinib versus other TKIs after CPI treatment in the real-world management of patients with metastatic renal cell carcinoma (mRCC).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 293-293
Author(s):  
Florence Marteau ◽  
Brooke Harrow ◽  
Christine McCarthy ◽  
Joel Wallace ◽  
Alisha Monnette ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Real World ◽  
Renal Cell ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
P Value ◽  
The Real ◽  
The Us

293 Background: Checkpoint inhibitors (CPIs) are a treatment option for patients with metastatic renal cell carcinoma (mRCC), but there is limited clinical data on the efficacy of targeted therapies following CPI treatment. Cabozantinib is a tyrosine kinase inhibitor (TKI) that targets multiple receptor kinases implicated in tumorigenesis. In the US, cabozantinib is approved for use in patients with advanced RCC including after CPI treatment. Methods: This retrospective observational cohort study (NCT04353765) evaluated outcomes associated with cabozantinib or other TKIs (axitinib, lenvatinib, pazopanib, sorafenib, sunitinib) in patients with mRCC following CPI treatment. Eligible patients initiated TKI therapy between May 1, 2016 and Sep 31, 2019 and had received a CPI as their last systemic treatment prior to TKI therapy. Patients were identified from the US Oncology Network iKnowMed electronic health record database through structured queries and a targeted chart review. The following real-world outcomes were assessed: 6-month response rate (RR6months; primary); overall response rate (ORR); overall survival (OS); time to treatment discontinuation (TTD); rates of dose reductions, and discontinuation due to adverse events (AEs). The p value for RR6months was used to test for non-inferiority. Results: Eligible patients ( n = 247) had a mean (SD) age of 65.9 (10.5) years and 74.1% were male; 75.7% ( n = 187) received cabozantinib and 24.3% ( n = 60) received other TKIs. All patients had intermediate or poor MSKCC score; more poor-risk patients received cabozantinib than other TKIs (28.9% vs 20%). Outcomes data are shown in the Table. Compared with other TKIs, cabozantinib was associated with a significantly higher RR6months and ORR, and TTD was twice as long with cabozantinib. Discontinuation due to AEs was more frequent with other TKIs than with cabozantinib, although this was not statistically significant; 21.7% of discontinuations occurred during the first 3 months of treatment. AEs leading to discontinuation were consistent with the known safety profile of the products. Conclusions: In this mRCC population receiving routine care in the US, cabozantinib was used more frequently than other TKIs after CPI treatment. Cabozantinib was an effective and well tolerated option post-CPI, with a high response rate in the real-world setting.abozantinib was associated with a significantly higher response rate and a lower discontinuation rate due to AEs; TTD was double that of other TKIs. [Table: see text]

Q-TWiST analysis of tivozanib (T) versus sorafenib (S) in patients with advanced renal cell carcinoma (RCC) in the TIVO-3 study.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 298-298
Author(s):  
Michael Szarek ◽  
Michael N. Needle ◽  
Brian I. Rini ◽  
Sumanta K. Pal ◽  
David F. McDermott ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Phase Iii ◽  
P Value ◽  
Patient Centered ◽  
Health States ◽  
Significant Difference ◽  
Phase Iii Study ◽  
The Difference ◽  
Similar Survival ◽  
Mean Differences

298 Background: In the randomized phase III study TIVO-3, the VEGFR-TKI tivozanib (TIVO) increased progression-free survival with better tolerability but no difference in overall survival (OS) relative to sorafenib (SORA) as third- or fourth-line therapy in patients with metastatic RCC. These results provide motivation to apply quality-adjusted time without symptoms of disease and toxicity (Q-TWiST) methods to quantify the net health benefits of TIVO, in the presence of similar survival, when compared to SORA. Methods: In application of Q-TWiST, patient-level OS was subdivided into three mutually exclusive states: time with toxicity (TOX), time without symptoms and toxicity (TWiST), and time after progression/relapse (REL). Mean Q-TWiST was calculated by applying utility coefficients of 0.5, 1.0, and 0.5 to the restricted mean (max 36 months follow-up) health states of TOX, TWiST, and REL, respectively; 95% CIs for the means and mean differences were estimated by bootstrap distributions. Relative Q-TWiST gain was defined as the mean absolute Q-TWiST difference divided by the SORA mean OS. Results: Mean TWiST was significantly longer for TIVO than for SORA (10.30 months v.5.35 months; Table). Mean REL time was significantly shorter for TIVO, with no difference in mean TOX time. Mean Q-TWiST was 15.04 and 12.78 months for TIVO and SORA, respectively, a statistically significant difference (p=0.0493). The relative gain for TIVO was 11.2%. Clinical trial information: NCT02627963 . Values in table are mean (95% CI) in months or p-value for difference in treatment group means. Conclusions: The difference in Q-TWiST in TIVO-3 was primarily driven by benefits of TIVO in TWiST, partially offset by superiority of SORA in REL time. As a third- or fourth-line treatment for RCC, TIVO significantly increased Q-TWiST relative to SORA, primarily through an increase in TWiST, which is generally considered to be the state with highest utility to patients. Consequently, Q-TWiST may be considered an alternative patient-centered measure of benefit of TIVO in these settings. [Table: see text]

Phase II Trial of 4′-Epi-Doxorubicin in Locally Advanced or Metastatic Gastric Cancer

1988 ◽  
Vol 74 (3) ◽  
pp. 313-315 ◽  
Author(s):  
Eduardo Cazap ◽  
Roberto Estevez ◽  
Mario Bruno ◽  
Daniel Levy ◽  
Carlos Algamiz ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Gastric Adenocarcinoma ◽  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Locally Advanced ◽  
Metastatic Gastric Cancer ◽  
Phase Iii ◽  
Future Studies ◽  
Phase Iii Trials

Patients with locally advanced or metastatic gastric adenocarcinoma received an i.v. bolus of 4′-epi-doxorubicin, 75/mg/m2/cycle, every 21 days. Partial responses were observed in 5 of 23 evaluable patients (21.7%). Treatment was generally well tolerated and toxicity was mild. The response rate to epirubicin appears to be very similar to that reported for doxorubicin. Larger doses of epirubicin could be safely used in future studies, and further evaluation of epirubicin in phase III trials is indicated.

scholarly journals Clinical Development of PARP Inhibitors in Treating Metastatic Castration-Resistant Prostate Cancer

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 860 ◽  
Author(s):  
Jacob J. Adashek ◽  
Rohit K. Jain ◽  
Jingsong Zhang
Keyword(s):  
Prostate Cancer ◽  
Unmet Need ◽  
Parp Inhibitors ◽  
Phase Iii ◽  
Clinical Activity ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Phase Ii Studies ◽  
Phase Iii Trials ◽  
Signaling Inhibitors

The approval of upfront abiraterone for castration-sensitive prostate cancer and the approval of enzalutamide and apalutamide for non-metastatic castration-resistant prostate cancer have led to early utilization of potent androgen receptor (AR) signaling inhibitors in treating advanced prostate cancer. There is an unmet need to develop novel therapies beyond targeting AR signaling for metastatic castration-resistant prostate cancer (mCRPC). Poly (ADP-ribose) polymerase inhibitors (PARPi) belong to a class of targeted agents being developed for the treatment of homologous recombination repair (HRR) deficient tumors. Olaparib, rucaparib, niraparib, veliparib, and talazoparib were evaluated in early phase trials as a monotherapy for HRR-deficient mCRPC. Among them, olaparib and rucaparib have breakthrough designations for BRCA1/2-mutated mCRPC. Phase II studies also reported clinical activity of the PARPi and abiraterone combination and the PARPi checkpoint inhibitor combination in HRR-intact mCRPC. Ongoing phase III trials are testing these combinations as frontline or later line treatments for mCRPC. This review summarizes the critical clinical data as well as ongoing clinical trials for developing PARPi in treating mCRPC.

scholarly journals Comparative effectiveness of improvement in pain and physical function for baricitinib versus adalimumab, tocilizumab and tofacitinib monotherapies in rheumatoid arthritis patients who are naïve to treatment with biologic or conventional synthetic disease-modifying antirheumatic drugs: a matching-adjusted indirect comparison

RMD Open ◽  
2020 ◽  
Vol 6 (1) ◽  
pp. e001131 ◽  
Author(s):  
B Fautrel ◽  
B Zhu ◽  
P C Taylor ◽  
M van de Laar ◽  
P Emery ◽  
...  
Keyword(s):  
Physical Function ◽  
Indirect Comparison ◽  
Health Assessment ◽  
Pain Reduction ◽  
Phase Iii ◽  
Disease Modifying Antirheumatic Drugs ◽  
Antirheumatic Drugs ◽  
Phase Iii Trials ◽  
Disease Modifying ◽  
The Difference

ObjectiveTo compare improvement in pain and physical function for patients treated with baricitinib, adalimumab, tocilizumab and tofacitinib monotherapy from randomised, methotrexate (MTX)-controlled trials in conventional synthetic disease-modifying antirheumatic drugs (csDMARDs)/biologic (bDMARD)-naïve RA patients using matching-adjusted indirect comparisons (MAICs).MethodsData were from Phase III trials on patients receiving monotherapy baricitinib, tocilizumab, adalimumab, tofacitinib or MTX. Pain was assessed using a visual analogue scale (0–100 mm) and physical function using the Health Assessment Questionnaire-Disability Index (HAQ-DI). An MAIC based on treatment-arm matching, an MAIC with study-level matching and Bucher’s method without matching compared change in outcomes between therapies. Matching variables included age, gender, baseline disease activity and baseline value of outcome measure.ResultsWith all methods, greater improvements were observed in pain and HAQ-DI at 6 months for baricitinib compared with adalimumab and tocilizumab (p<0.05). Differences in treatment effects (TEs) favouring baricitinib for pain VAS for treatment-arm matching, study-level matching and Bucher’s method, respectively, were −12, −12 and −12 for baricitinib versus adalimumab and −7, −7 and −9 for baricitinib versus tocilizumab; the difference in TEs for HAQ-DI was −0.28, −0.28 and −0.30 for adalimumab and −0.23, −0.23 and −0.26 for tocilizumab. For baricitinib versus tofacitinib, no statistically significant differences for pain improvement were observed except with one of the three methods (Bucher method) and none for HAQ-DI.ConclusionsResults suggest greater pain reduction and improved physical function for baricitinib monotherapy compared with tocilizumab and adalimumab monotherapy. No statistically significant differences in pain reduction and improved physical function were observed between baricitinib and tofacitinib with the MAIC analyses.

Carboplatin (C) plus paclitaxel (P) versus carboplatin plus pegylated liposomal doxorubicin (PLD) in patients with advanced ovarian cancer (AOC): Final analysis of the MITO-2 randomized multicenter trial.

2010 ◽  
Vol 28 (18_suppl) ◽  
pp. LBA5033-LBA5033 ◽  
Author(s):  
S. Pignata ◽  
G. Scambia ◽  
A. Savarese ◽  
R. Sorio ◽  
E. Breda ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Response Rate ◽  
Multivariable Analysis ◽  
Advanced Ovarian Cancer ◽  
Final Analysis ◽  
Phase Iii ◽  
P Value ◽  
First Line ◽  
Significant Difference ◽  
Line Chemotherapy

LBA5033 Background: CP is standard first-line chemotherapy for AOC. MITO-2 (Multicentre Italian Trials in Ovarian Cancer) is an academic multicenter randomized phase III study, testing whether C-PLD is more effective than CP. Methods: AOC chemo-naïve patients (pts), stage IC-IV, aged≤75, ECOG PS≤2, were randomized to CP (C AUC5 + P 175 mg/m2,d1q3w) or to C-PLD (C AUC5 + PLD 30 mg/m2,d1q3w), both for 6 cycles. Primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), response rate, toxicity and quality of life (QoL). To have 80% power in detecting a 0.80 HR in PFS, with 2-sided α error 0.05, 632 events were needed and 820 pts were planned. Response rate and toxicity have been reported at ASCO 2009 (abs #LBA5508). All analyses are based on intention to treat. Results: From Jan ’03 to Nov ’07, 820 pts were randomized, 410 to each arm. Median age was 57 yrs (range 21-77). Stage III (60%) and IV (21%) were prevalent. A plateau in PFS events was reached before obtaining the planned number. Thus, following an IDMC recommendation, the final analysis was done with 556 events occurred as of December 31, 2009. This size is consistent with HR to be detected equal to 0.79, with 80% power. With a median follow-up of 40.2 months, median PFS was 19.0 and 16.8 months with C-PLD and CP, respectively (HR 0.95, 95%CI 0.81-1.13, log-rank p value=0.58). Lack of significant difference was confirmed (HR 0.96, 95%CI 0.81-1.14) at multivariable analysis adjusted by stage, PS, residual disease, age and size of the institution. There was no heterogeneity of treatment effect among major subgroups. With 313 deaths recorded, median OS was 61.6 and 53.2 months with C-PLD and CP, respectively (HR 0.89, 95%CI 0.72-1.12, log-rank p value=0.32). QoL data will be presented at the meeting. Conclusions: In the MITO-2 trial, C-PLD was not found to be superior to CP, which remains the standard first-line chemotherapy for AOC.However, given the observed confidence interval and the different toxicity profile, C-PLD could be considered an alternative to standard therapy. Study was partially supported by Schering-Plough. [Table: see text]

Randomized phase II study of pharmacodynamic separation (PDS) of pemetrexed (Pem) and erlotinib (Erl) versus pem alone in patients (pts) with advanced non-small cell lung cancer (NSCLC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8097-8097 ◽  
Author(s):  
Tianhong Li ◽  
Bilal Piperdi ◽  
William Vincent Walsh ◽  
Mimi Kim ◽  
Rasim Gucalp ◽  
...  
Keyword(s):  
Phase Ii ◽  
Primary Endpoint ◽  
Performance Status ◽  
Progression Free Survival ◽  
Dose Schedule ◽  
Phase Iii ◽  
Smoking History ◽  
Clinical Activity ◽  
P Value ◽  
Randomized Phase Ii

8097 Background: Preclinical and phase I studies showed that PDS optimizes cytotoxicity of concurrent EGFR inhibitors and chemotherapy. We conducted a randomized phase II trial to assess relative efficacy of Pem alone (Arm A) versus Pem +Erl on a PDS dose-schedule (Arm B) as 2nd-line therapy in pts with advanced NSCLC (NCT00950365). Methods: Eligible pts were randomized 2:1 (Arm B: A), stratified by sex, smoking history, and performance status (0/1 vs 2). Accrual was restricted to non-squamous histology in 2009. Treatment: Arm A – Pem 500 mg/m2IV on day 1; Arm B – Pem + Erl 150 mg po QD on days 2-17. 1 cycle = 3 weeks. Primary endpoint was progression-free survival (PFS). 50 pts in Arm B were needed to detect an increase in median PFS from ~3 to 4.5 months. Results: 83 pts were entered. Age: 63 yo. Female: 42 (53%). Smoking ≥15PY: 58 (72%). Nonsquamous: 78 (99%). The primary endpoint of the study was met: Efficacy results from 79 eligible pts showed 1.6-fold longer PFS in Arm B (4.6 m) compared to Arm A (2.8 m). Although the study was not designed to directly compare two arms, p value was 0.052. Toxicity: G3/4 Hem (A/B): 8(30%)/12(23%); Neutropenia with infection (A/B): 0/3(6%). G3/4 Non-Hem (A/B): skin rash: 0/3(6%); diarrhea: 0/2(4%); joint pain: 1(4%)/6(11.5%). Treatment related death (A/B): 0/1. Interstitial lung disease (A/B): 0/1. Conclusions: PDS of Pem and Erl is well tolerated and has promising clinical activity in 2nd-line non-squamous NSCLC. Ongoing correlative studies aim to identify a subgroup of patients who might benefit most from this treatment, which will guide the design of a confirmatory phase III study. (UL1 RR024146, P30CA093373, Lilly, Astellas) Clinical trial information: NCT00950365. [Table: see text]

Patterns of osteoporosis (OP) in survivors of colorectal cancer (CRC) enrolled on SWOG trials.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 10056-10056
Author(s):  
Afsaneh Barzi ◽  
Dawn L. Hershman ◽  
Cathee Till ◽  
Heinz-Josef Lenz ◽  
Howard S. Hochster ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Fracture Risk ◽  
Cancer Patients ◽  
Phase Iii ◽  
P Value ◽  
National Hospital Discharge Survey ◽  
Prostate Cancer Prevention ◽  
The Difference ◽  
Using Data ◽  
Colorectal Cancer Patients

10056 Background: There are currently 1.5 million CRC survivors in US and this number will continue to rise with advancements in treatment. The risk of OP in CRC survivors has not been well described. Methods: We used data from 3 SWOG CRC treatment trials, all of which were phase III and had long term follow-up. Enrollees were linked to Medicare claim files for identification of OP and fractures using HCPCS and ICD9 codes. First, we compared patterns of osteoperosis and fracture risk by sex in colorectal cancer patients. To assess whether patterns of fracture risk by sex differed between patients with vs. without colorectal cancer, we compared the difference in fracture risk by sex in colorectal cancer patients to the difference in fracture risk by sex in the general U.S. population, using data from the National Health Interview Survey (NHIS) and the National Hospital Discharge Survey (NHDS). Finally, we assessed whether absolute estimates of osteoperosis and fracture risk differed between men with colorectal cancer and men without colorectal cancer. Comparison data for men without colorectal cancer were obtained from the placebo arm of the Prostate Cancer Prevention trial (PCPT). Results: We linked 1233 CRC cases with Medicare claims. The median age at CRC diagnosis was marginally higher for women (65 vs 64 ys, p = 0.03). 47% of females, 15% of men with CRC, and 19% of men without CRC had a OP diagnosis. The female to male ratio of osteoporotic fracture in general U.S. population was 1.67, while the same ratio in CRC survivors was 2.84, an increase of 70% (p-value < 0.001). Conclusions: Our study indicates that the risk disparity for OP fracture for females is much greater in CRC survivors than in the general U.S. population. This may be due to more OP diagnoses for female CRC survivors, but not for male CRC survivors.

Cabozantinib for metastatic castration-resistant prostate cancer (mCRPC) following docetaxel: Combined analysis of two phase III trials.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 225-225 ◽  
Author(s):  
Gregory Russell Pond ◽  
Guru Sonpavde ◽  
Karim Fizazi ◽  
Johann S. De Bono ◽  
Ethan M Basch ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Survival Data ◽  
Regression Models ◽  
Hazard Ratio ◽  
Phase Iii ◽  
P Value ◽  
Computer Assisted ◽  
Two Phase ◽  
Combining Data ◽  
Phase Iii Trials

225 Background: Two phase III trials, COMET-1 and COMET-2, have reported that cabozantinib did not extend overall survival (OS) outcomes compared to prednisone and prednisone plus mitoxantrone respectively, in unselected post-docetaxel patients with mCRPC. We conducted a retrospective analysis of a combined dataset of these trials in an attempt to identify a benefit in subsets of patients based on prognostic risk factors. Methods: Baseline characteristics and survival data were combined for COMET-1 and COMET-2. Prognostic ability of baseline factors on survival was evaluated using Cox proportional hazards regression models, which incorporated the factors in the modern post-docetaxel nomogram and overall bone scan lesion area (BSLA) by computer-assisted analysis. Regression models included trial as a stratification factor. Evaluation of potentially benefited subsets was performed by the use of interaction terms between the factors and cabozantinib. The hazard ratio between cabozantinib and comparator arms was evaluated after adjusting for baseline prognostic factors. All tests were 2-sided and a p-value ≤0.05 was considered statistically significant. Results: A total of 1147 post-docetaxel patients with mCRPC were available (1028 from COMET-1 and 119 from COMET-2). Age, albumin, LDH and BSLA were statistically significant prognostic factors in addition to variables from the Halabi model (site of metastases, pain, docetaxel-free interval, ECOG-PS, hemoglobin, alkaline phosphatase, PSA). There was no consistent interaction effect on survival between cabozantinib vs. comparator arms for any prognostic group. After adjusting for multiple potential prognostic factors, treatment with cabozantinib vs. comparator was associated with an observed hazard ratio of 0.77 (95% CI = 0.65 to 0.92, p = 0.003) for survival. Conclusions: After combining data from both COMET-1 and COMET-2 trials, no differential effect of cabozantinib on survival was observed for any prognostic risk factor. A modest treatment effect of cabozantinib on OS was observed after controlling for multiple potential prognostic factors.

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