scholarly journals Molecular profiling of advanced malignancies guides first-line N-of-1 treatments in the I-PREDICT treatment-naïve study

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Jason K. Sicklick ◽  
Shumei Kato ◽  
Ryosuke Okamura ◽  
Hitendra Patel ◽  
Mina Nikanjam ◽  
...  
Keyword(s):  
Disease Control ◽  
Progression Free Survival ◽  
Complete Response ◽  
Disease Control Rate ◽  
Unknown Primary ◽  
Combination Therapies ◽  
First Line ◽  
Free Survival ◽  
Treatment Naïve ◽  
Matching Score

Abstract Background Malignancies are molecularly complex and become more resistant with each line of therapy. We hypothesized that offering matched, individualized combination therapies to patients with treatment-naïve, advanced cancers would be feasible and efficacious. Patients with newly diagnosed unresectable/metastatic, poor-prognosis cancers were enrolled in a cross-institutional prospective study. Methods A total of 145 patients were included in the study. Genomic profiling (tissue and/or circulating tumor DNA) was performed in all patients, and PD-L1 immunohistochemistry, tumor mutational burden, and microsatellite status assessment were performed in a subset of patients. We evaluated safety and outcomes: disease-control rate (stable disease for ≥ 6 months or partial or complete response), progression-free survival (PFS), and overall survival (OS). Results Seventy-six of 145 patients (52%) were treated, most commonly for non-colorectal gastrointestinal cancers, carcinomas of unknown primary, and hepatobiliary malignancies (53% women; median age, 63 years). The median number of deleterious genomic alterations per patient was 5 (range, 0–15). Fifty-four treated patients (71%) received ≥ 1 molecularly matched therapy, demonstrating the feasibility of administering molecularly matched therapy. The Matching Score, which reflects the percentage of targeted alterations, correlated linearly with progression-free survival (R2 = 0.92; P = 0.01), and high (≥ 60%) Matching Score was an independent predictor of improved disease control rate [OR 3.31 (95% CI 1.01–10.83), P = 0.048], PFS [HR 0.55 (0.28–1.07), P = 0.08], and OS [HR 0.42 (0.21–0.85), P = 0.02]. Serious adverse event rates were similar in the unmatched and matched groups. Conclusions Personalized combination therapies targeting a majority of a patient’s molecular alterations have antitumor activity as first-line treatment. These findings underscore the feasibility and importance of using tailored N-of-1 combination therapies early in the course of lethal malignancies. Trial registration I-PREDICT (NCT02534675) was registered on August 25, 2015.

First-line treatment of iNHL or MCL patients with BR or R-CHOP/R-CVP: Results of the BRIGHT 5-year follow-up study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 7500-7500 ◽  
Author(s):  
Ian Flinn ◽  
Richard van der Jagt ◽  
Julie E. Chang ◽  
Peter Wood ◽  
Tim E. Hawkins ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Complete Response ◽  
Rank Test ◽  
First Line ◽  
Open Label ◽  
Free Survival ◽  
Non Hodgkin Lymphoma ◽  
Duration Of Response ◽  
Treatment Naïve

7500 Background: BRIGHT, a phase 3, open-label, noninferiority study comparing efficacy and safety of bendamustine plus rituximab (BR) vs rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) or rituximab with cyclophosphamide, vincristine and prednisone (R-CVP) in treatment-naive patients (pts) with indolent non-Hodgkin lymphoma (iNHL) or mantle cell lymphoma (MCL), showed that the complete response rate for first-line BR was statistically noninferior to R-CHOP/R-CVP ( Blood 2014). Pts were monitored for ≥5 years (yr) to assess the overall effect of BR or R-CHOP/R-CVP in a controlled clinical setting. This analysis reports the time-to-event variables of the 5-yr follow-up (FU) study. Methods: Pts with iNHL or MCL randomized to 6-8 cycles of BR or R-CHOP/R-CVP underwent complete assessments at end of treatment, then were monitored regularly. Progression-free survival (PFS), event-free survival (EFS), duration of response (DOR) and overall survival (OS) were compared using a stratified log-rank test. Results: Of 447 randomized pts, 224 received BR, 104 R-CHOP, and 119 R-CVP; 419 entered the FU. The median FU time was 65.0 and 64.1 months for BR and R-CHOP/R-CVP, respectively. The 5-yr PFS rate was 65.5% (95% CI 58.5-71.6) and 55.8% (48.4-62.5), and OS was 81.7% (75.7-86.3) and 85% (79.3-89.3) for BR and R-CHOP/R-CVP, respectively. The hazard ratio (95% CI) for PFS was 0.61 (0.45-0.85; P= .0025), EFS 0.63 (0.46-0.84; P= .0020), DOR 0.66 (0.47-0.92; P= .0134), and OS 1.15 (0.72-1.84; P= .5461) comparing BR vs R-CHOP/R-CVP. Similar results were found in iNHL [PFS 0.70 (0.49-1.01; P= .0582)] and MCL [PFS 0.40 (0.21-0.75; P= .0035)], with the strongest effect in MCL. Use of R maintenance was similar, 43% in BR and 45% in R-CHOP/R-CVP. B was included as second-line in 27 (36%) of the 75 pts requiring therapy who originally received R-CHOP/R-CVP. Comparable safety profiles with expected adverse events were observed in the FU study in BR vs R-CHOP/R-CVP. Conclusions: The long-term FU of the BRIGHT study has confirmed that PFS, EFS, and DOR were significantly better for BR, and OS was not statistically different between BR and R-CHOP/R-CVP. The safety profile was as previously reported. Clinical trial information: NCT00877006.

Outcomes after retreatment with MAPK inhibitors and immune checkpoint inhibitors in melanoma patients

2021 ◽  
Author(s):  
Oana D Persa ◽  
Cornelia Mauch
Keyword(s):  
Disease Control ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Univariate Analysis ◽  
Progression Free Survival ◽  
Advanced Melanoma ◽  
Disease Control Rate ◽  
Unknown Primary ◽  
Free Survival ◽  
Mapk Inhibitors

Background: When patients with advanced melanoma progress after MAPK inhibitor (MAPKI) and immune checkpoint inhibitor (ICI) treatment, they can either undergo chemotherapy or rechallenge with previously used treatments. Methods: The outcomes of 48 patients retreated with MAPKIs and 50 patients retreated with ICIs following progression were retrospectively analyzed. Results: Upon retreatment with MAPKIs, the disease control rate was 60%. Univariate analysis of possible risk factors associated with short progression-free survival upon MAPKI treatment showed elevated lactate dehydrogenase to be associated with decreased progression-free survival. Disease control rate after ICI retreatment was 24%. Melanoma of unknown primary was associated with prolonged progression-free survival upon ICI retreatment. Conclusion: Retreatment with MAPKIs or ICIs is a feasible option for patients with advanced melanoma.

scholarly journals 177Lu-DOTATATE Plus Radiosensitizing Capecitabine Versus Octreotide Long-Acting Release as First-Line Systemic Therapy in Advanced Grade 1 or 2 Gastroenteropancreatic Neuroendocrine Tumors: A Single-Institution Experience

2021 ◽  
pp. 1167-1175
Author(s):  
Swayamjeet Satapathy ◽  
Bhagwant R. Mittal ◽  
Ashwani Sood ◽  
Apurva Sood ◽  
Rakesh Kapoor ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Systemic Therapy ◽  
Objective Response ◽  
Progression Free Survival ◽  
First Line ◽  
Gastroenteropancreatic Neuroendocrine Tumors ◽  
Free Survival ◽  
Octreotide Lar ◽  
Treatment Naïve ◽  
Long Acting

PURPOSE To compare the efficacy and safety of 177Lu-DOTATATE plus radiosensitizing capecitabine and octreotide long-acting release (LAR) as first-line systemic therapy in advanced well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs). MATERIALS AND METHODS Data of consecutive patients of advanced inoperable or metastatic grade 1 or 2 GEP-NETs treated with first-line 177Lu-DOTATATE plus radiosensitizing capecitabine or octreotide LAR from September 2012 to December 2019 were collected and analyzed for response, toxicity, and survival outcomes. RESULTS Seventy-six patients (median age: 53 years; range 14-81 years) with treatment-naïve advanced grade 1 or 2 GEP-NETs were included. Thirty-six patients received a median cumulative dose of 27.3 GBq of 177Lu-DOTATATE intravenously at 8-12 weeks' intervals along with 1,250 mg/m2 oral capecitabine on days 0-14 of each cycle of 177Lu-DOTATATE, whereas 40 patients were administered 30 mg octreotide LAR intramuscularly every 4 weeks. Using response evaluation criteria in solid tumor 1.1, the objective response rate was 38% in the 177Lu-DOTATATE arm compared with 15% in the octreotide LAR arm ( P = .025), whereas the disease control rates were 88% and 67% in 177Lu-DOTATATE and octreotide LAR arms, respectively ( P = .035). The median durations of progression-free survival in the 177Lu-DOTATATE and octreotide LAR arms were 54 months and 16 months, respectively ( P = .017), whereas the median overall survival was not reached and not significantly different across both the arms. Of the treatment-related adverse events, no major difference was observed in the occurrence of grade 3 or 4 toxicities between the two treatment arms. CONCLUSION First-line systemic 177Lu-DOTATATE plus radiosensitizing capecitabine achieved better radiologic response and longer progression-free survival compared with octreotide LAR in patients with advanced grade 1 or 2 GEP-NETs. Future randomized controlled trials are, however, required to determine the best treatment sequence for the treatment-naïve patients with advanced GEP-NETs.

scholarly journals Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION)

Blood ◽  
2014 ◽  
Vol 123 (4) ◽  
pp. 494-500 ◽  
Author(s):  
Elias Jabbour ◽  
Hagop M. Kantarjian ◽  
Giuseppe Saglio ◽  
Juan Luis Steegmann ◽  
Neil P. Shah ◽  
...  
Keyword(s):  
Overall Survival ◽  
Myeloid Leukemia ◽  
Progression Free Survival ◽  
Early Response ◽  
First Line ◽  
Phase 3 ◽  
Free Survival ◽  
Key Points ◽  
Treatment Naïve

Key Points In a 3-year follow-up of the DASatinib versus Imatinib Study In treatment-Naive CML patients trial, first-line dasatinib resulted in faster and deeper responses compared with imatinib. Deeper responses at 3, 6, and 12 months were associated with better 3-year progression-free survival and overall survival.

scholarly journals Post first-line dacarbazine or temozolomide in neuroendocrine carcinoma

2020 ◽  
Vol 9 (6) ◽  
pp. 498-505
Author(s):  
Thomas Couronne ◽  
Paul Girot ◽  
Julien Hadoux ◽  
Thierry Lecomte ◽  
Alice Durand ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Unknown Primary ◽  
Line Treatment ◽  
First Line ◽  
Morphological Response ◽  
Free Survival ◽  
Significant Difference ◽  
Secondary Endpoints ◽  
Morphological Responses ◽  
Line Chemotherapy

Objective First-line chemotherapy in metastatic neuroendocrine carcinomas (NECs) is based on etoposide and platinum. However, there is no standard concerning second-line treatment. The objective of this study was to evaluate efficacy and tolerance of dacarbazine or temozolomide in metastatic digestive NEC as post first-line treatment. Material and methods This study included patients with a metastatic NEC of digestive or unknown primary site. All patients received platinum-etoposide as first-line chemotherapy. Primary endpoint was progression-free survival (PFS). Secondary endpoints were clinical/morphological responses, toxicity, and overall survival (OS). Results Twenty-seven patients were included: 17 received dacarbazine and 10 temozolomide as post-first line treatments. Median PFS was 3.0 (95%CI (2.2;3.7)) months. There was no significant difference between dacarbazine and temozolomide on PFS. Clinical and morphological responses were found in 12 and 9 patients, respectively. Median OS was 7.2 (95%CI (2.2;12.2)) months. The toxicity profile was that expected with such treatments. Conclusion LV5FU2-dacarbazine or temozolomide-capecitabine chemotherapies allow a temporary clinical response for almost half of patients and/or a morphological response for a third of patients.

scholarly journals Inflammatory Markers Predict Survival in Patients With Advanced Gastric and Colorectal Cancers Receiving Anti–PD-1 Therapy

2021 ◽  
Vol 9 ◽  
Author(s):  
Xiaona Fan ◽  
Dan Wang ◽  
Wenjing Zhang ◽  
Jinshuang Liu ◽  
Chao Liu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Disease Control ◽  
Inflammatory Markers ◽  
Overall Response Rate ◽  
Response Rate ◽  
Progression Free Survival ◽  
Disease Control Rate ◽  
Free Survival ◽  
Lymphocyte Ratio

There is a lack of useful biomarkers for predicting the efficacy of anti–programmed death-1 (PD-1) therapy for advanced gastric and colorectal cancer. To address this issue, in this study we investigated the correlation between inflammatory marker expression and survival in patients with advanced gastric and colorectal cancer. Data for 111 patients with advanced gastric and colorectal cancer treated with anti–PD-1 regimens were retrospectively analyzed. Neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), and clinical characteristics of each patient were selected as the main variables. Overall response rate, disease control rate, and progression-free survival were primary endpoints, and overall survival and immune-related adverse events (irAEs) were secondary endpoints. The chi-squared test and Fisher’s exact test were used to evaluate relationships between categorical variables. Uni- and multivariate Cox regression analyses were performed, and median progression-free survival and overall survival were estimated with the Kaplan–Meier method. The overall response rate and disease control rate of anti–PD-1therapy in advanced gastric and colorectal tumors were 12.61 and 66.66%, respectively. The patients with MLR < 0.31, NLR < 5, and PLR < 135 had a significantly higher disease control rate than those with MLR > 0.31, NLR > 5, and PLR > 135 (P < 0.05). The multivariate analysis revealed that MLR < 0.31, BMI > 18.5, and anti–PD-1 therapy in first-line were associated with prolonged PFS. MLR < 0.31 and BMI > 18.5 were associated with prolonged overall survival. The irAE rate differed significantly between PLR groups, and PLR < 135 was associated with an increased rate of irAEs (P = 0.028). These results indicate that the inflammatory markers NLR, MLR, and PLR have clinical utility for predicting survival or risk of irAEs in patients with advanced gastric cancer and colorectal cancer.

scholarly journals Surgery for Unresectable Stage IIIC and IV Melanoma in the Era of New Systemic Therapy

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1176 ◽  
Author(s):  
Stephanie A. Blankenstein ◽  
Maureen J. B. Aarts ◽  
Franchette W. P. J. van den Berkmortel ◽  
Marye J. Boers-Sonderen ◽  
Alfons J. M. van den Eertwegh ◽  
...  
Keyword(s):  
Disease Control ◽  
Systemic Therapy ◽  
Progression Free Survival ◽  
Complete Response ◽  
Stage Iiic ◽  
Free Survival ◽  
Unresectable Stage ◽  
Melanoma Treatment ◽  
Melanoma Patients

Opportunities for surgical treatment in metastatic melanoma patients have re-emerged due to the development of novel systemic therapeutics over the past decade. The aim of this study is to present data on outcomes of surgery in patients with unresectable stage IIIC and IV melanoma, who have previously been treated with immunotherapy or targeted therapy. Data was extracted from the Dutch Melanoma Treatment Registry (DMTR) on 154 patients obtaining disease control to systemic therapy and undergoing subsequent surgery. Disease control was defined as a complete response (CR), which was seen in 3.2% of patients; a partial response (PR), seen in 46.1% of patients; or stable disease (SD), seen in 44.2% of patients. At a median follow-up of 10.0 months (interquartile range 4–22) after surgery, the median overall survival (OS) had not been reached in our cohort and median progression-free survival (PFS) was 9.0 months (95% CI 6.3–11.7). A CR or PR at first follow-up after surgery was associated with both a better OS and PFS compared to stable or progressive disease (p < 0.001). We conclude that selected patients can benefit from surgery after achieving disease control with systemic therapy.

A phase II trial of trastuzumab combined with irinotecan in patients with advanced HER2-positive chemo-refractory gastric cancer: OGSG1203 (HERBIS-5).

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 128-128 ◽  
Author(s):  
Kazuhiro Nishikawa ◽  
Daisuke Sakai ◽  
Junji Kawada ◽  
Ryohei Kawabata ◽  
Tomono Kawase ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Overall Survival ◽  
Disease Control ◽  
Intravenous Infusion ◽  
Response Rate ◽  
Progression Free Survival ◽  
Disease Control Rate ◽  
Efficacy And Safety ◽  
Her2 Positive ◽  
Free Survival

128 Background: Irinotecan is a key drug in second- or further-line chemotherapy for patients with advanced gastric cancer. Continuous administration of trastuzumab beyond first progression is expected to contribute to the benefit of chemotherapy for HER2-positive gastric cancer. We assessed the efficacy and safety of combination chemotherapy with trastuzumab and irinotecan in Japanese patients with advanced HER2-positive chemo-refractory gastric cancer. Methods: Intravenous infusion of irinotecan every 2 weeks at a dose of 150 mg/m2; intravenous infusion of trastuzumab at a dose of 8 mg/kg on day 1 of the first cycle, followed by 6 mg/kg every 3 weeks. Administration of irinotecan and trastuzumab were repeated in independent schedules. The primary endpoint was disease control rate. The secondary endpoints were adverse events, response rate, time-to-treatment failure, progression-free survival, overall survival, and response rate stratified by prior trastuzumab use. This study was conducted by the Osaka Gastrointestinal Cancer Chemotherapy Study Group (OGSG). Results: From October 2012 to Augst 2014, 30 patients were enrolled and one patient withdrew before study treatment. Accordingly, 29 patients were assessable for efficacy and safety. The disease control rate was 65.5% [95% C.I. 45.7 - 82.1%], and the response rate was 20.7% [95% C.I. 8.0 - 39.7%]. The median progression free survival and the median overall survival were 3.7 and 7.5 months, respectively. The major grade 3/4 toxic effects were neutropenia (24%); anemia (24%); leucopenia (21%); anorexia (11%); fatigue (14%); hypoalbuminemia (24%); and hypokalemia (14%). One death (NOS) was considered to be related to the study. Conclusions: The results of combination Trastuzumab with irinotecan showed feasible and promising efficacy against advanced HER2-positive chemo-refractory gastric cancer. These findings indicated that trastuzumab continuation use might be beneficial. Clinical trial information: 000008626.

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