scholarly journals Temsirolimus: A Review of its Use in the Treatment of Advanced Renal Cell Carcinoma

2009 ◽  
Vol 1 ◽  
pp. CMT.S2349 ◽  
Author(s):  
Fanny Chan ◽  
Erika E. Samlowski ◽  
Wolfram E. Samlowski
Keyword(s):  
Renal Cancer ◽  
Kinase Inhibitors ◽  
Single Agent ◽  
Objective Response ◽  
Mammalian Target Of Rapamycin ◽  
The United States ◽  
Treated Group ◽  
Phase Iii ◽  
Clinical Activity ◽  
Metastatic Renal Cancer

The mTOR (mammalian target of rapamycin) signaling pathway was discovered during studies of the immunosuppressive agent rapamycin. This pathway regulates cell growth, protein synthesis and angiogenesis in response to environmental factors. The mTOR complex-1 inhibitor temsirolimus was derived from rapamycin to have less immunosuppressive and improved solubility characteristics. The safety, tolerability and efficacy of temsirolimus have been well established in clinical trials. Drug related toxicity included rash, mucositis, asthenia, nausea, hyperglycemia, hypophosphatemia, anemia, and hypertriglyceridemia. An active and well-tolerated single agent dose is 25 mg i.v. weekly. A large Phase III trial in poor-prognosis patients with metastatic renal cancer compared i.v weekly temsirolimus administration to subcutaneous interferon alpha (IFNα), or a combination of temsirolimus plus IFNα. This study established that median overall survival was improved to 10.9 months in the temsirolimus group compared to 7.3 months in IFNα-treated group (0.73 hazard ratio for death; 95% confidence interval [CI], 0.58 to 0.92; P = 0.008). A modest objective response rate of 8.6%, 4.8%, and 8.1%, respectively was observed in the three groups, associated with a median time to treatment failure of 3.8 months for temsirolimus alone, 1.9 months for IFNα, and 2.5 months for the combination. These results led to approval of temsirolimus for the treatment of renal cancer in the United States. Temsirolimus is clearly indicated for first-line therapy of Motzer “poor risk” renal cancer and aggressive non-clear cell renal cancer. Temsirolimus may be useful after failure of VEGF tyrosine kinase inhibitors. Clinical activity in other tumor types, such as endometrial cancer has been observed. Temsirolimus is therefore an important new agent for cancer treatment.

Hand–foot syndrome (HFS) as a potential biomarker of efficacy in patients (pts) with metastatic renal cell carcinoma (mRCC) treated with sunitinib (SU).

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 320-320 ◽  
Author(s):  
M. D. Michaelson ◽  
D. P. Cohen ◽  
S. Li ◽  
R. J. Motzer ◽  
B. Escudier ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Single Agent ◽  
Objective Response ◽  
Progression Free Survival ◽  
Time Dependent ◽  
Phase Iii ◽  
Rank Test ◽  
Significant Independent Predictor ◽  
Potential Biomarker

320 Background: HFS and related skin toxicities are common side effects of tyrosine kinase inhibitors such as SU, a multitargeted inhibitor of VEGF and PDGF receptors plus other receptor tyrosine kinases. In a randomized phase III trial of treatment-naïve mRCC pts, SU showed superior progression-free survival (PFS) and objective response rate (ORR) over interferon-alfa, with a median PFS of 11 mo and median overall survival (OS) of 26.4 mo, establishing SU as a reference standard of care (Motzer et al, 2009). In this retrospective analysis, correlations between SU-associated HFS and efficacy endpoints were investigated in mRCC pts from 5 clinical trials in the first- and second-line treatment settings. Methods: Analyses included pooled data from 770 pts who received single-agent SU as 50 mg/d on a 4-week-on/2-week-off schedule (n=544; 71%) or 37.5 mg continuous once-daily dosing (n=226; 29%). Median PFS and OS were estimated by Kaplan–Meier methods and compared between pts with vs without HFS using a log-rank test. ORR was compared by Pearson's chi-square test. Tumor response was assessed by investigators and adverse events were recorded regularly. Multivariate and time-dependent covariate analyses were performed. Results: Of 770 pts, 179 (23%) developed any-grade HFS, compared with 591 (77%) who did not. Most instances of HFS (63%) initially occurred during the first 3 treatment cycles. Pts who developed HFS had significantly better ORR (55.6% vs. 32.7%), PFS (14.3 vs. 8.3 mo), and OS (38.3 vs. 18.9 mo) than pts who did not develop HFS (p<0.0001). In a multivariate analysis, SU-associated HFS remained a significant independent predictor of both PFS and OS (and of OS by time-dependent covariate analysis). Conclusions: In mRCC pts, SU-associated HFS was significantly and independently associated with improved clinical outcomes. Overall, pts who did not develop HFS still had substantial benefit from SU. However, the presence of HFS identified a subset of pts that manifested highly favorable efficacy results with SU. These findings suggest that development of HFS may serve as a predictive biomarker of SU efficacy, although prospective validation is warranted. [Table: see text]

MIRASOL (GOG 3045/ENGOT OV-55): A randomized, open-label, phase III study of mirvetuximab soravtansine versus investigator’s choice of chemotherapy in advanced high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancers with high folate-alpha (FRα) expression.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS6103-TPS6103
Author(s):  
Kathleen N. Moore ◽  
Toon Van Gorp ◽  
Jiuzhou Wang ◽  
Brooke Esteves ◽  
Patrick A Zweidler-McKay
Keyword(s):  
Fallopian Tube ◽  
Single Agent ◽  
Objective Response ◽  
Pegylated Liposomal Doxorubicin ◽  
Phase Iii ◽  
Clinical Activity ◽  
Antibody Drug Conjugate ◽  
Open Label ◽  
Fallopian Tube Cancer ◽  
Phase Iii Study

TPS6103 Background: Elevated FRα expression is a characteristic of several solid tumors, including epithelial ovarian cancer (EOC), thereby providing an attractive candidate for targeted therapeutic approaches. Mirvetuximab soravtansine is an antibody-drug conjugate (ADC) comprising a FRα-binding antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent that has shown consistent and meaningful single agent clinical activity, along with favorable tolerability, in patients with high FRα expressing tumors. Methods: MIRASOL is a randomized phase III study designed to evaluate the efficacy of mirvetuximab soravtansine compared with that of standard-of-care chemotherapy in adult patients with platinum-resistant EOC, primary peritoneal cancer, or fallopian tube cancer. Confirmation of high FRα positivity by immunohistochemistry (high expression; ≥ 75% of cells with PS2+ staining intensity) and ≤ 3 prior lines of therapy are required for inclusion. MIRASOL is designed to randomize 430 patients, 1:1 to Arm 1 (intravenous mirvetuximab soravtansine at a dose of 6 mg/kg, calculated using adjusted ideal body weight, on Day 1 of a 21-day cycle) or Arm 2 (investigators’ choice chemotherapy: paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary efficacy endpoint is progression-free survival (PFS; by investigator) and secondary endpoints include objective response rate, quality of life, overall survival, and safety and tolerability. MIRASOL opened for enrollment in December 2019. Clinical trial information: NCT04209855.

Efficacy, tolerability, and biologic activity of a novel regimen of tremelimumab (T) in combination with durvalumab (D) for patients (pts) with advanced hepatocellular carcinoma (aHCC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4508-4508 ◽  
Author(s):  
Robin Kate Kelley ◽  
Bruno Sangro ◽  
William Proctor Harris ◽  
Masafumi Ikeda ◽  
Takuji Okusaka ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Objective Response ◽  
Phase Iii ◽  
Clinical Activity ◽  
Advanced Hepatocellular Carcinoma ◽  
Biologic Activity ◽  
Initial Cohort ◽  
Circulating Lymphocytes ◽  
Duration Of Response

4508 Background: The combination of dual immune checkpoint inhibitors (ICI) T (anti–CTLA-4) and D (anti–PD-L1) showed tolerability with a promising objective response rate (ORR) in the initial cohort of this study (NCT02519348). Subsequent evaluation of pts with solid tumors treated with increasing doses of T suggested priming with a higher dose of T may induce a stronger immune response and enhance anti-tumor activity. Thus, the randomized expansion cohorts comprised 4 arms evaluating T and D as monotherapies and 2 T+D regimens, including a novel T+D regimen featuring a single, priming dose of T. Methods: ICI-naïve pts with aHCC who progressed on, were intolerant to, or refused sorafenib were randomized to one of two T+D combinations: T300+D (T 300 mg + D 1500 mg 1 dose followed by D Q4 weekly [Q4W]) or T75+D (T 75 mg Q4W + D 1500 mg Q4W [4 doses] followed by D Q4W); or single agent D (1500 mg Q4W) or T (750 mg Q4W). Safety was the primary endpoint. ORR by blinded, independent central review using RECIST v1.1, duration of response (DoR), circulating lymphocytes, and overall survival (OS) were assessed. Results: At data cut-off (09/02/2019), 332 pts were enrolled. Median follow-ups were 11.7 months (mo) for T300+D, 14.6 (T75+D), 8.9 (D), and 15.8 (T). Treatment-related adverse event (trAE) incidences are shown (Table); no deaths were attributed to trAEs for T300+D or T. The T300+D arm had the highest confirmed ORR (DoR not reached [NR]) and longest OS (Table). A unique proliferative T cell profile was identified for pts in the T300+D arm, suggesting additive biologic activity for the combination, and showed pts with an OR exhibited high cytotoxic (CD8) counts. Conclusions: The encouraging clinical activity and tolerable safety profile suggest T300+D provides the best benefit-risk profile as opposed to T75+D or monotherapies. The unique pharmacodynamic activity of the T300+D regimen further supports its use in aHCC. T300+D and D are being evaluated in the ongoing phase III HIMALAYA study (NCT03298451) in first-line HCC vs sorafenib. Funding: AstraZeneca. Clinical trial information: NCT02519348 . [Table: see text]

TROPiCS-04: Study of sacituzumab govitecan in metastatic or locally advanced unresectable urothelial cancer that has progressed after platinum and checkpoint inhibitor therapy.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. TPS498-TPS498
Author(s):  
Petros Grivas ◽  
Scott T. Tagawa ◽  
Joaquim Bellmunt ◽  
Maria De Santis ◽  
Ignacio Duran ◽  
...  
Keyword(s):  
Clinical Benefit ◽  
Topoisomerase I ◽  
Progressive Disease ◽  
Group Performance ◽  
Checkpoint Inhibitor ◽  
Single Agent ◽  
Objective Response ◽  
Locally Advanced ◽  
Eastern Cooperative Oncology Group ◽  
Phase Iii

TPS498 Background: Treatment options are limited for patients with locally advanced unresectable or metastatic urothelial carcinoma (mUC) who progress following prior platinum-based and checkpoint inhibitor (CPI) therapy. Sacituzumab govitecan (SG) is an antibody-drug conjugate consisting of an anti–Trop-2 monoclonal antibody coupled to SN-38 (an active metabolite of irinotecan, a topoisomerase-I inhibitor) via a unique hydrolyzable linker. A phase II registrational study, TROPHY-U-01 study, confirmed the initial positive efficacy signal in mUC. SG demonstrated an objective response rate (ORR) of 27% and median overall survival (OS) of 10.5 months in patients with mUC (median 3 prior lines of therapy and 87% with ≥1 Bellmunt risk factors) who progressed after prior platinum-based and CPI therapies (n=113; Loriot ESMO 2020). The results compared favorably with historic single-agent chemotherapy (ORR ~10%; OS ≤7 months). A phase III trial has been initiated to confirm these findings. Methods: TROPiCS-04 (NCT04527991) is a global, multicenter, open-label, randomized, controlled trial in patients with locally advanced unresectable or mUC who progressed after prior platinum-based and CPI therapies (with Eastern Cooperative Oncology Group performance status 0–1 and adequate hematologic, hepatic, and renal function). Patients will be randomized 1:1 to receive SG 10 mg/kg intravenously (IV) on day 1 and 8 of 21-day cycles or single-agent treatment of physician’s choice (paclitaxel 175 mg/m2, docetaxel 75 mg/m2, or vinflunine 320 mg/m2 IV on day 1 of 21-day cycles) until progressive disease, unacceptable toxicity, or withdrawal of consent. Treatment beyond progressive disease may be permitted in patients deemed to be receiving clinical benefit per investigator assessment. Approximately 482 patients will be enrolled to provide 90% power on the primary endpoint of OS. Secondary endpoints include progression-free survival, ORR, clinical benefit rate, duration of response (all per Response Evaluation Criteria in Solid Tumors v1.1), safety, and quality of life. Study initiation is ongoing and enrollment begins in Q4 2020 across ~90 sites. Clinical trial information: NCT04527991.

scholarly journals Canadian perspectives: update on inhibition of ALK-positive tumours in advanced non-small-cell lung cancer

2018 ◽  
Vol 25 (5) ◽  
Author(s):  
B. Melosky ◽  
P. Cheema ◽  
J. Agulnik ◽  
R. Albadine ◽  
D. G. Bebb ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Single Agent ◽  
Small Cell ◽  
Phase Iii ◽  
Small Cell Lung ◽  
Anaplastic Lymphoma ◽  
Alk Inhibitor ◽  
Alk Positive

BackgroundInhibition of the anaplastic lymphoma kinase (alk) oncogenic driver in advanced non-small-cell lung carcinoma (nsclc) improves survival. In 2015, Canadian thoracic oncology specialists published a consensus guideline about the identification and treatment of ALK-positive patients, recommending use of the alk inhibitor crizotinib in the first line. New scientific literature warrants a consensus update.MethodsClinical trials of alk inhibitor were reviewed to assess benefits, risks, and implications relative to current Canadian guidance in patients with ALK-positive nsclc.ResultsRandomized phase iii trials have demonstrated clinical benefit for single-agent alectinib and ceritinib used in treatment-naïve patients and as second-line therapy after crizotinib. Phase ii trials have demonstrated activity for single-agent brigatinib and lorlatinib in further lines of therapy. Improved responses in brain metastases were observed for all second- and next/third-generation alk tyrosine kinase inhibitors in patients progressing on crizotinib. Canadian recommendations are therefore revised as follows:Patients with advanced nonsquamous nsclc have to be tested for the presence of an ALKrearrangement.Treatment-naïve patients with ALK-positive disease should initially be offered single-agent alectinib or ceritinib, or both sequentially.Crizotinib-refractory patients should be treated with single-agent alectinib or ceritinib, or both sequentially.Further treatments could include single-agent brigatinib or lorlatinib, or both sequentially.Patients progressing on alk tyrosine kinase inhibitors should be considered for pemetrexed-based chemotherapy.Other systemic therapies should be exhausted before immunotherapy is considered.SummaryMultiple lines of alk inhibition are now recommended for patients with advanced nsclc with an ALKrearrangement.

scholarly journals KRASoncogene in lung cancer: focus on molecularly driven clinical trials

2016 ◽  
Vol 25 (139) ◽  
pp. 71-76 ◽  
Author(s):  
Emmanuelle Kempf ◽  
Benoît Rousseau ◽  
Benjamin Besse ◽  
Luis Paz-Ares
Keyword(s):  
Kinase Inhibitors ◽  
Mammalian Target Of Rapamycin ◽  
Growth Factor Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Phase Iii ◽  
Phase Iii Trial ◽  
Lung Cancers ◽  
Molecular Abnormalities ◽  
Mitogen Activated Protein ◽  
Pathway Inhibition

KRASmutations are the most frequent molecular abnormalities found in one out of four nonsmall cell lung cancers (NSCLC). Their incidence increases in cases of adenocarcinoma, smokers and Caucasian patients. Their negative value in terms of prognosis and responsiveness to both standard chemotherapy and targeted therapies remains under debate. Many drugs have been developed specifically forKRAS-mutated NSCLC patients. Direct inhibition ofRASactivation failed to show any clinical efficacy. Inhibition of downstream targets of the mitogen-activated protein kinase (MEK) pathway is a promising strategy: phase II combinations of MEK 1/2 kinase inhibitors with chemotherapy doubled patients’ clinical outcomes. One phase III trial in such a setting is ongoing. Double inhibition of MEK and epidermal growth factor receptor proteins is currently being assessed in early-phase trials. The association with mammalian target of rapamycin pathway inhibition leads to non-manageable toxicity. Other strategies, such as inhibition of molecular heat-shock proteins 90 or focal adhesion kinase are currently assessed. Abemaciclib, a cyclin-dependent kinase 4/6 inhibitor, showed promising results in a phase I trial, with a 54% disease control rate. Results of an ongoing phase III trial are warranted. Immunotherapy might be the next relevant step inKRAS-mutated NSCLC management due to the high burden of associated mutations and neo-antigens.

Outcomes with novel combinations in non-clear cell renal cell carcinoma(nccRCC): ORACLE study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4580-4580
Author(s):  
Deepak Kilari ◽  
Aniko Szabo ◽  
Pooja Ghatalia ◽  
Tracy L Rose ◽  
Nicole Weise ◽  
...  
Keyword(s):  
Clear Cell ◽  
Objective Response ◽  
Mammalian Target Of Rapamycin ◽  
Progression Free Survival ◽  
Mtor Inhibitors ◽  
New Combination ◽  
Clinical Activity ◽  
Cell Renal Cell Carcinoma ◽  
Clear Cell Rcc ◽  
Rhabdoid Differentiation

4580 Background: Despite advances in the treatment of clear cell RCC, there is a paucity of data to guide management of nccRCC due to the heterogeneity and rarity of these tumors. The clinical activity of new combination therapies (including immunotherapy (IO), anti-vascular endothelial growth factor inhibitors (VEGF), and mammalian target of rapamycin (mTOR) inhibitors) in metastatic nccRCC is not known. Methods: In this multicenter retrospective analysis, we explored the efficacy of combination systemic therapies in patients with nccRCC. Baseline and follow-up demographic, clinical, treatment, and radiographic data were collected. The primary endpoint was objective response rate (ORR) assessed by investigator review. Secondary endpoints include progression- free survival (PFS), disease control rate (DCR), median duration of response (DOR), overall survival (OS), and biomarker correlates. Results: Among 66 included patients, median age was 59 yr; 60% were male and 62% white. Histologies included papillary (38%), chromophobe (17%), unclassified (24%), translocation (12%), and other (9 %). Sarcomatoid and/or rhabdoid differentiation was present in 18%, 70% had prior nephrectomy, 86% were IMDC intermediate/poor risk, 29% and 32% had liver and bone metastasis respectively. 67% received combination treatment in the first line. Comparison of outcomes based on treatment regimen is shown in the table. Conclusions: Antitumor activity was observed with novel combinations in nccRCC which warrants further prospective studies. Response rates and survival with combination therapy in this dataset remain inferior to rates seen in clear cell RCC.[Table: see text]

scholarly journals CheckMate-032 Study: Efficacy and Safety of Nivolumab and Nivolumab Plus Ipilimumab in Patients With Metastatic Esophagogastric Cancer

2018 ◽  
Vol 36 (28) ◽  
pp. 2836-2844 ◽  
Author(s):  
Yelena Y. Janjigian ◽  
Johanna Bendell ◽  
Emiliano Calvo ◽  
Joseph W. Kim ◽  
Paolo A. Ascierto ◽  
...  
Keyword(s):  
Gastroesophageal Junction ◽  
Objective Response ◽  
Locally Advanced ◽  
Survival Rates ◽  
Progression Free Survival ◽  
The United States ◽  
Phase Iii ◽  
Programmed Death Ligand 1 ◽  
Programmed Death ◽  
Esophagogastric Cancer

Purpose Metastatic esophagogastric cancer treatments after failure of second-line chemotherapy are limited. Nivolumab demonstrated superior overall survival (OS) versus placebo in Asian patients with advanced gastric or gastroesophageal junction cancers. We assessed the safety and efficacy of nivolumab and nivolumab plus ipilimumab in Western patients with chemotherapy-refractory esophagogastric cancers. Patients and Methods Patients with locally advanced or metastatic chemotherapy–refractory gastric, esophageal, or gastroesophageal junction cancer from centers in the United States and Europe received nivolumab or nivolumab plus ipilimumab. The primary end point was objective response rate. The association of tumor programmed death-ligand 1 status with response and survival was also evaluated. Results Of 160 treated patients (59 with nivolumab 3 mg/kg, 49 with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, 52 with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg), 79% had received two or more prior therapies. At the data cutoff, investigator-assessed objective response rates were 12% (95% CI, 5% to 23%), 24% (95% CI, 13% to 39%), and 8% (95% CI, 2% to 19%) in the three groups, respectively. Responses were observed regardless of tumor programmed death-ligand 1 status. With a median follow-up of 28, 24, and 22 months across the three groups, 12-month progression-free survival rates were 8%, 17%, and 10%, respectively; 12-month OS rates were 39%, 35%, and 24%, respectively. Treatment-related grade 3/4 adverse events were reported in 17%, 47%, and 27% of patients in the three groups, respectively. Conclusion Nivolumab and nivolumab plus ipilimumab demonstrated clinically meaningful antitumor activity, durable responses, encouraging long-term OS, and a manageable safety profile in patients with chemotherapy-refractory esophagogastric cancer. Phase III studies evaluating nivolumab or nivolumab plus ipilimumab in earlier lines of therapy for esophagogastric cancers are underway.

Randomized Phase III Study of Temozolomide Versus Dacarbazine in the Treatment of Patients With Advanced Metastatic Malignant Melanoma

2000 ◽  
Vol 18 (1) ◽  
pp. 158-158 ◽  
Author(s):  
M.R. Middleton ◽  
J.J. Grob ◽  
N. Aaronson ◽  
G. Fierlbeck ◽  
W. Tilgen ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Objective Response ◽  
Area Under The Curve ◽  
Systemic Exposure ◽  
Parent Drug ◽  
Progression Free Survival ◽  
Treated Group ◽  
Phase Iii ◽  
Health Related ◽  
Moderate Nausea

PURPOSE: : To compare, in 305 patients with advanced metastatic melanoma, temozolomide and dacarbazine (DTIC) in terms of overall survival, progression-free survival (PFS), objective response, and safety, and to assess health-related quality of life (QOL) and pharmacokinetics of both drugs and their metabolite, 5-(3-methyltriazen-1-yl)imidazole-4-carboximide (MTIC). PATIENTS AND METHODS: Patients were randomized to receive either oral temozolomide at a starting dosage of 200 mg/m2/d for 5 days every 28 days or intravenous (IV) DTIC at a starting dosage of 250 mg/m2/d for 5 days every 21 days. RESULTS: In the intent-to-treat population, median survival time was 7.7 months for patients treated with temozolomide and 6.4 months for those treated with DTIC (hazards ratio, 1.18; 95% confidence interval [CI], 0.92 to 1.52). Median PFS time was significantly longer in the temozolomide-treated group (1.9 months) than in the DTIC-treated group (1.5 months) (P = .012; hazards ratio, 1.37; 95% CI, 1.07 to 1.75). No major difference in drug safety was observed. Temozolomide was well tolerated and produced a noncumulative, transient myelosuppression late in the 28-day cycle. The most common nonhematologic toxicities were mild to moderate nausea and vomiting, which were easily managed. Temozolomide therapy improved health-related QOL; more patients showed improvement or maintenance of physical functioning at week 12. Systemic exposure (area under the curve) to the parent drug and the active metabolite, MTIC, was higher after treatment with oral temozolomide than after IV administration of DTIC. CONCLUSION: Temozolomide demonstrates efficacy equal to that of DTIC and is an oral alternative for patients with advanced metastatic melanoma.

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