Background
Most targeted anticancer therapies, as well as cytotoxic and radiation therapies, are encumbered by the development of secondary resistance by cancer cells. Resistance is a complex ...phenomenon involving multiple mechanisms, including activation of signaling pathways such as phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR). Novel strategies to overcome resistance by targeting these signaling pathways are being evaluated.
Methods
PubMed and key cancer congress abstracts were searched until July 2012 for preclinical and clinical data relating to the PI3K/AKT/mTOR pathway and anticancer treatment resistance, and use of PI3K/AKT/mTOR inhibitors in resistant cancer cell lines and patient populations.
Results
Activation of the PI3K/AKT/mTOR pathway is frequently implicated in resistance to anticancer therapies, including biologics, tyrosine kinase inhibitors, radiation, and cytotoxics. As such, inhibitors of the PI3K/AKT/mTOR pathway are being rapidly evaluated in preclinical models and in clinical studies to determine whether they can restore therapeutic sensitivity when given in combination. In breast cancer, non-small-cell lung cancer, and glioblastoma, we find compelling preclinical evidence to show that inhibitors of PI3K or mTOR can restore sensitivity in resistant cells. Although clinical evidence is less mature, a recent Phase III study with the mTORC1 inhibitor everolimus in patients with advanced breast cancer resistant to aromatase inhibition and several Phase I/II studies with PI3K inhibitors demonstrate proof-of-concept, warranting future clinical evaluation.
Conclusion
Current preclinical and clinical evidence suggest that inhibitors of the PI3K/AKT/mTOR pathway could have utility in combination with other anticancer therapies to circumvent resistance by cancer cells. Multiple clinical studies are ongoing.
The landscape of cancer therapy has been transformed by advances in clinical next‐generation sequencing, genomically targeted therapies, and immunotherapies. Well designed clinical trials and ...efficient clinical trial conduct are crucial for advancing our understanding of cancer, improving patient outcomes, and identifying personalized treatments. Basket trials have emerged as one of the efficient modern clinical trial designs that evaluate the efficacy of these therapies across multiple cancer types based on specific molecular alterations or biomarkers, irrespective of histology or anatomic location. This review delves into the evolution of basket trials in cancer drug development, highlighting their potential prospects and current obstacles. The design of basket trials involves screening patients for specific molecular alterations or biomarkers and enrolling them in the trial to receive the targeted therapy under investigation. Statistical considerations play a crucial role in the design, analysis, and interpretation of basket trials. Several notable examples of basket trials that have led to US Food and Drug Administration approval for uncommon molecular alterations (e.g., NTRK fusions, BRAF mutations, RET and FGFR1 alterations) are discussed, including LOXO‐TRK (ClinicalTrials.gov identifier NCT02122913)/SCOUT (ClinicalTrials.gov identifier NCT02637687)/NAVIGATE (ClinicalTrials.gov identifier NCT02576431)/STARTRK (ClinicalTrials.gov identifiers NT02097810, NT02568267), VE‐BASKET (ClinicalTrials.gov identifier NCT01524978), ROAR Basket (ClinicalTrials.gov identifier NCT02034110), LIBRETTO‐001 (ClinicalTrials.gov identifier NCT03157128), ARROW (ClinicalTrials.gov identifier NCT03037385), FIGHT‐203 (ClinicalTrials.gov identifier NCT03011372), and the National Cancer Institute‐Molecular Analysis for Therapy Choice trial (ClinicalTrials.gov identifier NCT02465060). Basket trials have the potential to revolutionize cancer treatment by identifying effective therapies for patients based on specific molecular alterations or biomarkers rather than traditional histology‐based approaches.
Plain Language Summary
To gain more knowledge about cancer, improve patient outcomes, and discover personalized treatments, it is crucial to conduct clinical trials efficiently.
One effective type of clinical trial is called a basket trial.
In basket trials, new treatments are tested on various types of cancer, regardless of their location in the body; instead, researchers focus on specific abnormalities in the cancer cells.
Basket trials offer hope that we can find personalized treatments that are more effective for each individual battling cancer.
Advances in next‐generation sequencing, targeted therapies, and immunotherapies have transformed cancer therapy. Efficient basket trials evaluate the effectiveness of these therapies across different types of cancer based on specific molecular alterations, offering potential for personalized treatments and revolutionizing cancer care.
The antibody-drug conjugate trastuzumab-DM1 (T-DM1) combines the biologic activity of trastuzumab with targeted delivery of a potent antimicrotubule agent, DM1, to human epidermal growth factor ...receptor 2 (HER2)-overexpressing cancer cells. Based on results from a phase I study that showed T-DM1 was well tolerated at the maximum-tolerated dose of 3.6 mg/kg every 3 weeks, with evidence of efficacy, in patients with HER2-positive metastatic breast cancer (MBC) who were previously treated with trastuzumab, we conducted a phase II study to further define the safety and efficacy of T-DM1 in this patient population.
This report describes a single-arm phase II study (TDM4258g) that assessed efficacy and safety of intravenous T-DM1 (3.6 mg/kg every 3 weeks) in patients with HER2-positive MBC who had tumor progression after prior treatment with HER2-directed therapy and who had received prior chemotherapy.
With a follow-up of ≥ 12 months among 112 treated patients, the objective response rate by independent assessment was 25.9% (95% CI, 18.4% to 34.4%). Median duration of response was not reached as a result of insufficient events (lower limit of 95% CI, 6.2 months), and median progression-free survival time was 4.6 months (95% CI, 3.9 to 8.6 months). The response rates were higher among patients with confirmed HER2-positive tumors (immunohistochemistry 3+ or fluorescent in situ hybridization positive) by retrospective central testing (n = 74). Higher response rates were also observed in patients whose tumors expressed ≥ median HER2 levels by quantitative reverse transcriptase polymerase chain reaction for HER2 expression, compared with patients who had less than median HER2 levels. T-DM1 was well tolerated with no dose-limiting cardiotoxicity. Most adverse events (AEs) were grade 1 or 2; the most frequent grade ≥ 3 AEs were hypokalemia (8.9%), thrombocytopenia (8.0%), and fatigue (4.5%).
T-DM1 has robust single-agent activity in patients with heavily pretreated, HER2-positive MBC and is well tolerated at the recommended phase II dose.
The combination of a BRAF inhibitor (dabrafenib) and a MEK inhibitor (trametinib) in patients with metastatic melanoma produced a significantly higher response rate than dabrafenib alone. Median ...progression-free survival was 9.4 months, as compared with 5.8 months with dabrafenib alone.
Pharmacologic inhibition of the mitogen-activated protein kinase (MAPK) pathway has proved to be a major advance in the treatment of metastatic melanoma. The use of vemurafenib and dabrafenib, agents that block MAPK signaling in patients with melanoma and the BRAF V600E mutation, has been associated with prolonged survival and progression-free survival, respectively, in randomized phase 3 trials involving patients with previously untreated melanoma.
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Trametinib mediates blockade of MAPK kinase (MEK), which is downstream of BRAF in the MAPK pathway and has been associated with improved progression-free and overall survival in BRAF V600 melanoma (comprising both V600E and V600K mutations). . . .
Amplified PI3K/Akt/mTOR signaling is common in metastatic breast cancer (MBC). The mTOR inhibitor everolimus improves progression-free survival (PFS) when added to steroidal aromatase inhibitor ...therapy. This randomized phase II trial compares the efficacy of paclitaxel/bevacizumab/everolimus and paclitaxel/bevacizumab/placebo as first-line treatment for MBC. Patients with untreated HER2-negative MBC were randomized (1:1) to receive 28-day cycles of paclitaxel 90 mg/m
2
IV (days 1, 8, and 15) and bevacizumab 10 mg/kg IV (days 1, 15) with either everolimus 10 mg (Arm 1) or placebo (Arm 2) daily. Treatment continued (evaluation every 8 weeks) until progression or unacceptable toxicity. Treatment of 110 patients allowed detection of an improvement in median PFS from 11 to 16 months (70 % power,
α
= 0.10). Between August 2009 and June 2011, 113 patients (median age 58 years; 88 % ER or PR positive) were randomized (Arm 1, 56; Arm 2, 57). Patients in both arms received a median of six treatment cycles. Median PFS (95 % CI) was 9.1 months (6.8–18.8) for Arm 1, and 7.1 months (5.6–10.8) for Arm 2 (
p
= 0.89). Comparisons of other efficacy endpoints were also similar in the two treatment arms. Patients receiving everolimus had more anemia, stomatitis, diarrhea, rash, and arthralgia/myalgia, although the overall incidence of severe (grade 3/4) toxicity was similar. The addition of everolimus did not improve the efficacy of weekly paclitaxel/bevacizumab as first-line treatment for patients with HER2-negative MBC. These results contrast with the demonstrated efficacy of adding everolimus to either hormonal or HER2-targeted therapy in previously treated patients.
Resistance to hormone therapy through activation of cellular pathways involving mTOR can develop in postmenopausal hormone-receptor–positive breast cancer. Adding an mTOR inhibitor to an aromatase ...inhibitor improved outcomes in patients who had disease progression during hormone therapy.
Endocrine therapy is the cornerstone of treatment for patients with hormone-receptor (HR)–positive advanced breast cancer. In postmenopausal patients, aromatase inhibitors (e.g., letrozole and anastrozole) have become the treatment of choice in first-line therapy.
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Unfortunately, not all patients have a response to first-line endocrine therapy (primary or de novo resistance), and even patients who have a response will eventually relapse (acquired resistance). On disease progression, second-line treatment options include other classes of aromatase inhibitors (steroidal or nonsteroidal) and the estrogen-receptor (ER) antagonists fulvestrant and tamoxifen.
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The study of resistance to endocrine therapies in HR-positive breast cancer has aimed at . . .
Lower grade gliomas (LGGs) are malignant brain tumors. Current therapy is associated with short- and long-term toxicity. Progression to higher tumor grade is associated with contrast enhancement on ...MRI. The majority of LGGs harbor mutations in the genes encoding isocitrate dehydrogenase 1 or 2 (
). Vorasidenib (AG-881) is a first-in-class, brain-penetrant, dual inhibitor of the mutant IDH1 and mutant IDH2 enzymes.
We conducted a multicenter, open-label, phase I, dose-escalation study of vorasidenib in 93 patients with mutant
(m
) solid tumors, including 52 patients with glioma that had recurred or progressed following standard therapy. Vorasidenib was administered orally, once daily, in 28-day cycles until progression or unacceptable toxicity. Enrollment is complete; this trial is registered with ClinicalTrials.gov, NCT02481154.
Vorasidenib showed a favorable safety profile in the glioma cohort. Dose-limiting toxicities of elevated transaminases occurred at doses ≥100 mg and were reversible. The protocol-defined objective response rate per Response Assessment in Neuro-Oncology criteria for LGG in patients with nonenhancing glioma was 18% (one partial response, three minor responses). The median progression-free survival was 36.8 months 95% confidence interval (CI), 11.2-40.8 for patients with nonenhancing glioma and 3.6 months (95% CI, 1.8-6.5) for patients with enhancing glioma. Exploratory evaluation of tumor volumes in patients with nonenhancing glioma showed sustained tumor shrinkage in multiple patients.
Vorasidenib was well tolerated and showed preliminary antitumor activity in patients with recurrent or progressive nonenhancing m
LGG.
Summary Background Rovalpituzumab tesirine is a first-in-class antibody-drug conjugate directed against delta-like protein 3 (DLL3), a novel target identified in tumour-initiating cells and expressed ...in more than 80% of patients with small-cell lung cancer. We aimed to assess the safety and activity of rovalpituzumab tesirine in patients who progressed after one or more previous regimen. Methods We conducted a phase 1 open-label study at ten cancer centres in the USA. Eligible patients were aged 18 years or older and had histologically or cytologically confirmed small-cell lung cancer or large-cell neuroendocrine tumours with progressive measurable disease (according to Response Evaluation Criteria in Solid Tumors RECIST, version 1.1) previously treated with one or two chemotherapeutic regimens, including a platinum-based regimen. We assigned patients to dose-escalation or expansion cohorts, ranging from 0·05 mg/kg to 0·8 mg/kg rovalpituzumab tesirine intravenously every 3 weeks or every 6 weeks, followed by investigation of the dose schedules 0·3 mg/kg and 0·4 mg/kg every 6 weeks and 0·2 mg/kg every 3 weeks. Primary objectives were to assess the safety of rovalpituzumab tesirine, including the maximum tolerated dose and dose-limiting toxic effects. The primary activity endpoint was objective response by intention-to-treat analysis. This study is registered with ClinicalTrials.gov , number NCT01901653 . The study is closed to enrolment; this report focuses on the cohort with small-cell lung cancer. Findings Between July 22, 2013, and Aug 10, 2015, 82 patients were enrolled, including 74 patients with small-cell lung cancer and eight with large-cell neuroendocrine carcinoma, all of whom received at least one dose of rovalpituzumab tesirine. Dose-limiting toxic effects of rovalpituzumab tesirine occurred at a dose of 0·8 mg/kg every 3 weeks, including grade 4 thrombocytopenia (in two of two patients at that dose level) and grade 4 liver function test abnormalities (in one patient). The most frequent grade 3 or worse treatment-related adverse events in 74 patients with small-cell lung cancer were thrombocytopenia (eight 11%), pleural effusion (six 8%), and increased lipase (five 7%). Drug-related serious adverse events occurred in 28 (38%) of 74 patients. The maximum tolerated dose of rovalpituzumab tesirine was 0·4 mg/kg every 3 weeks; the recommended phase 2 dose and schedule is 0·3 mg/kg every 6 weeks. At active doses of rovalpituzumab tesirine (0·2 mg/kg or 0·4 mg/kg every 3 weeks or 0·3 mg/kg or 0·4 mg/kg every 6 weeks), 11 (18%) of 60 assessable patients had a confirmed objective response. 11 (18%) of 60 assessable patients had a confirmed objective response, including ten (38%) of 26 patients confirmed to have high DLL3 expression (expression in 50% or more of tumour cells). Interpretation Rovalpituzumab tesirine shows encouraging single-agent antitumour activity with a manageable safety profile. Further development of rovalpituzumab tesirine in DLL3-expressing malignant diseases is warranted. Funding Stemcentrx Inc.
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