ABSTRACT
BACKGROUND: Patient selection is key in Phase I studies, and prognosis can be difficult to estimate in heavily pre-treated patients. Previous prognostic models like the Royal Marsden Hospital (RMH) score or using the neutrophil-lymphocyte ratio (NLR) have not been validated in current novel therapies nor in the Asian Phase I population. METHODS: We conducted a retrospective review of 414 patients with solid tumours participating in Phase I studies at our centre between October 2013 and December 2020. RESULTS: The RMH model showed poorer prognosis with increasing scores [RMH score 1, HR 1.28 (95% CI: 0.96-1.70); RMH score 2, HR 2.27 (95% CI: 1.62-3.17); RMH score 3, HR 4.14 (95% CI: 2.62-6.53)]. NLR did not improve the AUC of the model. Poorer ECOG status (ECOG 1 vs. 0: HR = 1.59 (95% CI = 1.24-2.04), P < 0.001) and primary tumour site (GI vs. breast cancer: HR = 3.06, 95% CI = 2.16-4.35, P < 0.001) were prognostic. CONCLUSIONS: We developed a NCIS prognostic score with excellent prognostic ability for both short-term and longer-term survival (iAUC: 0.71 [95% CI 0.65-0.76]), and validated the RMH model in the largest Asian study to date.
Subject(s)
Breast Neoplasms , Humans , Female , Prognosis , Treatment Outcome , Breast Neoplasms/therapy , Lymphocytes , Patient Selection , Retrospective Studies , NeutrophilsABSTRACT
BACKGROUND: Adding intraperitoneal paclitaxel (IP-PTX) to paclitaxel/5-fluoropyrimidine has shown promising results in patients with gastric cancer peritoneal metastases (GCPM) but has not been studied with standard-of-care platinum/fluoropyrimidine combinations. Our goal to was evaluate IP-PTX with capecitabine/oxaliplatin (XELOX) in GCPM. METHODS: Forty-four patients with GCPM received IP PTX (40 mg/m2, Days 1, 8), oral capecitabine (1000 mg/m2 twice daily, Days 1-14) and intravenous oxaliplatin (100 mg/m2, Day 1) in 21-day cycles. Patients with synchronous GCPM underwent conversion surgery if they had good response after chemotherapy, conversion to negative cytology, no extraperitoneal metastasis, and no peritoneal disease during surgery. The primary endpoint was overall survival and secondary endpoints were progression-free survival and safety. Outcomes from the trial were compared against a matched cohort of 39 GCPM patients who received systemic chemotherapy (SC) comprising platinum/fluoropyrimidine. RESULTS: The median OS for the IP and SC groups was 14.6 and 10.6 months (hazard ratio [HR] 0.44; 95% confidence interval [CI], 0.26-0.74; p = 0.002). The median PFS for the IP and SC group was 9.5 and 4.4 months respectively (HR 0.39; 95% CI 0.25-0.66; p < 0.001). Patients in the SC group were younger (IP vs. SC, 61 vs. 56 years, p = 0.021) and had better performance status (ECOG 0, IP vs. SC, 47.7% vs. 76.9%, p = 0.007) compared with the IP cohort. In IP group, conversion surgery was performed in 36.1% (13/36) of patients, with a median OS of 24.2 (95% CI 13.1-35.3) months and 1-year OS of 84.6%. CONCLUSIONS: IP PTX with XELOX is a promising treatment option for GCPM patients. In patients with good response, conversion surgery was feasible with favourable outcomes.
Subject(s)
Peritoneal Neoplasms , Stomach Neoplasms , Humans , Capecitabine , Oxaliplatin/therapeutic use , Stomach Neoplasms/pathology , Paclitaxel , Peritoneal Neoplasms/secondary , Platinum/therapeutic use , Fluorouracil , Deoxycytidine , Antineoplastic Combined Chemotherapy ProtocolsABSTRACT
BACKGROUND: We previously reported that low-dose, short-course sunitinib prior to neoadjuvant doxorubicin-cyclophosphamide (AC) normalised tumour vasculature and improved perfusion, but resulted in neutropenia and delayed subsequent cycles in breast cancer patients. This study combined sunitinib with docetaxel, which has an earlier neutrophil nadir than AC. METHODS: Patients with advanced solid cancers were randomized 1:1 to 3-weekly docetaxel 75 mg/m2, with or without sunitinib 12.5 mg daily for 7 days prior to docetaxel, stratified by primary tumour site. Primary endpoints were objective-response (ORR:CR + PR) and clinical-benefit rate (CBR:CR + PR + SD); secondary endpoints were toxicity and progression-free-survival (PFS). RESULTS: We enrolled 68 patients from 2 study sites; 33 received docetaxel-sunitinib and 35 docetaxel alone, with 33 breast, 25 lung and 10 patients with other cancers. There was no difference in ORR (30.3% vs 28.6%, p = 0.432, odds-ratio [OR] 1.10, 95% CI 0.38-3.18); CBR was lower in the docetaxel-sunitinib arm (48.5% vs 71.4%, p = 0.027 OR 0.37, 95% CI 0.14-1.01). Median PFS was shorter in the docetaxel-sunitinib arm (2.9 vs 4.9 months, hazard-ratio [HR] 2.00, 95% CI 1.15-3.48, p = 0.014) overall, as well as in breast (4.2 vs 5.6 months, p = 0.048) and other cancers (2.0 vs 5.3 months, p = 0.009), but not in lung cancers (2.9 vs 4.1 months, p = 0.597). Median OS was similar in both arms overall (9.9 vs 10.5 months, HR 0.92, 95% CI 0.51-1.67, p = 0.789), and in the breast (18.9 vs 25.8 months, p = 0.354), lung (7.0 vs 6.7 months, p = 0.970) and other cancers (4.5 vs 8.8 months, p = 0.449) subgroups. Grade 3/4 haematological toxicities were lower with docetaxel-sunitinib (18.2% vs 34.3%, p = 0.132), attributed to greater discretionary use of prophylactic G-CSF (90.9% vs 63.0%, p = 0.024). Grade 3/4 non-haematological toxicities were similar (12.1% vs 14.3%, p = 0.792). CONCLUSIONS: The addition of sunitinib to docetaxel was well-tolerated but did not improve outcomes. The possible negative impact in metastatic breast cancer patients is contrary to results of adding sunitinib to neoadjuvant AC. These negative results suggest that the intermittent administration of sunitinib in the current dose and schedule with docetaxel in advanced solid tumours, particularly breast cancers, is not beneficial. TRIAL REGISTRATION: The study was registered ( NCT01803503 ) prospectively on clinicaltrials.gov on 4th March 2013.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasms/drug therapy , Adult , Aged , Case-Control Studies , Docetaxel/administration & dosage , Female , Follow-Up Studies , Humans , Male , Middle Aged , Neoplasms/pathology , Prognosis , Sunitinib/administration & dosage , Survival RateABSTRACT
BACKGROUND: Hepatocellular carcinoma is the third leading cause of cancer-related deaths worldwide. In the heterogeneous group of hepatocellular carcinomas, those with characteristics of embryonic stem-cell and progenitor-cell gene expression are associated with the worst prognosis. The oncofetal gene SALL4, a marker of a subtype of hepatocellular carcinoma with progenitor-like features, is associated with a poor prognosis and is a potential target for treatment. METHODS: We screened specimens obtained from patients with primary hepatocellular carcinoma for the expression of SALL4 and carried out a clinicopathological analysis. Loss-of-function studies were then performed to evaluate the role of SALL4 in hepatocarcinogenesis and its potential as a molecular target for therapy. To assess the therapeutic effects of a peptide that targets SALL4, we used in vitro functional and in vivo xenograft assays. RESULTS: SALL4 is an oncofetal protein that is expressed in the human fetal liver and silenced in the adult liver, but it is reexpressed in a subgroup of patients who have hepatocellular carcinoma and an unfavorable prognosis. Gene-expression analysis showed the enrichment of progenitor-like gene signatures with overexpression of proliferative and metastatic genes in SALL4-positive hepatocellular carcinomas. Loss-of-function studies confirmed the critical role of SALL4 in cell survival and tumorigenicity. Blocking SALL4-corepressor interactions released suppression of PTEN (the phosphatase and tensin homologue protein) and inhibited tumor formation in xenograft models in vivo. CONCLUSIONS: SALL4 is a marker for a progenitor subclass of hepatocellular carcinoma with an aggressive phenotype. The absence of SALL4 expression in the healthy adult liver enhances the potential of SALL4 as a treatment target in hepatocellular carcinoma. (Funded by the Singapore National Medical Research Council and others.).
Subject(s)
Biomarkers, Tumor/metabolism , Carcinoma, Hepatocellular/metabolism , Liver Neoplasms/metabolism , Liver/metabolism , Transcription Factors/genetics , Adult , Animals , Carcinoma, Hepatocellular/genetics , Gene Expression , Gene Expression Regulation, Neoplastic , Humans , Liver Neoplasms/genetics , Metabolic Networks and Pathways/physiology , Mice , Mice, Inbred Strains , PTEN Phosphohydrolase/metabolism , Prognosis , Transcription Factors/antagonists & inhibitors , Transcription Factors/metabolism , Transplantation, Heterologous , Tumor Cells, CulturedABSTRACT
Introduction: Molecular profiling of metastatic breast cancer (MBC) through the widespread use of next-generation sequencing (NGS) has highlighted actionable mutations and driven trials of targeted therapy matched to tumour molecular profiles, with improved outcomes reported using such an approach. Here, we review NGS results and treatment outcomes for a cohort of Asian MBC patients in the phase I unit of a tertiary centre. Methods: Patients with MBC referred to a phase I unit underwent NGS via Ion AmpliSeq Cancer Hotspot v2 (ACH v2, 2014-2017) prior to institutional change to FoundationOne CDx (FM1; 2017-2022). Patients were counselled on findings and enrolled on matched therapeutic trials, where available. Outcomes for all subsequent treatment events were recorded to data cut-off on January 31, 2022. Results: A total of 215 patients were enrolled with successful NGS in 158 patients. The PI3K/AKT/PTEN pathway was the most altered with one or more of the pathway member genes PIK3/AKT/PTEN affected in 62% (98/158) patients and 43% of tumours harbouring a PIK3CA alteration. Tumour mutational burden (TMB) was reported in 96/109 FM1 sequenced patients, with a mean TMB of 5.04 mt/Mb and 13% (12/96) with TMB ≥ 10 mt/Mb. Treatment outcomes were evaluable in 105/158 patients, with a pooled total of 216 treatment events recorded. Matched treatment was administered in 47/216 (22%) events and associated with prolonged median progression-free survival (PFS) of 21.0 weeks [95% confidence interval (CI) 11.7, 26.0 weeks] versus 12.1 weeks (95% CI 10.0, 15.4 weeks) in unmatched, with hazard ratio (HR) for progression or death of 0.63 (95% CI 0.41, 0.97; p = 0.034). In the subgroup of PIK3/AKT/PTEN-altered MBC, the HR for progression or death was 0.57 (95% CI 0.35, 0.92; p = 0.02), favouring matched treatment. Per-patient overall survival (OS) analysis (n = 105) showed improved survival for patients receiving matched treatment versus unmatched, with median OS (mOS) of 30.1 versus 11.8 months, HR = 0.45 (95% CI 0.24, 0.84; p = 0.013). Objective response rate (ORR) in the overall population was similar in matched and unmatched treatment events (23.7% versus 17.2%, odds ratio of response 1.14 95% CI 0.50, 2.62; p = 0.75). Conclusions: Broad-panel NGS in MBC is feasible, allowing therapeutic matching, which was associated with improvements in PFS and OS.
ABSTRACT
Background: CDK4/6-inhibitors have demonstrated similar efficacy and are considered an effective first-line endocrine treatment of patients with hormone-receptor positive (HR+)/human-epidermal-growth-factor-receptor-2 negative (HER2-) metastatic breast cancer (MBC) in the endpoint of progression-free survival (PFS). Amongst these, palbociclib was first to achieve regulatory approval, followed subsequently by ribociclib and abemaciclib. However, recent updates of overall survival (OS) showed inconsistencies in the OS benefit for palbociclib compared with the other two CDK4/6-inhibitors. With the lack of head-to-head comparison studies, our study sought to compare indirect survival outcomes between CDK4/6-inhibitors in this setting using a novel reconstructive algorithm. Methods: Phase III randomized trials comparing first-line aromatase inhibitor with/without a CDK4/6-inhibitor in post-menopausal patients with HR+/HER2- MBC were identified through systemic review and literature search of online archives of published manuscripts and conference proceedings. A graphical reconstructive algorithm was utilized to retrieve time-to-event data from reported Kaplan-Meier OS and PFS plots to allow for comparison of survival outcomes. Survival analyses were conducted with Cox proportional-hazards model with a shared-frailty term. Results: Three randomized phase III trials-PALOMA-2, MONALEESA-2 and MONARCH-3-comprising 1827 patients were included. Indirect pairwise comparisons of all CDK4/6-inhibitors showed no significant PFS differences (all p > 0.05). Likewise, indirect treatment comparison between ribociclib vs. palbociclib (one-stage: HR = 0.903, 95%-CI: 0.746-1.094, p = 0.297), abemaciclib vs. palbociclib (one-stage: HR = 0.843, 95%-CI: 0.690-1.030, p = 0.094) and abemaciclib vs. ribociclib (one-stage: HR = 0.933, 95%-CI: 0.753-1.157, p = 0.528) failed to demonstrate a significant OS difference. Conclusions: Findings from this indirect treatment comparison suggest no significant PFS or OS differences between CDK4/6-inhibitors in post-menopausal patients with HR+/HER2- MBC.
ABSTRACT
BACKGROUND: Fluoropyrimidines are commonly used in the treatment of metastatic breast cancer (MBC), and trifluridine/tipiracil (FTD/TPI) has shown activity in patients with colorectal and gastric cancers despite prior exposure to fluoropyrimidines. We investigate the role of FTD/TPI in patients with MBC with or without prior fluoropyridines in a single-arm phase II study. METHODS: Patients with MBC were enroled first into a run-in dose confirmation phase, followed by two parallel cohorts including patients with (Cohort A) and without (Cohort B) prior exposure to fluoropyrimidines, where they were treated with FTD/TPI. Primary objectives for each cohort included determination of progression-free survival (PFS), and secondary objectives included determination of objective response rates (ORR), safety, and tolerability. RESULTS: Seventy-four patients (42 Cohort A, 32 Cohort B) were enroled, all of whom were evaluable for toxicity and survival, with 72 evaluable for response. Median PFS was 5.7 months (95% confidence interval 3.8-8.3) and 9.4 months (95% CI 5.5-14.0) respectively in Cohorts A and B. Responses were observed regardless of prior exposure to fluoropyrimidines, with ORR of 19.5% (95% CI 8.8-34.9) and 16.1% (95% CI 5.5-33.7) in Cohorts A and B, and 6-month clinical benefit rates of 56.1% (95% CI 39.7-71.5) and 61.3% (95% CI 42.2-78.2) respectively. The safety profile was consistent with known toxicities of FTD/TPI, including neutropenia, fatigue, nausea, and anorexia, mitigated with dose modifications. CONCLUSION: FTD/TPI showed promising antitumour activity with manageable toxicity and is a clinically valid option in patients with MBC.
ABSTRACT
BACKGROUND: Phosphatase of regenerating liver-3 (PRL-3) is involved in cellular processes driving metastasis, cell proliferation, invasion, motility and survival. It has been shown to be upregulated and overexpressed in cancer tissue, in contrast to low or no expression in most normal tissue. PRL3-zumab is a first-in-class humanized antibody that specifically binds to PRL-3 oncotarget with high affinity and has been shown to reduce tumor growth and increase survival. OBJECTIVE: In the study, we aimed to determine the safety and efficacy of PRL3-zumab in patients with advanced solid tumors and hematological malignancies. METHODS: We conducted a phase I, first-in-human study in advanced solid tumors and hematological malignancies to investigate the safety, tolerability and efficacy of PRL3-zumab. Response rates were evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) for solid tumors. For acute myeloid leukemia (AML) patients, bone marrow response criteria based on the European Leukaemia Network (ELN) 2017 guidelines for AML were used. We also explored the pharmacokinetics and pharmacodynamic relationships of PRL3-zumab in patients. This study was registered with ClinicalTrials.gov: NCT03191682. RESULTS: In the dose-escalation cohort, 11 patients with advanced solid tumors were enrolled into the study. An additional 12 patients with solid tumors and four patients with AML were enrolled in the dose-expansion cohort. Maximum tolerability was not achieved in this study, as there were no dose-limiting toxicities. Potential treatment-emergent adverse events were grade 1 increased stoma output and fatigue and grade 2 vomiting. Best response observed was stable disease in three solid-tumor patients (11.1%). The pharmacokinetics of PRL3-zumab were dose proportional, consistent with an IgG type monoclonal antibody. CONCLUSIONS: PRL3-zumab, a first-in-class humanized antibody, was safe and tolerable in solid tumors and hematological malignancies.
Subject(s)
Antineoplastic Agents , Hematologic Neoplasms , Leukemia, Myeloid, Acute , Neoplasms , Humans , Neoplasms/drug therapy , Antineoplastic Agents/therapeutic use , Antibodies, Monoclonal/therapeutic use , Hematologic Neoplasms/drug therapy , Maximum Tolerated DoseABSTRACT
BACKGROUND: Varlitinib is a highly potent, small-molecule, pan-HER inhibitor targeting HER1, HER2, and HER4. It has demonstrated activity in gastric, biliary tract, and breast cancers. OBJECTIVE: We conducted a phase Ib dose confirmation study to determine safety and early efficacy signals of varlitinib in combination with chemotherapy (paclitaxel ± carboplatin) ± subcutaneous trastuzumab. METHODS: Eligible patients had advanced or metastatic solid tumors. A 3+3 dose de-escalation study design was used and pharmacokinetic analyses of varlitinib and paclitaxel were performed. RESULTS: Thirty-seven patients were enrolled into eight cohorts with median 4 (0-14) prior lines of palliative systemic therapies. Carboplatin area under the curve 1.5 and paclitaxel 80 mg/m2 weekly with varlitinib 500 mg twice daily continuously was de-escalated over four dose levels to 300 mg twice daily intermittently (4 days on, 3 days off) due to dose-limiting toxicities, most commonly neutropenia, febrile neutropenia, and electrolyte disturbances, with the triplet combination deemed intolerable and unable to be developed further. Varlitinib was then combined with paclitaxel alone; the recommended phase II dose of varlitinib was 300 mg twice daily intermittently. The addition of subcutaneous trastuzumab 600 mg was safe with no dose-limiting toxicities. Thirty-one patients were evaluable for response: 35.5% partial response, 41.9% stable disease. Twenty patients had HER2+ metastatic breast cancer with a median of 4 (0-14) treatment lines, 8/20 continued on single-agent varlitinib after completing chemotherapy for a median of 5.1 (range 2.0-13.3) months. A pharmacokinetic analysis showed that plasma exposure of varlitinib was dose dependent. Varlitinib administration did not significantly affect the maximum concentration or area under the curve of paclitaxel. CONCLUSIONS: The recommended phase II dose of varlitinib with paclitaxel is 300 mg twice daily intermittently dosed. This is active in HER2+ metastatic breast cancer. Subcutaneous trastuzumab can be added safely to varlitinib and paclitaxel. This combination is currently being evaluated as neoadjuvant therapy in HER2+ breast cancer (NCT02396108). CLINICAL TRIAL REGISTRATION: NCT02396108, date of registration: 25 March, 2015.
Subject(s)
Breast Neoplasms , Paclitaxel , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Carboplatin/pharmacology , Carboplatin/therapeutic use , Female , Humans , Paclitaxel/pharmacology , Paclitaxel/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Trastuzumab/pharmacology , Trastuzumab/therapeutic use , Treatment OutcomeABSTRACT
BACKGROUND: Breast cancers are heterogeneous with variable clinical courses and treatment responses. OBJECTIVE: We sought to evaluate dynamic changes in the molecular landscape of HER2-negative tumors treated with chemotherapy and anti-angiogenic agents. PATIENTS AND METHODS: Newly diagnosed HER2-negative breast cancer patients received low-dose sunitinib or bevacizumab prior to four 2-weekly cycles of dose-dense doxorubicin and cyclophosphamide. Tumor biopsies were obtained at baseline, after 2 weeks and after 8 weeks of chemotherapy. Next-generation sequencing was performed to assess for single nucleotide variants (SNVs) and copy number alterations (CNAs) of 440 cancer-related genes (ACTOnco®). Observed genomic changes were correlated with the Miller-Payne histological response to treatment. RESULTS: Thirty-four patients received sunitinib and 18 received bevacizumab. In total, 77% were hormone receptor positive (HER2-/HR+) and 23% were triple negative breast cancers (TNBC). New therapy-induced mutations were infrequent, occurring only in 13%, and appeared early after a single cycle of treatment. Seventy-two percent developed changes in the variant allele frequency (VAF) of pathogenic SNVs; the majority (51%) of these changes occurred early at 2 weeks and were sustained for 8 weeks. Changes in VAF of SNVs were most commonly seen in the PI3K/mTOR/AKT pathway; 13% developed changes in pathogenic mutations, which potentially confer sensitivity to PIK3CA inhibitors. Tumors with poor Miller-Payne response to treatment were less likely to experience changes in VAF of SNVs compared with those with good response (50% [7/14] vs 15% [4/24] had no changes observed at any timepoint, p = 0.029). CONCLUSIONS: Serial molecular profiling identifies early therapy-induced genomic alterations, which may guide future selection of targeted therapies in breast cancer patients who progress after standard chemotherapy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT02790580 (first posted June 6, 2016).
Subject(s)
Breast Neoplasms , Triple Negative Breast Neoplasms , Angiogenesis Inhibitors/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bevacizumab/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Female , High-Throughput Nucleotide Sequencing , Humans , Receptor, ErbB-2/genetics , Receptor, ErbB-2/therapeutic use , Sunitinib/therapeutic use , Triple Negative Breast Neoplasms/drug therapyABSTRACT
PURPOSE: RET is an estrogen response gene with preclinical studies demonstrating cross-talk between the RET and estrogen receptor (ER) pathways. We investigate the role of lenvatinib, a multikinase inhibitor with potent activity against RET, in patients with metastatic breast cancer. PATIENTS AND METHODS: Patients with advanced ER+/HER2- breast cancer were treated with lenvatinib plus letrozole in a phase Ib/II trial. Primary objectives included safety and recommended phase II dose (RP2D) determination in phase Ib, and objective response rates (ORR) in phase II dose expansion. RESULTS: Sixteen patients were recruited in dose finding, where deescalating doses of lenvatinib from 20 to 14 mg were investigated. Lenvatinib 14 mg plus letrozole 2.5 mg daily was determined as RP2D. Thirty-one patients with 5 median lines of prior therapy in the metastatic setting (range, 0-11) were recruited in dose expansion. In this cohort, ORR was 23.3% [95% confidence interval (CI) 9.9%-42.3%], with median duration of response (DoR) of 6.9 months [interquartile range (IQR) 5.9 to 13.1]. Clinical benefit rate ≥6 months (CBR) was 50.0% (95% CI, 31.3%-68.7%). Similar efficacy was observed in the subgroup of 25 patients who progressed on prior CDK4/6 inhibitor therapy [ORR 20.0% (95% CI, 6.8%-40.7%), median DoR 6.9 months (IQR 5.9-13.1), and CBR 52.0% (95% CI, 31.3%-72.2%)]. Pharmacodynamic studies showed target modulation, with paired tumor biopsies indicating downregulation of RET/pERK and improved vascular normalization index. CONCLUSIONS: Lenvatinib plus letrozole had manageable toxicity, with target engagement and preliminary antitumor activity observed, supporting further assessment in randomized studies.
Subject(s)
Breast Neoplasms , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Biomarkers, Tumor/genetics , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Female , Humans , Letrozole , Phenylurea Compounds , Postmenopause , Quinolines , Receptor, ErbB-2/metabolism , Receptors, Estrogen/genetics , Receptors, Estrogen/metabolismABSTRACT
Cyclin-dependent kinase 4/6 (CDK4/6) and PI3K inhibitors synergize in PIK3CA-mutant ER-positive HER2-negative breast cancer models. We conducted a phase Ib trial investigating the safety and efficacy of doublet CDK4/6 inhibitor palbociclib plus selective PI3K inhibitor taselisib in advanced solid tumors, and triplet palbociclib plus taselisib plus fulvestrant in 25 patients with PIK3CA-mutant, ER-positive HER2-negative advanced breast cancer. The triplet therapy response rate in PIK3CA-mutant, ER-positive HER2-negative cancer was 37.5% [95% confidence interval (CI), 18.8-59.4]. Durable disease control was observed in PIK3CA-mutant ER-negative breast cancer and other solid tumors with doublet therapy. Both combinations were well tolerated at pharmacodynamically active doses. In the triplet group, high baseline cyclin E1 expression associated with shorter progression-free survival (PFS; HR = 4.2; 95% CI, 1.3-13.1; P = 0.02). Early circulating tumor DNA (ctDNA) dynamics demonstrated high on-treatment ctDNA association with shorter PFS (HR = 5.2; 95% CI, 1.4-19.4; P = 0.04). Longitudinal plasma ctDNA sequencing provided genomic evolution evidence during triplet therapy. SIGNIFICANCE: The triplet of palbociclib, taselisib, and fulvestrant has promising efficacy in patients with heavily pretreated PIK3CA-mutant ER-positive HER2-negative advanced breast cancer. A subset of patients with PIK3CA-mutant triple-negative breast cancer derived clinical benefit from palbociclib and taselisib doublet, suggesting a potential nonchemotherapy targeted approach for this population.This article is highlighted in the In This Issue feature, p. 1.
Subject(s)
Breast Neoplasms , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Class I Phosphatidylinositol 3-Kinases/genetics , Fulvestrant , Humans , Imidazoles , Oxazepines , Phosphatidylinositol 3-Kinases , Piperazines , Pyridines , Receptor, ErbB-2/geneticsABSTRACT
Significance: Cancer cells exhibit altered metabolic pathways to keep up with biosynthetic and reduction-oxidation needs during tumor proliferation and metastasis. The common induction of metabolic pathways during cancer progression, regardless of cancer histio- or genotype, makes cancer metabolism an attractive target for therapeutic exploitation. Recent Advances: Emerging data suggest that these altered pathways may even result in resistance to anticancer therapies. Identifying specific metabolic dependencies that are unique to cancer cells has proved challenging in this field, limiting the therapeutic window for many candidate drug approaches. Critical Issues: Cancer cells display significant metabolic flexibility in nutrient-limited environments, hampering the longevity of suppressing cancer metabolism through any singular approach. Combinatorial "synthetic lethal" approaches may have a better chance for success and promising strategies are reviewed here. The dynamism of the immune system adds a level of complexity, as various immune populations in the tumor microenvironment often share metabolic pathways with cancer, with successive alterations during immune activation and quiescence. Decoding the reprogramming of metabolic pathways within cancer cells and stem cells, as well as examining metabolic symbiosis between components of the tumor microenvironment, would be essential to further meaningful drug development within the tumor's metabolic ecosystem. Future Directions: In this article, we examine evidence for the therapeutic potential of targeting metabolic alterations in cancer, and we discuss the drawbacks and successes that have stimulated this field.
Subject(s)
Antineoplastic Agents/pharmacology , Metabolic Networks and Pathways/drug effects , Neoplasms/drug therapy , Neoplasms/metabolism , Humans , Neoplasms/pathologyABSTRACT
c-MET receptors are activated in cancers through genomic events like tyrosine kinase domain mutations, juxtamembrane splicing mutation and amplified copy numbers, which can be inhibited by c-MET small molecule inhibitors. Here, we discover that the most common polymorphism known to affect MET gene (N375S), involving the semaphorin domain, confers exquisite binding affinity for HER2 and enables METN375S to interact with HER2 in a ligand-independent fashion. The resultant METN375S/HER2 dimer transduces potent proliferative, pro-invasive and pro-metastatic cues through the HER2 signaling axis to drive aggressive squamous cell carcinomas of the head and neck (HNSCC) and lung (LUSC), and is associated with poor prognosis. Accordingly, HER2 blockers, but not c-MET inhibitors, are paradoxically effective at restraining in vivo and in vitro models expressing METN375S. These results establish METN375S as a biologically distinct and clinically actionable molecular subset of SCCs that are uniquely amenable to HER2 blocking therapies.
Subject(s)
Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/pathology , Proto-Oncogene Proteins c-met/genetics , Proto-Oncogene Proteins c-met/metabolism , Receptor, ErbB-2/metabolism , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/mortality , Cell Line, Tumor , Head and Neck Neoplasms/drug therapy , Head and Neck Neoplasms/genetics , Head and Neck Neoplasms/mortality , Head and Neck Neoplasms/pathology , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Mice , Mutation , Phenotype , Phosphorylation/drug effects , Polymorphism, Genetic , Prognosis , Protein Binding , Protein Interaction Domains and Motifs , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins c-met/chemistry , Receptor, ErbB-2/antagonists & inhibitors , Signal Transduction/drug effects , Xenograft Model Antitumor AssaysABSTRACT
PURPOSE: Natural killer (NK) cells exert antibody-dependent cell cytotoxicity (ADCC). We infused expanded, activated autologous NK cells to potentiate trastuzumab-mediated ADCC in patients with HER2-positive malignancies. PATIENTS AND METHODS: In a phase I trial, patients with treatment-refractory HER2-positive solid tumors received trastuzumab, with or without bevacizumab, and autologous NK cells expanded by 10-day coculture with K562-mb15-41BBL cells. Primary objectives included safety and recommended phase II dose determination; secondary objectives included monitoring NK-cell activity and RECIST antitumor efficacy. RESULTS: In 60 cultures with cells from 31 subjects, median NK-cell expansion from peripheral blood was 340-fold (range, 91-603). NK cells expressed high levels of CD16, the mediator of ADCC, and exerted powerful killing of trastuzumab-targeted cells. In the 22 subjects enrolled in phase I dose escalation, trastuzumab plus NK cells were well tolerated; MTD was not reached. Phase IB (n = 9) included multiple cycles of NK cells (1 × 107/kg) and addition of bevacizumab. Although no objective response was observed, 6 of 19 subjects who received at least 1 × 107/kg NK cells at cycle 1 had stable disease for ≥6 months (median, 8.8 months; range 6.0-12.0). One patient, the only one with the high-affinity F158V CD16 variant, had a partial response. Peripheral blood NK cells progressively downregulated CD16 postinfusion; paired tumor biopsies showed increased NK cells, lymphocytic infiltrates, and apoptosis posttreatment. CONCLUSIONS: NK-cell therapy in combination with trastuzumab was well tolerated, with target engagement and preliminary antitumor activity, supporting continued assessment of this approach in phase II trials.
Subject(s)
Breast Neoplasms/therapy , Immunotherapy/methods , Killer Cells, Natural/transplantation , Receptor, ErbB-2/metabolism , Stomach Neoplasms/therapy , Trastuzumab/administration & dosage , Adult , Aged , Biopsy , Breast Neoplasms/blood , Breast Neoplasms/immunology , Breast Neoplasms/pathology , Coculture Techniques , Combined Modality Therapy/methods , Dose-Response Relationship, Drug , Female , Humans , K562 Cells , Killer Cells, Natural/immunology , Male , Middle Aged , Receptor, ErbB-2/analysis , Response Evaluation Criteria in Solid Tumors , Stomach Neoplasms/blood , Stomach Neoplasms/immunology , Stomach Neoplasms/pathology , Transplantation, Autologous/methods , Trastuzumab/adverse effectsABSTRACT
Preclinical studies have demonstrated synergy between PARP and PI3K/AKT pathway inhibitors in BRCA1 and BRCA2 (BRCA1/2)-deficient and BRCA1/2-proficient tumors. We conducted an investigator-initiated phase I trial utilizing a prospective intrapatient dose- escalation design to assess two schedules of capivasertib (AKT inhibitor) with olaparib (PARP inhibitor) in 64 patients with advanced solid tumors. Dose expansions enrolled germline BRCA1/2-mutant tumors, or BRCA1/2 wild-type cancers harboring somatic DNA damage response (DDR) or PI3K-AKT pathway alterations. The combination was well tolerated. Recommended phase II doses for the two schedules were: olaparib 300 mg twice a day with either capivasertib 400 mg twice a day 4 days on, 3 days off, or capivasertib 640 mg twice a day 2 days on, 5 days off. Pharmacokinetics were dose proportional. Pharmacodynamic studies confirmed phosphorylated (p) GSK3ß suppression, increased pERK, and decreased BRCA1 expression. Twenty-five (44.6%) of 56 evaluable patients achieved clinical benefit (RECIST complete response/partial response or stable disease ≥ 4 months), including patients with tumors harboring germline BRCA1/2 mutations and BRCA1/2 wild-type cancers with or without DDR and PI3K-AKT pathway alterations. SIGNIFICANCE: In the first trial to combine PARP and AKT inhibitors, a prospective intrapatient dose- escalation design demonstrated safety, tolerability, and pharmacokinetic-pharmacodynamic activity and assessed predictive biomarkers of response/resistance. Antitumor activity was observed in patients harboring tumors with germline BRCA1/2 mutations and BRCA1/2 wild-type cancers with or without somatic DDR and/or PI3K-AKT pathway alterations.This article is highlighted in the In This Issue feature, p. 1426.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , BRCA1 Protein/metabolism , BRCA2 Protein/metabolism , Phthalazines/therapeutic use , Piperazines/therapeutic use , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Pyrimidines/therapeutic use , Pyrroles/therapeutic use , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Female , Humans , Middle Aged , Phthalazines/pharmacology , Piperazines/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Pyrimidines/pharmacology , Pyrroles/pharmacologyABSTRACT
Poly-(ADP-ribose) polymerase (PARP) inhibitors act through synthetic lethality in cells with defects in homologous recombination (HR) DNA repair caused by molecular aberrations such as BRCA mutations, and is approved for treatment in ovarian cancer, with promising clinical activity against other HR defective tumors including breast and prostate cancers. Three PARP inhibitors have been FDA approved, while another two have shown promising activity and are in late stage development. Nonetheless, both primary and secondary resistance to PARP inhibition have led to treatment failure, and the development of predictive biomarkers and the ability to identify and overcome mechanisms of resistance is vital for optimization of its clinical utility. Additionally, there has been evidence that PARP inhibition may have a therapeutic role beyond HR deficient tumors which warrants further investigation, both as single agent and in combination with other therapeutic modalities like cytotoxic chemotherapy, radiation, targeted therapy and immunotherapy. With new strategies to overcome resistance and expand its therapeutic utility, PARP inhibitors are likely to become a staple in our armamentarium of drugs in cancer therapeutics.
ABSTRACT
In the era of personalized medicine, tumor sampling is paramount to enable the assessment of actionable molecular aberrations to help rationalize and guide treatment decisions. Longitudinal tracking of such aberrations may also be helpful to detect emerging drug resistance and to allow for timely modifications to ongoing therapies to improve patient outcomes. Nevertheless, tumor tissue sampling involves an invasive procedure with potential risks to patients and involves logistical challenges. As such, other less invasive and safer methods such as blood sampling for molecular profiling has been gaining traction. In this article, we discuss the concept of circulating tumor DNA, the technology platforms available for its interrogation, and its current applications in the clinic. We also envision how circulating tumor DNA may be applied at multiple time points along a patient's cancer journey to guide diagnosis, prognostication, and therapeutic decisions.