The current analysis was performed to evaluate the impact of PIK3CA hotspot mutations on everolimus efficacy in BOLERO-2 participants, using cell-free DNA (cfDNA) from plasma samples collected at the ...time of patient randomisation.
PIK3CA H1047R, E545K, and E542K mutations in plasma-derived cfDNA were analysed by droplet digital PCR (ddPCR). Median PFS was estimated for patient subgroups defined by PIK3CA mutations in each treatment arm.
Among 550 patients included in cfDNA analysis, median PFS in everolimus vs placebo arms was similar in patients with tumours that had wild-type or mutant PIK3CA (hazard ratio (HR), 0.43 and 0.37, respectively). Everolimus also prolonged median PFS in patients with PIK3CA H1047R (HR, 0.37) and E545K/E542K mutations (HR=0.30) with a similar magnitude.
Mutation analysis of plasma-derived cfDNA by ddPCR suggests that PFS benefit of everolimus was maintained irrespective of PIK3CA genotypes, consistent with the previous analysis of archival tumour DNA by next-generation sequencing.
Abstract Many genomic abnormalities have been identified in various subsets of prostate cancer, but until now, few genes have been associated with the progression of this cancer. High activity of ...protein serine/threonine kinase CK2 has been observed in various solid tumours and this alteration has been linked both to growth-related functions and to suppression of cellular apoptosis. Here, we provide the first evidence for a strong association between a nuclear localization of CK2 α , evaluated by immunohistochemistry, and poor prognostic factors in a retrospective cohort of 131 human prostate adenocarcinomas. Nuclear CK2 α localization is significantly correlated with higher Gleason score, more locally advanced disease (cT3–T4) and more perineural or lymphatic invasion ( p < 0.0019 to 0.046). In contrast, despite a strong trend, no significant relationship was found between higher initial PSA and nuclear CK2 α localization. Thus, this previously undescribed molecular heterogeneity is the first step in defining CK2 as both a potential biomarker and a promising target in human prostate cancer.
Endocrine therapy (ET)-based regimens are the mainstay of treatment for patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer. ...With the introduction of new treatment classes, it is important to examine patient symptoms and health-related quality of life (HRQoL) at the start of this changing therapeutic landscape. This real-world study describes the patient-reported outcomes (PROs) of women with HR+/HER2- advanced breast cancer receiving ET-based regimens who were naïve to systemic treatment in the advanced setting across five European countries (EU5).
Data were collected between March and July 2017 from surveyed oncologists and their patients at a single time point using the multinational Adelphi Advanced Breast Cancer Disease Specific Programme™. Patients completed PRO questionnaires on HRQoL (EORTC QLQ-C30), pain severity and interference, and work and activity impairment. A multiple linear regression model explored factors associated with HRQoL.
Across EU5, 226 physicians provided data on 781 women with HR+/HER2- advanced breast cancer taking their first ET-based regimen for advanced disease, of whom 252 provided PRO data. This subset had a mean age of 67.1 years, 94% were postmenopausal, 89% were diagnosed with advanced breast cancer at initial presentation, 79% had stage IV disease (66% of these patients had bone metastases and 38% had visceral metastases, including 18% with liver metastases) and 77% were on endocrine-only therapy as their initial treatment for advanced disease. The mean EORTC QLQ-C30 global health score (50.9) was worse than the reference value for patients with advanced breast cancer (60.2). Fatigue, pain, and insomnia were the most severe symptoms, and mean functioning scores were also worse than reference values. "Worst pain" and "pain interference" were moderate/severe for 42 and 80% of patients. Mean activity impairment was 44%, and greater activity impairment was associated with poorer HRQoL.
Despite receiving first-line ET-based regimens for advanced disease, these women had a poor HRQoL and high levels of symptoms, pain, pain interference and activity impairment. New treatments that maintain a stable disease state and reduce activity impairment may have a positive effect on the HRQoL of those living with advanced breast cancer.
The 8p12 locus (containing the FGFR1 tyrosine kinase gene) is frequently amplified in squamous cell lung cancer. However, it is currently unknown which of the 8p12-amplified tumors are also sensitive ...to fibroblast growth factor receptor (FGFR) inhibition. We found that, in contrast with other recurrent amplifications, the 8p12 region included multiple centers of amplification, suggesting marked genomic heterogeneity. FGFR1-amplified tumor cells were dependent on FGFR ligands in vitro and in vivo. Furthermore, ectopic expression of FGFR1 was oncogenic, which was enhanced by expression of MYC. We found that MYC was coexpressed in 40% of FGFR1-amplified tumors. Tumor cells coexpressing MYC were more sensitive to FGFR inhibition, suggesting that patients with FGFR1-amplified and MYC-overexpressing tumors may benefit from FGFR inhibitor therapy. Thus, both cell-autonomous and non-cell-autonomous mechanisms of transformation modulate FGFR dependency in FGFR1-amplified lung cancer, which may have implications for patient selection for treatment with FGFR inhibitors.
Amplification of FGFR1 is one of the most frequent candidate targets in lung cancer. Here, we show that multiple factors affect the tumorigenic potential of FGFR1, thus providing clinical hypotheses for refinement of patient selection.
The current exploratory analysis was performed to evaluate the efficacy and safety of everolimus for treatment of human epidermal growth factor receptor 2-positive (HER2+) advanced breast cancer in ...the Asian subset of patients in the BOLERO-1 trial.
Postmenopausal women with HER2+ advanced breast cancer, who had not received systemic therapy for advanced disease, were randomized 2:1 to receive everolimus or placebo, plus trastuzumab and paclitaxel. The two primary end points were investigator-assessed progression-free survival (PFS) in the full population and in the hormone receptor-negative (HR-) subpopulation. Secondary end points included assessment of the objective response rate, the clinical benefit rate, and safety.
In the Asian subset, median PFS was similar in the everolimus (n = 198) and placebo (n = 105) arms in the full analysis set (hazard ratio = 0.82 (95% CI 0.61-1.11)). In the HR- subpopulation, everolimus prolonged median PFS by 10.97 months vs placebo (25.46 vs 14.49 months; hazard ratio = 0.48 (95% CI 0.29-0.79)). In the everolimus arm of the Asian subset, the most common adverse events of any grade were stomatitis (62.2%), diarrhea (48.0%), rash (43.4%) and neutropenia (42.3%). Neutropenia (grade 3: 27.6%; grade 4: 4.6%) and decreased neutrophil count (grade 3: 11.2%; grade 4: 3.6%) were the most frequent grade 3/4 adverse events. Serious adverse events included pneumonia (5.1%), pneumonitis (3.1%), and interstitial lung disease (3.1%). There were three deaths (1.5%) during treatment in the everolimus arm vs none in the placebo arm.
The efficacy and safety of everolimus plus trastuzumab and paclitaxel as first-line treatment for HER2+ advanced breast cancer in the Asian subset was consistent with that reported previously in the overall population.
ClinicalTrials.gov, NCT00876395 . Registered on 2 April 2009.
MUC1 over-expression in renal clear-cell carcinoma (RCC) is associated with poor prognosis. This phase II study determined the efficacy and tolerability of TG4010, a cancer vaccine based on a ...modified vaccinia virus expressing MUC1 and interleukin-2, in combination with cytokines, as first-line therapy in metastatic RCC. Thirty-seven patients with progressive, MUC1-positive RCC received TG4010 10⁸ pfu/inj weekly for 6 weeks, then every 3 weeks until progression, when TG4010 was continued in combination with interferon-α2a and interleukin-2. Assessments included clinical response (primary endpoint), safety, time to treatment failure (TTF), overall survival (OS), and immune response. No objective clinical responses occurred. Five of the 27 evaluable patients (18%) had stable disease for >6 months with TG4010 alone and six of 20 patients (30%) had stable disease for >6 months with TG4010 plus cytokines. Median TTF was 4.1, 3.6, and 9.3 months for monotherapy, combination therapy, and overall, respectively. Median OS was 19.3 months for all patients and 22.4 months combination therapy recipients. The most frequent TG4010-related adverse events were minor-to-moderate injection-site reactions, fatigue, and flu-like symptoms. Six of 28 patients showed a MUC1 CD4⁺ T cell proliferative response during therapy. Anti-MUC1 CD8⁺ T cells were detected before and after therapy in 3 and 4 patients, respectively. MUC1-specific CD8⁺ T cell responses were associated with longer survival. Therapy with TG4010 plus cytokines appears to be feasible and well tolerated in patients with metastatic RCC. However, these data should be interpreted with caution, as additional prospective studies are necessary to clarify the clinical efficacy of this therapy.
Abstract Objective This phase II investigated efficacy and tolerability of gefitinib in combination with paclitaxel (P) and carboplatin (C) for second-line treatment of patients (pts) with ovarian, ...tubal or peritoneal adenocarcinoma. Patients and methods Women (> 18 years) with platinum-resistant/refractory (relapsed < 6 months), or platinum-sensitive (relapsed > 6 months) disease after first-line platinum-based and P chemotherapy. Pts received 6–8 cycles of gefitinib (500 mg/day), P (175 mg/m2 3 h infusion) and C (AUC 5) every 3 weeks, followed by gefitinib alone. The primary endpoint was objective response rate (ORR) (RECIST or Rustin criteria). Results Sixty-eight patients (26 resistant/refractory and 42 sensitive) were enrolled (median age: 57 years). ORR and disease control rates were 19.2% and 69.2% for resistant/refractory, and 61.9% and 81.0%, for sensitive disease. Median time to progression and overall median survivals were 6.1 and 16.9 months for resistant/refractory and 9.2 and 25.7 months for sensitive disease. Grade 3/4 toxicities (in ≥ 10% patients) were neutropenia (59%), diarrhea (25%), leukopenia (22%), anemia (13%), and acne (13%). Two secondary myelodysplastic syndromes (MDS) and one secondary acute leukemia occurred during treatment, and one MDS 34 months after treatment discontinuation. Conclusion Gefitinib, administered in combination with paclitaxel and carboplatin, provides a good clinical response but associated with an increased risk of hematologic disorders.
Purpose This two-part, first-in-human study was initiated in patients with advanced solid tumors harboring genetic alterations in fibroblast growth factor receptors (FGFRs) to determine the maximum ...tolerated dose (MTD), the recommended phase II dose (RP2D), and the schedule, safety, pharmacokinetics, pharmacodynamics, and antitumor activity of oral BGJ398, a selective FGFR1-3 tyrosine kinase inhibitor. Patients and Methods Adult patients were treated with escalating dosages of BGJ398 5 to 150 mg once daily or 50 mg twice daily continuously in 28-day cycles. During expansion at the MTD, patients with FGFR1-amplified squamous cell non-small-cell lung cancer (sqNSCLC; arm 1) or other solid tumors with FGFR genetic alterations (mutations/amplifications/fusions) received BGJ398 daily on a continuous schedule (arm 2), or on a 3-weeks-on/1-week-off schedule (arm 3). Results Data in 132 patients from the escalation and expansion arms are reported (May 15, 2015, cutoff). The MTD, 125 mg daily, was determined on the basis of dose-limiting toxicities in four patients (100 mg, grade 3 aminotransferase elevations n = 1; 125 mg, hyperphosphatemia n = 1; 150 mg, grade 1 corneal toxicity n = 1 and grade 3 aminotransferase elevations n = 1). Common adverse events in patients treated at the MTD (n = 57) included hyperphosphatemia (82.5%), constipation (50.9%), decreased appetite (45.6%), and stomatitis (45.6%). A similar safety profile was observed using the 3-weeks-on/1-week-off schedule (RP2D). However, adverse event-related dose adjustments/interruptions were less frequent with the 3-weeks-on/1-week-off (50.0%) versus the continuous (73.7%) schedule. Antitumor activity (seven partial responses six confirmed) was demonstrated with BGJ398 doses ≥ 100 mg in patients with FGFR1-amplified sqNSCLC and FGFR3-mutant bladder/urothelial cancer. Conclusion BGJ398 at the MTD/RP2D had a tolerable and manageable safety profile and showed antitumor activity in several tumor types, including FGFR1-amplified sqNSCLC and FGFR3-mutant bladder/urothelial cancers.
TPS2701 Background: Immune checkpoint inhibitors have transformed the treatment of multiple tumor types, including melanoma and squamous cell carcinoma of the head and neck (SCCHN). However, some ...patients (pts) with locally advanced disease still recur after surgery and adjuvant therapies. In melanoma, neoadjuvant pembrolizumab followed by adjuvant pembrolizumab was shown to improve event-free survival (EFS) compared to adjuvant pembrolizumab only (1). In SCCHN, two cycles of neoadjuvant pembrolizumab resulted in a two-fold increase in the frequency of pathological tumor response compared with one cycle (2). IO102-IO103 is an investigational therapeutic cancer vaccine that targets both tumor and immune-suppressive cells in the tumor microenvironment. IO102-IO103 treatment promotes inflammation and potentiates anti-tumor activity via activation and expansion of T cells against IDO1 and/or PD-L1 positive cells. Treatment with IO102-IO103 plus nivolumab in anti-PD-1 naïve metastatic melanoma showed 80% objective response rate including 50% complete response and was well tolerated in a phase 1/2 trial (3). We aim to investigate the activity of IO102-IO103 plus pembrolizumab in the perioperative setting in melanoma and SCCHN. Methods: IOB-032//PN-E40 (NCT05280314) is a Phase 2, open-label, multi-cohort trial aiming to evaluate safety, anti-tumor and immunological activity of IO102-IO103 in combination with pembrolizumab as neoadjuvant and adjuvant treatment. Pts with resectable tumors classified as melanoma (Cohorts A and C) or SCCHN (Cohort B) are eligible. Cohorts A and B are single-arm 15 patient cohorts. Following completion of Cohort A, additional 30 stage III melanoma pts will be randomized 1:1 to receive neo-adjuvant treatment with either IO102-IO103 plus pembrolizumab or pembrolizumab alone (Cohort C). During the neoadjuvant period, study treatment is every 3 weeks (Q3W) for 3 cycles (melanoma) or 2-3 cycles (SCCHN). Surgery will be performed between 1 and 3 weeks after the last neoadjuvant dose, followed by adjuvant treatment with IO102-IO103 and pembrolizumab or pembrolizumab alone Q3W for 15 cycles. Pts in Cohort C with poor pathological response to pembrolizumab alone in the neoadjuvant phase (>10% residual viable tumor) may cross over to receive the combination treatment post-surgery at the discretion of the investigator. The primary endpoint is major pathological response (≤10% residual viable tumor) at surgery (central assessment). Secondary endpoints include safety, EFS and disease-free survival. Furthermore, paired pre- and post-treatment tumor tissue and blood samples will be collected for translational research. The study will be conducted in the US, EU and Australia and began enrolment in December 2023. 1. Patel, NEJM 2023. 2. Oliveira, Sci Immunol. 2023. 3. Kjeldsen, Nat Med. 2021. Clinical trial information: EudraCTNo.2022-502787-20-00; ClinicalTrials.govNo.NCT05280314 .
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