Annals of Oncology最新文献

Background: Prospective data comparing watch-and-wait (WW) to mandatory total mesorectal excision (TME) in patients with locally advanced rectal cancer (LARC) remains limited, as randomized control trials assessing these two treatment approaches are considered impractical. This pooled analysis of the CAO/ARO/AIO-12 and OPRA trials analyzes survival outcomes among LARC patients managed with either a selective WW or mandatory TME strategy following total neoadjuvant therapy (TNT).

Patients and methods: The CAO/ARO/AIO-12 and OPRA trials were multicenter, phase II trials that randomized patients with stage II/III rectal cancer to receive either induction or consolidation chemotherapy as part of TNT. All patients in the CAO/ARO/AIO-12 trial underwent TME within six weeks of completing TNT. The OPRA trial allowed patients with a complete or near-complete response to enter WW while those with an incomplete response proceeded to TME. The primary endpoint of the present pooled analysis was disease-free survival (DFS). Secondary endpoints included distant recurrence-free survival (DRFS), local recurrence-free survival (LRFS) and overall survival (OS).

Results: This pooled analysis included 628 patients (n=304 CAO/ARO/AIO-12; n=324 OPRA). Median follow-up was 3.6 (IQR 1.13) and 5.1 (IQR 2.2) years, respectively. Patients in the CAO/ARO/AIO-12 trial were more likely to have cT3/4 and cN positive disease while patients in the OPRA trial had tumors closer to the anal verge. Compliance to TNT and rates of grade 3+ adverse events were similar between studies. There were no differences in DFS, DRFS, LRFS or OS based on treatment strategy or TNT treatment arm.

Conclusions: This pooled analysis demonstrated equivalent oncologic outcomes between patients treated with mandatory TME and selective WW strategies following TNT. These results strengthen available evidence indicating that WW is a safe treatment option for patients with an excellent response to neoadjuvant therapy.

Background: The availability and affordability of safe, effective cancer therapies are core requirements for effective cancer control. Global disparities exist in access, however, yielding unequal cancer outcomes. The goal of this study was to provide updated data regarding the formulary availability, out-of-pocket costs, and accessibility of cancer medicines in countries across the full spectrum of economic development areas.

Methods: This study was conducted through an online survey based on a previously validated methodology. It evaluated the formulary availability, out of pocket costs, and actual accessibility of essential generic cancer medication commonly used for a wide range of cancers, including those on the 22nd WHO Model List of Essential Medicines (EML), and cancer medications used in eight high-incidence cancers. A total of 853 field reporters from 170 countries were invited to participate. The collected data were collated and peer-reviewed on the ESMO website, with final adjustments made accordingly.

Results: Data were collected by 317 reporters and 231 peer reviewers across 126 countries. The study revealed that patients in most high-income countries can access cancer medications without significant out-of-pocket expenditure, including novel treatments with high ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS) scores. Conversely, in lower-middle and low-income countries, 40% of traditional chemotherapy agents deemed essential in the WHO EML are only available at full cost to patients.

Conclusions: This dataset provides a new and updated 'Global Reference' to enhance accountability for inequalities in access and availability of cancer medicines and to identify challenges and shortcomings to drive public health policies and positively impact national cancer control planning.

Background: The currently approved frontline treatments for diffuse pleural mesothelioma (DPM) are ipilimumab-nivolumab or platinum-pemetrexed. The addition of bevacizumab to chemotherapy improves overall survival (OS). While single-agent immunotherapy or chemotherapy-immunotherapy combinations are superior to chemotherapy monotherapy, there is a potential for synergistic triple combination of chemotherapy, bevacizumab, and immunotherapy.

Patients and methods: BEAT-meso is an international open-label, 1:1 randomised phase III trial, with stratification factors histology and stage aiming to determine the efficacy and safety of adding atezolizumab (1200 mg, Q3W until progression) to bevacizumab (15 mg/kg, Q3W until progression) and standard chemotherapy (4-6 cycles of carboplatin AUC5 with pemetrexed 500 mg/m2, Q3W; ABC versus BC) as first-line treatment for advanced DPM. The primary endpoint is OS in all randomised patients, aiming to a relative benefit of 29% (HR=0.708). Secondary endpoints include progression-free survival (PFS), adverse events (AEs) and symptom-specific and global quality of life (QoL).

Results: Between 30/04/2019 and 7/03/2022, 400 patients were randomised, 200 per arm. 65% had ECOG performance status 1 and 78% had epithelioid histology. At a median follow-up of 35 months (data cut-off 1/09/2023), the median OS was 20.5 months for ABC versus 18.1 months for BC (HR(95%CI): 0.84(0.66-1.06); p=0.14). Median PFS was significantly longer for ABC than BC (9.2 vs 7.6 months); HR: 0.72(0.59-0.89); p=0.0021). Histology showed significant treatment interaction for both PFS and OS, with OS HR: 0.51(0.32-0.80) for non-epithelioid and 1.01(0.77-1.32) for epithelioid (interaction p=0.012). Grade≥3 treatment-related AEs were reported in 55% of patients in ABC and 47% in BC, QoL was maintained with ABC with no clinically meaningful differences from BC.

Conclusions: The significant benefit in median PFS for ABC found in this study translated into a numerical but not significant increase in median OS. Thus, the primary endpoint was not met. In the pre-specified analysis by histology, superior OS and PFS were found for ABC in non-epithelioid cases.

Purpose: To assess the association between neoadjuvant therapy and overall survival (OS) in patients with left-sided resectable pancreatic cancer (RPC) compared to upfront surgery.

Background: Left-sided pancreatic cancer is associated with worse OS compared to right-sided pancreatic cancer. Although neoadjuvant therapy is currently seen as not effective in patients with RPC, current randomized trials included mostly patients with right-sided RPC.

Methods: International multicenter retrospective study including consecutive patients after left-sided pancreatic resection for pathology-proven RPC, either after neoadjuvant therapy or upfront surgery in 76 centers from 18 countries on 4 continents (2013-2019). Primary endpoint is OS from diagnosis. Time-dependent Cox regression analysis was performed to investigate the association of neoadjuvant therapy with OS, adjusting for confounders at time of diagnosis. Adjusted OS probabilities were calculated.

Results: Overall, 2,282 patients after left-sided pancreatic resection for RPC were included of whom 290 patients (13%) received neoadjuvant therapy. The most common neoadjuvant regimens were (m)FOLFIRINOX (38%) and gemcitabine-nab-paclitaxel (22%). After upfront surgery, 72% of patients received adjuvant chemotherapy, mostly a single-agent regimen (74%). Neoadjuvant therapy was associated with prolonged OS compared to upfront surgery (adjusted HR=0.69 [95%CI 0.58-0.83]) with an adjusted median OS of 53 vs. 37 months (P=0.0003) and adjusted 5-year OS rates of 47% vs. 35% (P=0.0001) compared to upfront surgery. Interaction analysis demonstrated a stronger effect of neoadjuvant therapy in patients with a larger tumor (P_interaction=0.003) and higher serum CA19-9 (P_interaction=0.005). In contrast, the effect of neoadjuvant therapy was not enhanced for splenic artery (P_interaction=0.43), splenic vein (P_interaction=0.30), retroperitoneal (P_interaction=0.84), and multivisceral (P_interaction=0.96) involvement.

Conclusions: Neoadjuvant therapy in patients with left-sided RPC was associated with improved OS compared to upfront surgery. The impact of neoadjuvant therapy increased with larger tumor size and higher serum CA19-9 at diagnosis. Randomized controlled trials on neoadjuvant therapy specifically in patients with left-sided RPC are needed.

Background: Osimertinib is the standard first-line treatment for advanced epidermal growth factor receptor (EGFR)-mutated NSCLC. However, treatment resistance is inevitable and increased c-Met protein expression correlates with resistance. Telisotuzumab vedotin (Teliso-V) is an antibody-drug conjugate that targets c-Met protein overexpression. Herein, we report the results of a phase 1/1b trial evaluating Teliso-V plus osimertinib in patients with NSCLC after progression on osimertinib.

Patients and methods: This multicenter, open-label study (NCT02099058) enrolled patients with advanced EGFR-mutated, c-Met protein-overexpressing, non-squamous NSCLC that had progressed on prior osimertinib. Patients received Teliso-V (intravenously, every 2 weeks) plus osimertinib (orally, 80 mg once daily). Teliso-V was evaluated at 1.6 mg/kg in a safety lead-in phase and escalated to 1.9 mg/kg. Dose expansion included both doses. Endpoints included safety and tolerability, pharmacokinetics, objective response rate (ORR), duration of response (DOR), and progression-free survival (PFS).

Results: A total of 38 patients received Teliso-V (1.6 mg/kg, n=20; 1.9 mg/kg, n=18) plus osimertinib and were included in this analysis. No dose-limiting toxicities were observed. Most frequent any-grade treatment-emergent adverse events (TEAEs) were peripheral sensory neuropathy (50%), peripheral edema (32%), and nausea (24%). Most common grade 3/4 TEAEs were anemia (11%) and pulmonary embolism (8%). Five TEAEs led to death; none were reported as being related to Teliso-V or osimertinib. The pharmacokinetic profile of Teliso-V plus osimertinib was similar to Teliso-V monotherapy. After a median follow-up of 7.4 months, ORR was 50.0% per independent central review (ICR) (DOR not reached), and median PFS per ICR was 7.4 months (95% CI: 5.4, NR).

Conclusions: Teliso-V plus osimertinib had promising activity and a manageable safety profile in patients with c-Met protein-overexpressing, EGFR-mutated non-squamous NSCLC after progression on osimertinib. This combination has the potential to address an unmet medical need in this patient population.

Clinicaltrials:

Gov id: NCT02099058.

Background: The FOxTROT trial has reported advantages of neoadjuvant chemotherapy (NAC) in locally advanced colon cancer (LACC). Here we present results of the embedded randomized phase II trial testing the addition of panitumumab to neoadjuvant FOLFOX compared with FOLFOX alone in RAS and BRAF-wild-type patients and with biomarker hyperselction.

Patients and methods: Patients had operable, CT-predicted stage T3-4, N0-2, M0 colon adenocarcinoma. KRAS-wt pts allocated to NAC could optionally be sub-randomized 1:1 to FOLFOX ± panitumumab during the pre-operative phase. RAS/BRAF were tested by NGS; EREG/AREG by RNAseq. Primary endpoint is time to recurrence (TTR) in RAS/BRAF-wt patients; secondary endpoints include safety, histological downstaging, disease-free survival (DFS), colon cancer-specific survival (CCSS), overall survival (OS), and impact of primary tumor location and EREG/AREG.

Results: In total 269 KRAS-wt patients were enrolled into the embedded phase II trial. Extended RAS/BRAF data were available for 232 (83%) patients; 22/232(9.5%) were RAS-mutant; 41/210(20%) were BRAF-mutant. Median follow up was 42 months. In 169 RAS/BRAF-wt patients there was a trend towards reduced recurrences with FOLFOX plus panitumumab compared with FOLFOX (12% vs 21%, HR=0.51, p=0.09); significant improvements were seen for DFS, CCSS and OS. Within the hyperselected EREG/AREG high group, there was significant reduction in recurrences with panitumumab. Panitumumab was not associated with increased pathological regression of the primary tumor (TRG 1-3 16% vs 22%,p=0.27). FOLFOX plus panitumumab was associated with higher rates of grade 3 diarrhoea (8% vs 3%,) and rash (22% vs 2%).

Conclusion: This exploratory analysis from a randomized phase II study shows a non-significant improvement in TTR from the addition of neoadjuvant panitumumab to peri-operative FOLFOX in RAS/BRAF-wt LACC. Hyperselection with EREG/AREG status was associated with increased efficacy. A dedicated prospective trial within a biomarker selected population is under development.

Clinical trials registration: ISRCTN87163246.