Concurrent cisplatin-based chemoradiotherapy (CCRT) is the standard treatment for locally advanced head and neck cancer (LAHNC); however, it also results in substantial treatment-related toxicities. Oxaliplatin has similar radiosensitisation mechanisms to cisplatin and, if found to have equivalent efficacy in LAHNCs, has the potential to replace cisplatin in CCRT protocols.

NRG Oncology/Alliance LU005 (ClinicalTrials.gov identifier: NCT03811002) tested the addition of atezolizumab to concurrent chemoradiation (CRT) in this open-label, phase III international trial.

The Pediatric Hodgkin Consortium hypothesized that by increasing chemotherapeutic dose density for Hodgkin lymphoma (HL) they could increase the complete response (CR) rate among patients with favorable-risk HL after 8 weeks of Stanford V (vinblastine, doxorubicin, vincristine, bleomycin, mechlorethamine, etoposide and prednisone) compared with 8 weeks of VAMP (vinblastine, Adriamycin [doxorubicin], methotrexate, and prednisone). This would translate to a decrease in patients who required radiation therapy (RT) to achieve a cure. The HOD08 study was a phase 2 multicenter, investigator-initiated single-arm trial for patients aged ≤21 years with previously untreated stage 1A or 2A HL without mediastinal bulk or extranodal disease extension and <3 sites of disease. Treatment consisted of a modified 8-week Stanford V regimen. Modified, tailored, field RT was administered only to disease sites achieving less than a CR. The primary objective was to increase CR rate after 8 weeks of chemotherapy by at least 20% (from an estimated 44% to 64%) compared with patients treated on a previous trial (HOD99). HOD08 enrolled 85 patients with HL and 72 were evaluable for the primary objective, of whom 55 (76.4%) achieved a CR at all sites and did not receive RT. The 5-year event-free survival and overall survival rates for the entire cohort were 87.4% (95% confidence interval [CI], 80.4-95.0) and 98.7% (95% CI, 96.2-100), respectively. A dose-dense modified Stanford V regimen reduced the proportion of pediatric patients with low-risk HL who received RT while maintaining excellent outcomes. This trial was registered at www.clinicaltrials.gov as #NCT00846742.

Locally advanced pancreatic cancer (LAPC) accounts for 30% of pancreatic cancers. We assessed the efficacy and safety of a novel extended-release siRNA targeting KRASG12D/V mutations (siG12D-LODER) combined with chemotherapy in LAPC.

Patients with recurrent endometrial or ovarian cancer have poor survival outcomes. We evaluated the clinical efficacy and toxicity of copanlisib [a phosphatidylinositol 3-kinase (PI3K) inhibitor] and niraparib [a poly (ADP-ribose) polymerase inhibitor (PARPi)] in this patient population with translational insights.

Neoadjuvant chemo-immunotherapy is emerging as promising strategy in muscle-invasive bladder cancer (MIBC), yet its perioperative safety remains understudied. This post-hoc analysis of the AURA phase-II trial assesses surgical outcomes following neoadjuvant avelumab with or without chemotherapy.

Treatment-free remission (TFR) after discontinuation of ABL tyrosine kinase inhibitors (TKIs) is an important therapeutic goal in chronic myeloid leukemia (CML). Interferon-α (IFN) has been suggested to promote durable TFR. The phase 3 ENDURE trial (NCT03117816; EUDRA-CT 2016-001030-94) prospectively tested this hypothesis in patients with stable deep molecular remission after TKI therapy. A total of 203 patients were randomised 1:1 to receive ropeginterferon alfa-2b (ropeg-IFN; 100 µg subcutaneously every two weeks for 15 months, n = 95) or observation alone (n = 108) after TKI discontinuation. The primary endpoint was molecular relapse-free survival (MRFS), defined as time to loss of major molecular response (MMR) or death. At a median follow-up of 36 months, 25-month MRFS was 56% (95% confidence interval (CI), 45-66) with ropeg-IFN and 59% (95% CI, 49-68) with observation (hazard ratio (HR), 1.02; 95% CI, 0.68-1.55; P = 0.91). Among 83 patients with molecular data after TKI restart, 79 (95%) regained at least MMR, 78 within 12 months (median 3 months, interquartile range: 2-4 months). Ropeg-IFN was well tolerated (median administered dose of 92 µg, range 3-104), and no new safety signals were observed. Ropeg-IFN maintenance did not improve the probability of sustained TFR after TKI discontinuation.

MOUNTAINEER was a multicenter, open-label, phase 2 trial (NCT03043313) that evaluated the efficacy and safety of tucatinib plus trastuzumab, a dual HER2-targeted chemotherapy-free regimen. Patients were included if they had chemotherapy-refractory, HER2+, RAS wild-type unresectable or metastatic colorectal cancer. This final analysis reports updated efficacy and safety after a median follow-up of 32.4 months. Of the 84 patients who received tucatinib plus trastuzumab, the confirmed objective response rate was 39.3%; median duration of response was 15.2 months. Median progression-free survival was 8.1 months and overall survival was 23.9 months. Efficacy was relatively similar across central HER2+ testing methods. No clear association of treatment response with co-occurring biomarker alterations was seen. Few patients discontinued treatment due to adverse events; no treatment-emergent deaths occurred. Tucatinib plus trastuzumab showed clinically meaningful efficacy and favorable safety. Efficacy was observed irrespective of central HER2+ testing methods and in patients with heterogeneous tumor biomarker profiles.

Pancreatic ductal adenocarcinoma (PDAC) remains highly lethal and has poor immunogenicity, warranting the use of vaccines to guide and recruit the immune response. Building on prior efforts to achieve clinical immunotherapeutic responses against PDAC, we conducted a phase II study (NCT03190265) that combined attenuated mesothelin (MSLN)-secreting listeria vaccine (CRS-207) and GM-CSF-secreting allogeneic whole-cell vaccine (GVAX) along with checkpoint inhibition. Patients with metastatic PDAC who progressed on chemotherapy were enrolled in one of two treatment arms in a randomized fashion. CRS-207 was given with anti-PD-1 (nivolumab) and anti-CTLA4 (ipilimumab) with (arm A) or without (arm B) GVAX. The primary endpoint was the objective response rate (ORR), and the secondary endpoint was safety. Fifty-seven patients received at least one dose of treatment, with two partial responses (4% ORR), in both arm B. The response rates were not significantly different between the two arms. Related grade ≥3 adverse events were seen in 39 (68%) patients, including 33 events attributed to CRS-207. Mass cytometry analysis of serially obtained biospecimens demonstrated treatment-induced promotion of T-cell memory and infiltration into the tumor microenvironment (TME). Peptide-specific T-cell expansions in vitro, followed by T-cell receptor sequencing, revealed clones specific to MSLN and mutant KRAS within the tumor. Accompanying these antitumor T-cell responses was significant enrichment of myeloid cells. High myeloid and regulatory T-cell signatures correlated with poor responses. We conclude that GVAX/CRS-207 plus nivolumab and ipilimumab successfully generates and expands T-cell clones specific to MSLN and mutant KRAS within the PDAC TME, but immunotherapy-induced myeloid cell enrichment remains a barrier to greater efficacy. See related article by Sidiropoulos et al., p. 399.

Well-differentiated grade 3 neuroendocrine tumors (NETs) have recently been described as a distinct category, and randomized data regarding efficacy of therapy for these patients are scarce. In the phase 3 CABINET trial, cabozantinib improved PFS compared with placebo in patients with advanced, previously treated, progressive extra-pancreatic NETs (epNETs) and pancreatic NETs (pNETs) of all grades. Here, we evaluate if these results remain consistent in a subgroup of patients with well-differentiated G3 NETs. Patients with locally advanced or metastatic epNETs or pNETs were randomized 2:1 in independent cohorts to receive cabozantinib 60 mg daily vs placebo. We analyzed outcomes of the subset of patients with G3 NETs (Ki-67 > 20%), combining patients in the pNET and epNET cohorts due to small sample sizes. Twenty-four patients had G3 NETs, 16 randomized to cabozantinib and 8 to placebo. Primary sites included pancreas (n = 12), GI tract (n = 7), unknown primary sites (n = 3), and lung/thymus (n = 2). Median PFS for patients with G3 NETs treated with cabozantinib was 7.9 vs 3 months with placebo (HR = 0.15, 95% CI: 0.04-0.57, 1-sided log-rank P = 0.0034). The confirmed overall radiographic response rate was 25% (4/16) with cabozantinib vs 0% (0/8) with placebo. Safety outcomes were consistent with published data for the trial as a whole. Subset analysis of the CABINET trial showed improved PFS associated with cabozantinib vs placebo for G3 NETs of pancreatic and extra-pancreatic origin. Despite limited numbers, these results suggest that cabozantinib can be an effective option for patients with advanced G3 NETs. ClinicalTrials.gov Identifier: NCT03375320.

Standard therapy for PD-1 inhibitor-refractory recurrent or metastatic head and neck squamous-cell carcinoma (RM-HNSCC) has limited activity. Drugs bound to albumin selectively target cancer cells with upregulated macropinocytosis, a process driven by constitutively hyper-activated EGFR/RAS/PIK3CA signaling, which is common in HNSCC. Nanoparticle albumin-bound (nab)-paclitaxel is active in PD-1 inhibitor-naïve RM-HNSCC and alters immune cells to potentially prime tumor response and reverse resistance to PD-1 inhibitors.

To compare the sentinel lymph node (SLN) identification proportions using Indocyanine green with the standard radio colloid-blue dye method.

This prospective phase 2 trial (NCT06870942) aimed to evaluate whether stereotactic body radiation therapy (SBRT) combined with continued first-line PD-1 inhibitor-based therapy could overcome acquired resistance and prolong progression-free survival (PFS) in patients with oligoprogressive hepatocellular carcinoma (HCC).

The combination of reduced normal tissue damage and unaffected tumor control is referred to as Flash-effect. This phenomenon has been observed with ultra-high dose rate (UHDR) radiotherapy in preclinical models. The Flash-Skin I (NCT06549439) treated seven patients with melanoma skin metastasis. The treatment protocol included 2 × 9 Gy UHDR followed by 1 × 9 Gy conventional radiotherapy. Here we report on the implementation of the study at a converted C-arm clinical linear accelerator.

Both Transoral laser surgery (TLS) and radiotherapy are used in the treatment of T1aN0 glottic cancer with similar oncological outcomes. Retrospective studies suggest excellent local control with single vocal cord irradiation that targets only the affected vocal cord. So, the aim of this study was to compare the treatment outcome and toxicity of the classic radiotherapy field vs single vocal cord irradiation (SVCI) technique.

To compare oncologic outcomes and perioperative morbidity between simple hysterectomy (SH) and radical hysterectomy (RH) in patients with and without very low-risk early-stage cervical cancer from the phase III Simple Hysterectomy And PElvic node assessment (SHAPE) trial.

Despite successes in other malignancies, immune checkpoint blockade (ICB) has not demonstrated reproducible efficacy in mismatch repair-proficient (pMMR) colorectal cancer (CRC). Preclinical studies indicate that multitargeted combination immunotherapy may sensitize resistant tumors to immune-mediated killing. This trial was designed to test this hypothesis by combining agents to induce and augment an immune response in pMMR CRC.

In CARTITUDE-4, a single infusion of ciltacabtagene autoleucel (cilta-cel) significantly prolonged progression-free survival in patients with lenalidomide-refractory multiple myeloma. We report updated overall survival and longer-term efficacy and safety outcomes.

In the SCORES study ( NCT04908787 ), women with ovarian cancer that progressed within 6 months after completing platinum-based therapy were randomized (2:1) to receive suvemcitug (1.5 mg kg-1), an antibody to vascular endothelial growth factor or placebo every 2 weeks, with chemotherapy (paclitaxel, topotecan or PEGylated liposomal doxorubicin). The primary endpoint was progression-free survival (PFS). The key secondary endpoint was overall survival (OS). Other secondary endpoints included objective response rate, disease control rate, duration of response, quality of life, safety, pharmacokinetics and antidrug antibodies. Between June 5, 2021 and October 11, 2024, 421 participants were randomized (49.4% and 49.4% previously exposed to antiangiogenic agents and poly(ADP-ribose) polymerase inhibitors, respectively). Median PFS was 5.5 and 2.7 months in the suvemcitug and placebo arms, respectively (hazard ratio: 0.46, 95% confidence interval (CI): 0.35-0.60, P < 0.001), meeting the primary endpoint. Median OS was 15.3 versus 14.0 months, respectively (hazard ratio: 0.77, 95% CI: 0.60-0.99, P = 0.03). Decreased neutrophil count and decreased white blood cell count were the most common grade ≥3 treatment-emergent adverse events (TEAEs) in the suvemcitug arm. No suvemcitug-related grade 5 TEAE occurred. In conclusion, the addition of suvemcitug to chemotherapy significantly improved PFS and OS, with tolerable toxicities.

In the PROSELICA, a randomized controlled trial (RCT) comparing cabazitaxel 20 mg/m2 (C20) versus 25 mg/m2 (C25) in metastatic castration-resistant prostate cancer (mCRPC), one-variable-at-a-time subgroup analysis suggested possible heterogeneity in treatment effect (HTE) of C25 versus C20 among study participants. Novel predictive HTE analysis approaches may provide an in-depth understanding of such results.