No treatment has surpassed platinum-based chemotherapy in improving overall survival in patients with previously untreated locally advanced or metastatic urothelial carcinoma.
We conducted a phase 3, ...global, open-label, randomized trial to compare the efficacy and safety of enfortumab vedotin and pembrolizumab with the efficacy and safety of platinum-based chemotherapy in patients with previously untreated locally advanced or metastatic urothelial carcinoma. Patients were randomly assigned in a 1:1 ratio to receive 3-week cycles of enfortumab vedotin (at a dose of 1.25 mg per kilogram of body weight intravenously on days 1 and 8) and pembrolizumab (at a dose of 200 mg intravenously on day 1) (enfortumab vedotin-pembrolizumab group) or gemcitabine and either cisplatin or carboplatin (determined on the basis of eligibility to receive cisplatin) (chemotherapy group). The primary end points were progression-free survival as assessed by blinded independent central review and overall survival.
A total of 886 patients underwent randomization: 442 to the enfortumab vedotin-pembrolizumab group and 444 to the chemotherapy group. As of August 8, 2023, the median duration of follow-up for survival was 17.2 months. Progression-free survival was longer in the enfortumab vedotin-pembrolizumab group than in the chemotherapy group (median, 12.5 months vs. 6.3 months; hazard ratio for disease progression or death, 0.45; 95% confidence interval CI, 0.38 to 0.54; P<0.001), as was overall survival (median, 31.5 months vs. 16.1 months; hazard ratio for death, 0.47; 95% CI, 0.38 to 0.58; P<0.001). The median number of cycles was 12 (range, 1 to 46) in the enfortumab vedotin-pembrolizumab group and 6 (range, 1 to 6) in the chemotherapy group. Treatment-related adverse events of grade 3 or higher occurred in 55.9% of the patients in the enfortumab vedotin-pembrolizumab group and in 69.5% of those in the chemotherapy group.
Treatment with enfortumab vedotin and pembrolizumab resulted in significantly better outcomes than chemotherapy in patients with untreated locally advanced or metastatic urothelial carcinoma, with a safety profile consistent with that in previous reports. (Funded by Astellas Pharma US and others; EV-302 ClinicalTrials.gov number, NCT04223856.).
PD-1 immune checkpoint blockade provides significant clinical benefits for melanoma patients. We analyzed the somatic mutanomes and transcriptomes of pretreatment melanoma biopsies to identify ...factors that may influence innate sensitivity or resistance to anti-PD-1 therapy. We find that overall high mutational loads associate with improved survival, and tumors from responding patients are enriched for mutations in the DNA repair gene BRCA2. Innately resistant tumors display a transcriptional signature (referred to as the IPRES, or innate anti-PD-1 resistance), indicating concurrent up-expression of genes involved in the regulation of mesenchymal transition, cell adhesion, extracellular matrix remodeling, angiogenesis, and wound healing. Notably, mitogen-activated protein kinase (MAPK)-targeted therapy (MAPK inhibitor) induces similar signatures in melanoma, suggesting that a non-genomic form of MAPK inhibitor resistance mediates cross-resistance to anti-PD-1 therapy. Validation of the IPRES in other independent tumor cohorts defines a transcriptomic subset across distinct types of advanced cancer. These findings suggest that attenuating the biological processes that underlie IPRES may improve anti-PD-1 response in melanoma and other cancer types.
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•High mutational loads may predict better survival, but not response to anti-PD-1•BRCA2 mutations are enriched in melanomas responsive to anti-PD-1•A transcriptional signature is related to innate anti-PD-1 resistance (IPRES)•IPRES defines a transcriptomic subset across distinct types of advanced cancer
High mutational loads are associated with improved survival in melanoma patients but are not predictive of response to anti-PD-1 therapy, suggesting that other genomic and non-genomic features also contribute to response patterns on PD-1 checkpoint blockade therapy.
Background In subjects with psoriasis, inflammation and epidermal hyperplasia are thought to be controlled by T cell–derived cytokines. Evidence suggests that the TH 17 cell cytokine IL-17A (IL-17) ...might play a role in disease pathogenesis. Objective We sought to understand the effect that neutralization of IL-17 has on the clinical features of psoriasis and to understand the role that IL-17 has in inflammatory pathways underlying psoriasis in human subjects. Methods We examined skin lesions obtained from 40 subjects participating in a phase I, randomized, double-blind, placebo-controlled trial of the anti–IL-17 mAb ixekizumab (previously LY2439821) in which subjects received 5, 15, 50, or 150 mg of subcutaneous ixekizumab or placebo at weeks 0, 2, and 4. Results There were significant dose-dependent reductions from baseline in keratinocyte proliferation, hyperplasia, epidermal thickness, infiltration into the dermis and epidermis by T cells and dendritic cells, and keratinocyte expression of innate defense peptides at 2 weeks. By week 6, the skin appeared normal. Quantitative RT-PCR and microarrays revealed an ablation of the disease-defining mRNA expression profile by 2 weeks after the first dose of study drug. The effect of IL-17 blockade on expression of genes synergistically regulated by IL-17 and TNF-α was of higher magnitude at 2 weeks than in prior studies with TNF-α antagonism. Conclusion Our data suggest that IL-17 is a key “driver” cytokine that activates pathogenic inflammation in subjects with psoriasis. Neutralizing IL-17 with ixekizumab might be a successful therapeutic strategy in psoriasis.
Obinutuzumab (Gazyva™) is an intravenously administered, humanized and glycoengineered, type II anti-CD20 monoclonal antibody for the treatment of B-cell malignancies. It is approved in the US for ...use in combination with chlorambucil for the first-line treatment of chronic lymphocytic leukaemia (CLL), and has been filed for approval in the EU in this indication. The antibody is based on GlycArt Biotechnology's (later Roche Glycart AG) proprietary GlycoMAb® technology, which uses glycoengineered antibodies that specifically increase antibody-dependent cellular cytotoxicity and thereby increase immune-mediated target cell death. Obinutuzumab is a type II anti-CD20 antibody that induces enhanced direct cell death. The monoclonal antibody is in worldwide phase III development with Roche and its subsidiaries, Genentech and Chugai Pharmaceutical, as well as Biogen Idec, for diffuse large B-cell lymphoma and non-Hodgkin's lymphoma generally, and is also in phase III development in countries outside of the US and EU for CLL.
Sacituzumab govitecan (IMMU-132) is an antibody–drug conjugate (ADC) made from a humanized anti-Trop-2 monoclonal antibody (hRS7) conjugated with the active metabolite of irinotecan, SN-38. In ...addition to its further characterization, as the clinical utility of IMMU-132 expands to an ever-widening range of Trop-2-expressing solid tumor types, its efficacy in new disease models needs to be explored in a nonclinical setting. Unlike most ADCs that use ultratoxic drugs and stable linkers, IMMU-132 uses a moderately toxic drug with a moderately stable carbonate bond between SN-38 and the linker. Flow cytometry and immunohistochemistry disclosed that Trop-2 is expressed in a wide range of tumor types, including gastric, pancreatic, triple-negative breast (TNBC), colonic, prostate, and lung. While cell-binding experiments reveal no significant differences between IMMU-132 and parental hRS7 antibody, surface plasmon resonance analysis using a Trop-2 CM5 chip shows a significant binding advantage for IMMU-132 over hRS7. The conjugate retained binding to the neonatal receptor, but it lost greater than 60% of the antibody-dependent cell-mediated cytotoxicity activity compared to that of hRS7. Exposure of tumor cells to either free SN-38 or IMMU-132 demonstrated the same signaling pathways, with pJNK1/2 and p21WAF1/Cip1 upregulation followed by cleavage of caspases 9, 7, and 3, ultimately leading to poly-ADP-ribose polymerase cleavage and double-stranded DNA breaks. Pharmacokinetics of the intact ADC in mice reveals a mean residence time (MRT) of 15.4 h, while the carrier hRS7 antibody cleared at a similar rate as that of the unconjugated antibody (MRT ∼ 300 h). IMMU-132 treatment of mice bearing human gastric cancer xenografts (17.5 mg/kg; twice weekly × 4 weeks) resulted in significant antitumor effects compared to that of mice treated with a nonspecific control. Clinically relevant dosing schemes of IMMU-132 administered either every other week, weekly, or twice weekly in mice bearing human pancreatic or gastric cancer xenografts demonstrate similar, significant antitumor effects in both models. Current Phase I/II clinical trials (ClinicalTrials.gov, NCT01631552) confirm anticancer activity of IMMU-132 in cancers expressing Trop-2, including gastric and pancreatic cancer patients.
In the phase III HIMALAYA study (NCT03298451) in unresectable hepatocellular carcinoma (uHCC), STRIDE (Single Tremelimumab Regular Interval Durvalumab) significantly improved overall survival (OS) ...versus sorafenib; durvalumab monotherapy was noninferior to sorafenib for OS. Results reported herein are from a 4-year updated OS analysis of HIMALAYA.
Participants with uHCC and no previous systemic treatment were randomized to STRIDE (n = 393), durvalumab (n = 389), or sorafenib (n = 389). The updated data cut-off was 23 January 2023. OS and serious adverse events (AEs) were assessed. Additionally, baseline characteristics and subsequent therapies were analyzed in long-term survivors (≥36 months beyond randomization).
For STRIDE, durvalumab, and sorafenib, median 95% confidence interval (CI) follow-up was 49.12 months (46.95-50.17 months), 48.46 months (46.82-49.81 months), and 47.31 months (45.08-49.15 months), respectively. OS hazard ratio (95% CI) for STRIDE versus sorafenib was 0.78 (0.67-0.92). The 36-month OS rate for STRIDE was 30.7% versus 19.8% for sorafenib. The 48-month OS rate remained higher for STRIDE at 25.2%, versus 15.1% for sorafenib. The long-term OS benefit of STRIDE was observed across clinically relevant subgroups and was further improved in participants who achieved disease control. Long-term survivors with STRIDE (n = 103) included participants across clinically relevant subgroups, and 57.3% (59/103) had no reported subsequent anticancer therapy. No new serious treatment-related AEs occurred with STRIDE from the primary analysis (17.5%; 68/388). Durvalumab maintained OS noninferiority to sorafenib and no late-onset safety signals were identified.
These data represent the longest follow-up to date in phase III studies in uHCC. The unprecedented 3- and 4-year OS rates reinforce the sustained long-term OS benefit of STRIDE versus sorafenib. STRIDE maintained a tolerable yet differentiated safety profile from other current uHCC therapies. Results continue to support the long-term benefits of STRIDE in a diverse population, reflective of uHCC globally.
•This updated analysis of the phase III HIMALAYA study in uHCC showed sustained OS benefit with STRIDE vs sorafenib.•Four-year OS rates were 25.2% with STRIDE vs 15.1% with sorafenib.•STRIDE improved OS vs sorafenib across subgroups and further improved 3- and 4-year OS rates in those with disease control.•Subsequent anticancer systemic therapy was more common in the sorafenib vs STRIDE arm.•No new serious treatment-related AEs occurred after the primary analysis for STRIDE.
To evaluate the safety, pharmacokinetics, and pharmacodynamics of Hu5F9-G4 (5F9), a humanized IgG4 antibody that targets CD47 to enable phagocytosis.
Adult patients with solid tumors were treated in ...four cohorts: part A, to determine a priming dose; part B, to determine a weekly maintenance dose; part C, to study a loading dose in week 2; and a tumor biopsy cohort.
Sixty-two patients were treated: 11 in part A, 14 in B, 22 in C, and 15 in the biopsy cohort. Part A used doses that ranged from 0.1 to 3 mg/kg. On the basis of tolerability and receptor occupancy studies that showed 100% CD47 saturation on RBCs, 1 mg/kg was selected as the priming dose. In subsequent groups, patients were treated with maintenance doses that ranged from 3 to 45 mg/kg, and most toxicities were mild to moderate. These included transient anemia (57% of patients), hemagglutination on peripheral blood smear (36%), fatigue (64%), headaches (50%), fever (45%), chills (45%), hyperbilirubinemia (34%), lymphopenia (34%), infusion-related reactions (34%), and arthralgias (18%). No maximum tolerated dose was reached with maintenance doses up to 45 mg/kg. At doses of 10 mg/kg or more, the CD47 antigen sink was saturated by 5F9, and a 5F9 half-life of approximately 13 days was observed. Strong antibody staining of tumor tissue was observed in a patient at 30 mg/kg. Two patients with ovarian/fallopian tube cancers had partial remissions for 5.2 and 9.2 months.
5F9 is well tolerated using a priming dose at 1 mg/kg on day 1 followed by maintenance doses of up to 45 mg/kg weekly.
Ado-trastuzumab emtansine (T-DM1) is an antibody–drug conjugate that combines the antitumor properties of the humanized anti-human epidermal growth factor receptor 2 (HER2) antibody, trastuzumab, ...with the maytansinoid, DM1, a potent microtubule-disrupting agent, joined by a stable linker. Upon binding to HER2, the conjugate is internalized via receptor-mediated endocytosis, and an active derivative of DM1 is subsequently released by proteolytic degradation of the antibody moiety within the lysosome. Initial clinical evaluation led to a phase III trial in advanced HER2-positive breast cancer patients who had relapsed after prior treatment with trastuzumab and a taxane, which showed that T-DM1 significantly prolonged progression-free and overall survival with less toxicity than lapatinib plus capecitabine. In 2013, T-DM1 received FDA approval for the treatment of patients with HER2-positive metastatic breast cancer who had previously received trastuzumab and a taxane, separately or in combination, the first ADC to receive full approval based on a randomized study.
The therapeutic use of anti-PD-1/PD-L1 antibodies (nivolumab, pembrolizumab) is rapidly increasing. Given their mechanism of action that triggers T-cell activation, these immune checkpoint inhibitors ...induce specific adverse events that are mostly of immunologic origin. In this way, cutaneous toxicities represent the most frequent immune-related adverse events (irAEs). The purpose of this review is to summarize the most prevalent dermatologic complications induced by PD-1/PD-L1 immune checkpoint-blocking antibodies and to compare their dermatologic safety profile with anti-CTLA-4 ipilimumab.
More than 40% of melanoma patients treated with anti-PD-1 therapy are faced with dermatologic irAEs. However, these cutaneous complications usually remain self-limiting and readily manageable. Nonspecific macular papular rash and pruritus represent the most common manifestations. More characteristic lichenoid dermatitis or psoriasis may also develop. Vitiligo is also frequent in patients with melanoma but has not been reported in other types of solid cancers. Mucosal involvement may also occur, including xerostomia and lichenoid reactions. Although available data remain scarce, anti-PD-L1 antibodies present a similar dermatologic safety profile.
Dermatologic irAEs induced by PD-1 or PD-L1 blockade therapy rarely result in significant morbidity or permanent discontinuation of treatment. However, early recognition and appropriate management are crucial for restricting dose-limiting toxicities.
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic continues, with devasting consequences for human lives and the global economy
. The discovery and development of ...virus-neutralizing monoclonal antibodies could be one approach to treat or prevent infection by this coronavirus. Here we report the isolation of sixty-one SARS-CoV-2-neutralizing monoclonal antibodies from five patients infected with SARS-CoV-2 and admitted to hospital with severe coronavirus disease 2019 (COVID-19). Among these are nineteen antibodies that potently neutralized authentic SARS-CoV-2 in vitro, nine of which exhibited very high potency, with 50% virus-inhibitory concentrations of 0.7 to 9 ng ml
. Epitope mapping showed that this collection of nineteen antibodies was about equally divided between those directed against the receptor-binding domain (RBD) and those directed against the N-terminal domain (NTD), indicating that both of these regions at the top of the viral spike are immunogenic. In addition, two other powerful neutralizing antibodies recognized quaternary epitopes that overlap with the domains at the top of the spike. Cryo-electron microscopy reconstructions of one antibody that targets the RBD, a second that targets the NTD, and a third that bridges two separate RBDs showed that the antibodies recognize the closed, 'all RBD-down' conformation of the spike. Several of these monoclonal antibodies are promising candidates for clinical development as potential therapeutic and/or prophylactic agents against SARS-CoV-2.
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