2533 Background: Most pts with mNSCLC without actionable gene alterations have limited options after progression on first-line checkpoint inhibitor (CPI)–containing treatment (tx). Given failures of ...recent trials in this setting, single-agent chemotherapy remains the main tx option despite limited effectiveness (eg, docetaxel ORR 10–14%) and considerable toxicity. Acasunlimab is a bispecific antibody designed to elicit antitumor immune response via conditional 4-1BB activation strictly dependent on simultaneous PD-L1 binding. Preclinical and PK/PD findings support combining acasunlimab with additional PD-1 blockade to further potentiate anti-tumor activity and potentially extend durability. Initial results from the ongoing randomized, phase 2 trial (NCT05117242) evaluating acasunlimab as monotherapy (mono) and in combination with pembro (combo) in pts with mNSCLC are reported. Methods: Eligible pts had PD-L1+ mNSCLC, with progression after ≥1 prior anti–PD-(L)1 tx. Tumor PD-L1 status was assessed by central testing (TPS≥1%, PD-L1 IHC 22C3 PharmDx); this subset is presented in the efficacy analyses. Following safety run-in, pts were randomized to acasunlimab mono (arm A, 100 mg Q3W x 2 cycles then 500 mg Q6W) or combo (arm B, 100 mg + pembro 200 mg Q3W; arm C, 100 mg + pembro 400 mg Q6W). Primary efficacy endpoint was ORR per RECIST v1.1. Stratification factors were PD-L1 expression and histology. Results: As of Jan 9, 2024, 98 pts (63 with central PD-L1+ status) were enrolled: 23 (16) pts arm A; 39 (22) pts arm B; 36 (25) pts arm C. Among evaluable PD-L1+ pts, 86% received prior pembro tx; 64% had prior concurrent CPI + chemotherapy. Unconfirmed ORR and DCR were 31% and 50% for arm A, 25% and 65% for arm B, and 30% and 75% for arm C, respectively. Confirmed ORRs (and mDoR) were 13% (2 mo), 21% (6 mo), and 22% (NR), with 6-mo PFS rates of 0%, 18%, and 33% for arms A, B, and C, respectively. No responses were observed among centrally confirmed PD-L1-negative pts. The most common TRAEs (all grades; grade ≥3) were asthenia (17.4%; 8.7%), diarrhea (17.4%; 0%), nausea (17.4%, 0%), anemia (13%; 4.3%) and liver-related events (13%; 8.7%) for mono, and liver-related events (18.7%; 13.3%), fatigue (14.7%; 0%), asthenia (13.3%; 0%), and diarrhea (12%; 0%) for combo. Transaminase elevations were generally asymptomatic and manageable with steroids and/or tx delay. Early peripheral pharmacodynamics were consistent with acasunlimab-mediated immune activation in all arms, with a more pronounced increase in CD8 T-cell proliferation with combo. Conclusions: In PD-L1+ pts with mNSCLC following progression on prior CPI tx, acasunlimab + pembro combo showed a manageable safety profile and promising efficacy, with deeper responses and durable disease control in pts treated Q6W. Enrollment is ongoing. Clinical trial information: NCT05117242 .
BACKGROUNDReversible posterior leukoencephalopathy syndrome (PRES) is a relatively uniform clinical and neuroradiologic manifestation of central nervous system toxicity. The clinical features are ...headache, altered mental status, and visual disturbances. PRES is often associated with arterial hypertension but it is most usually related to drug toxicity. In fact, it has been related to immunosupressants, cytotoxic, and new antineoplastic-targeted therapies such as sorafenib, sunitinib, bevacizumab, bortezomib, rituximab, and etanercept.
CASE REPORTWe describe a most unusual case of nonconvulsive status epilepticus related to PRES induced by cetuximab in a patient with metastatic squamous cell carcinoma of the penis.
DISCUSSIONThis case emphasizes that in any patient receiving treatment with anti-epidermal growth factor receptor agents and showing a compatible clinical syndrome, PRES should be suspected. We also review the clinical and neuroradiologic features of PRES, discuss itsʼ pathogenesis, and highlight the importance of rapid recognition and withdrawal of the causative agent.
This meeting report summarizes the highlights of the II International Frontiers in Oncology meeting "The present and future of the RAS pathway: from function and genomics to inhibition" (RAS ...Frontiers) organized by the Center for Applied Medical Research (CIMA; Pamplona, SPAIN), the Clinic of the University of Navarra (CUN; Pamplona, SPAIN) and the Stanford Cancer Institute (SCI; Stanford University, CA, USA) in Pamplona (October 5-7, 2015). The RAS Frontiers meeting gathered together scientists from all over the world and featured the latest advances in the study of the RAS pathway covering aspects from basic research to translational and clinical investigation. Among the topics presented were novel mouse models that recapitulate human carcinogenesis and serve as preclinical platforms for drug testing, cutting-edge approaches for the identification of novel vulnerabilities and regulators of the RAS pathway, as well as current inhibitory strategies for the treatment of human RAS-driven cancers.
Due to the refractory nature of mutant KRAS lung adenocarcinoma (LUAD) to current therapies, identification of new molecular targets is essential. Genes with a prognostic role in mutant KRAS LUAD ...have proven to be potential molecular targets for therapeutic development. Here we determine the clinical, functional, and mechanistic role of inhibitor of differentiation-1 (Id1) in mutant KRAS LUAD. Analysis of LUAD cohorts from TCGA and SPORE showed that high expression of Id1 was a marker of poor survival in patients harboring mutant, but not wild-type KRAS. Abrogation of Id1 induced G2/M arrest and apoptosis in mutant KRAS LUAD cells. In vivo, loss of Id1 strongly impaired tumor growth and maintenance as well as liver metastasis, resulting in improved survival. Mechanistically, Id1 was regulated by the KRAS oncogene through JNK, and loss of Id1 resulted in downregulation of elements of the mitotic machinery via inhibition of the transcription factor FOSL1 and of several kinases within the KRAS signaling network. Our study provides clinical, functional, and mechanistic evidence underscoring Id1 as a critical gene in mutant KRAS LUAD and warrants further studies of Id1 as a therapeutic target in LUAD patients.
Abstract Introduction Treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) yields tumour responses in non-small cell lung cancer (NSCLC) patients harbouring ...activating EGFR mutations. However, even in long-lasting responses, resistance to EGFR TKIs invariably occurs. Areas covered This review examines resistance mechanisms to EGFR TKI treatment, which mainly arise from secondary EGFR mutations. Other resistance-inducing processes include mesenchymal–epithelial transition factor (MET) amplification, epithelial–mesenchymal transformation, phenotypic change from NSCLC to small-cell lung carcinoma, and modifications in parallel signalling pathways. Current therapeutic strategies to overcome these EGFR TKI resistance mechanisms focus on the inhibition or blocking of multiple members of the ErbB family. Several molecules which target multiple ErbB receptors are being investigated in NSCLC and other indications including afatinib, an ErbB Family Blocker, as well as dacomitinib and lapatinib. Novel, non-quinazoline, EGFR inhibitors, that also target EGFR activating and resistance (T790M) mutations, are currently under clinical development. Other therapeutic strategies include inhibition of parallel and downstream pathways, using agents which target heat shock protein (HSP)90 or poly (ADP-ribose) polymerase in addition to mammalian target of rapamycin (mTOR), monoclonal antibodies against the insulin-like growth factor-1 receptor, and fulvestrant-mediated oestrogen receptor regulation. Conclusion Improved understanding of mechanisms underlying resistance to EGFR TKIs emphasises the importance of a genotype-guided approach to therapy. Elucidation of resistance mechanisms is indeed crucial to target innovative therapeutic approaches and to improve the efficacy of anticancer regimes in NSCLC.
Abstract Id1 promotes carcinogenesis and metastasis, and predicts prognosis of non-small cell lung cancer (NSCLC)-adenocarcionoma patients. We hypothesized that Id1 may play a critical role in lung ...cancer colonization of the liver by affecting both tumor cells and the microenvironment. Depleted levels of Id1 in LLC (Lewis lung carcinoma cells, LLC shId1) significantly reduced cell proliferation and migration in vitro . Genetic loss of Id1 in the host tissue ( Id1 −/− mice) impaired liver colonization and increased survival of Id1 −/− animals. Histologically, the presence of Id1 in tumor cells of liver metastasis was responsible for liver colonization. Microarray analysis comparing liver tumor nodules from Id1 +/+ mice and Id1 −/− mice injected with LLC control cells revealed that Id1 loss reduces the levels of EMT-related proteins, such as vimentin. In tissue microarrays containing 532 NSCLC patients' samples, we found that Id1 significantly correlated with vimentin and other EMT-related proteins. Id1 loss decreased the levels of vimentin, integrinβ1, TGFβ1 and snail, both in vitro and in vivo . Therefore, Id1 enables both LLC and the host microenvironment for an effective liver colonization, and may represent a novel therapeutic target to avoid NSCLC liver metastasis.
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