Targeted Oncology最新文献

Background: Elranatamab is a heterodimeric humanized full-length bispecific antibody composed of one B-cell maturation antigen (BCMA) binding arm and one cluster of differentiation 3 (CD3) binding arm. Results from the MagnetisMM-3 study indicated deep and durable responses in patients with relapsed or refractory multiple myeloma (RRMM).

Objective: The current analysis was conducted to characterize the relationship between free (i.e., unbound) elranatamab exposure and objective response rate (ORR), complete response rate (CRR), progression-free survival (PFS), and duration of response (DOR), and the impact of potential covariates on these exposure-response (E-R) relationships.

Patients and methods: Data from four clinical studies and a wide dosing range were used for the E-R analysis. The E-R analyses of ORR and CRR were conducted by binomial logistic regression method, whereas Kaplan-Meier (KM) curves and Cox proportional hazards (PH) model were used for PFS and DOR.

Results: The analysis included data from 312 response-evaluable patients. The results suggested that higher elranatamab exposure and lower soluble BCMA (sBCMA) were associated with higher probability of achieving objective response (OR) and complete response (CR). For PFS, higher exposure was associated with longer PFS, which is driven by rapid responses or progression events within the initial treatment cycles. At later time points, a flat relationship between exposure and PFS was observed. No E-R relationship was identified for DOR.

Conclusions: The current analyses support the approved initial dosing regimen of elranatamab and the dosing switch to less frequent dosing in responding patients during later treatment cycles.

Clinicaltrials:

Gov identifiers: NCT03269136, NCT04798586, NCT04649359, and NCT05014412.

Background: In the phase 3 DREAMM-8 study (NCT04484623), belantamab mafodotin (anti-B-cell maturation antigen [BCMA] antibody-drug conjugate with a monomethyl auristatin F payload) with pomalidomide and dexamethasone (BPd) showed significant progression-free survival benefit in second-line or later relapsed/refractory multiple myeloma (RRMM).

Objective: This exposure-response analysis explored the relationship between belantamab mafodotin cycle 1 exposure and efficacy/safety and predicted the benefit-risk profile of belantamab mafodotin at an initial dose of 1.9 versus 2.5 mg/kg using DREAMM-8 data.

Patients and methods: In the BPd arm of DREAMM-8, belantamab mafodotin was dosed at 2.5 mg/kg intravenously in cycle 1, then at 1.9 mg/kg every 4 weeks from cycle 2 onward. Cycle 1 belantamab mafodotin and free payload exposures derived from population pharmacokinetic analysis were used to perform exposure-efficacy/exposure-safety analyses for probability of/time to first event. Selected covariate effects were evaluated.

Results: Higher belantamab mafodotin cycle 1 exposure was associated with deeper response (higher probabilities of complete response or better [≥ CR] and minimal residual disease negativity), but not with grade ≥ 3 ocular adverse events (oAEs)/ophthalmic exam findings. Benefit-risk assessment showed that an initial belantamab mafodotin dose of 1.9 mg/kg instead of 2.5 mg/kg would result in reduction in probability of ≥ CR without reduction in oAEs/ophthalmic exam findings.

Conclusions: An initial belantamab mafodotin dose of 2.5 mg/kg for BPd yields deeper responses versus 1.9 mg/kg with minimal change in safety outcomes in RRMM. DREAMM-8 (NCT04484623) was registered at clinicaltrials.gov (21 July 2020).

Background: Bispecific T-cell engagers (TCEs) are a promising modality for cancer treatment, and evaluation of dosing strategies, including utilization of body weight-based versus fixed dosing, is essential to ensure optimal therapeutic outcomes. Elranatamab is a bispecific TCE that targets B-cell maturation antigen (BCMA) on multiple myeloma cells and CD on T cells. Elranatamab is approved for relapsed or refractory multiple myeloma (RRMM).

Objective: Evaluate the impact of body weight on the pharmacokinetics (PK), safety, and efficacy of elranatamab.

Patients and methods: Data from the phase 2 MagnetisMM-3 trial (NCT04649359) were used to evaluate the impact of body weight on the PK, safety, and efficacy of elranatamab. This trial comprised two cohorts: cohort A included patients who had not previously received BCMA-directed therapy and cohort B included patients who had received prior BCMA-directed therapies. All patients received a 76-mg fixed dose of subcutaneous elranatamab once weekly after a two-step priming dose regimen. Blood samples were collected from MagnetisMM-3 trial patients for PK analysis. This study analyzed the PK, efficacy, and safety of elranatamab across body weight quartiles.

Results: The results demonstrated that when elranatamab was given at a fixed dose, the predose concentrations showed overlapping distributions with comparable medians, especially across the lowest three body weight quartiles, with a lower median for quartile 4, which was not considered clinically relevant. There were no clinically relevant differences in the safety profile between different body weight quartiles. With respect to efficacy, the overall response and complete response rates were comparable across body weight quartiles. A clinically meaningful objective response rate benefit with overlapping confidence intervals was observed across all four quartiles, consistent with the primary efficacy analysis. No trend was identified between body weight and progression-free survival and the duration of response on the basis of the Kaplan-Meier curves.

Conclusions: Concerns with flat dosing include the potential for overdosing those with lower body weights and underdosing individuals with higher body weights. However, this study provides evidence that fixed dosing of elranatamab is effective and demonstrated a consistent and manageable safety profile across a broad range of body weights. There is no significant impact of body weight on the PK, safety, or efficacy of elranatamab. These findings support the approved fixed dosing of elranatamab in patients with RRMM.

Clinicaltrials:

Gov identifier: NCT04649359.

The MET signaling pathway is dysregulated in several cancers through various mechanisms, including gene mutations, amplifications, rearrangements, and protein overexpression. MET inhibitors have demonstrated clinical benefits in solid tumors including non-small-cell lung cancer (NSCLC), highlighting the importance of optimizing MET alteration detection methods and cut-off values to enhance the efficacy of MET-targeted therapies and improve patient outcomes. Research on MET alterations has primarily focused on MET exon 14 skipping mutations, MET amplification, and MET overexpression. This review summarizes the frequency of MET alterations across different cancer types and the clinical validation of MET alterations in MET-targeted therapies, offering a detailed comparison of objective response rates (ORR) for therapies including crizotinib, capmatinib, tepotinib, savolitinib, telisotuzumab vedotin, telisotuzumab adizutecan, and amivantamab. The review also addresses the challenges in detecting MET exon 14 skipping mutations, such as issues with false positives and negatives, and underscores the need for standardization in MET amplification detection. Trials vary in their cut-offs for MET gene copy number (GCN) and MET/CEP7 ratio and MET expression detection methods, leading to inconsistencies in detection. Additionally, emerging technologies such as circulating tumor DNA (ctDNA) and circulating tumor cell (CTC) analyses have been investigated for their potential to improve MET alterations detection. This review also highlights studies that demonstrate the potential of MET ctDNA and CTC analyses to predict treatment responses and identify resistance mechanisms in MET-targeted therapies.

MYC is one of the most frequently altered genes in cancer with an estimated 70% prevalence of deregulation. Deregulated MYC is believed to promote cancer formation/progression via multiple mechanisms including tumour cell intrinsic mechanisms, altering the tumour microenvironment and promoting host immune suppression. Owing to the high prevalence of alterations and its causative role in tumorigenesis, MYC is a highly attractive target for new anticancer therapies. However, as MYC lacks a readily identifiably pocket for potential low molecular weight inhibitors and is predominantly located in the cell nucleus, it has proved difficult to target using standard pharmacological approaches. Recently, however, these problems appear to have been successfully resolved, with the discovery of promising anti-MYC compounds such as Omomyc or MYCi975. Both Omomyc and MYCi975 exhibit anti-cancer activity in several different animal models, with apparently little short-term toxicity. Furthermore, consistent with the ability of MYC to promote a pro-tumour microenvironment and induce immune evasion, treatment with Omomyc or MYCi975 was shown to increase uptake of anti-tumour lymphocytes and enhance response to immunotherapy. Currently, at least five anti-MYC compounds are being evaluated for potential anti-cancer activity in clinical trials. Results from a phase I trial with OMO-103 (a form of Omomyc) suggest that the inhibitor is well tolerated, with most of its adverse effects being at grade 1 level. Evidence of target inhibition was the finding of decreased expression of multiple MYC regulated genes.

Avelumab first-line maintenance is an approved treatment for cisplatin-eligible or -ineligible patients with advanced urothelial carcinoma (UC) who are progression free following first-line platinum-based chemotherapy, based on the results of the JAVELIN Bladder 100 phase 3 trial. In recent years, an increasing number of real-world studies have examined the effectiveness and safety of avelumab first-line maintenance in heterogeneous populations from different countries, expanding the clinical evidence base. In this podcast, we discuss findings from these real-world studies, which have complemented clinical trials and provided additional insights about overall effectiveness, treatment sequencing involving second-line enfortumab vedotin monotherapy or other options, and healthcare resource utilization. We also briefly discuss the evolving treatment landscape in advanced UC in addition to benefits and limitations of real-world studies in general. Overall, across multiple studies involving more than 3000 patients worldwide, real-world outcomes with avelumab first-line maintenance treatment have been consistent with findings from the JAVELIN Bladder 100 trial, confirming the clinical benefits of this treatment approach for patients with advanced UC who are encountered in day-to-day practice.

Background: The optimal duration of immunotherapy (ITH) remains undefined for patients with metastatic melanoma, and debates on de-escalation strategies are ongoing. Patients in the pivotal KEYNOTE and CheckMate trials who experienced a complete response (CR) on ITH had long-term responses, even after treatment was terminated early because of toxicity or at the physician's discretion.

Objective: Our study explores the duration of planned ITH drug holidays-intentional ITH suspension until disease progression off treatment-in patients with unresectable and metastatic melanoma treated for at least 6 months with ITH.

Patients and methods: We enrolled 222 patients who received anti-programmed cell death protein-1-based ITH, experienced stable disease, partial response, or complete response during ITH, and had no treatment-limiting toxicities.

Results: At a median follow-up of 63 months since the first ITH cycle, median overall survival after the drug holiday start (OS3) was not reached, and the 5-year OS3 rate was 79.3%. Median progression-free survival since the start of drug holiday (PFS3) was not reached, with a 3-year PFS3 rate of 65% for all patients, and the highest rate was in the complete response group (72.3%). After the drug holidays, upon disease progression off treatment, the objective response rate to ITH reintroduction was 58.9%. Again, durable, ongoing objective responses were achieved on ITH reintroduction after drug holidays. The best radiological response achieved before drug holidays correlated with the duration of ITH drug holidays, with the longest duration of disease control without treatment for complete responders.

Conclusions: Drug holidays in patients with unresectable and metastatic melanoma after an objective response or prolonged disease stabilization during ITH result in durable control of the disease, particularly in patients with complete response.

Background: Comprehensive genomic profiling (CGP) has become more generally accessible to patients with rare cancer, but data on the results and benefits are limited.

Objective: Our objective was to gain a real-world understanding of the molecular landscape and targeted treatment options in neuroendocrine tumors, neuroendocrine carcinomas, adrenocortical carcinomas, pheochromocytomas, and carcinoids.

Patients and methods: In this retrospective cohort study, we analyzed CGP results and clinical data from patients with neuroendocrine tumors, neuroendocrine carcinomas, adrenocortical carcinomas, pheochromocytomas, and carcinoids who were discussed in the CCCMunich^LMU Molecular Tumor Board (MTB) between May 2017 and April 2023.

Results: In total, 104 patients with endocrine and neuroendocrine neoplasms were discussed in the MTB. CGP was technically successful in 99 patients. The most commonly mutated genes were TP53 (29.3%), RB1 (11.1%), and KRAS (10.1%). The highest overall prevalence of pathogenic alterations was detected in neuroendocrine carcinomas (76.9%) and carcinoids (83.3%), and the lowest prevalence of pathogenic alterations was seen in adrenocortical carcinoma (37.5%). Of the 99 patients with successful CGP, 35 received a treatment recommendation from the MTB based on the CGP results. Of these, ten patients ultimately received the recommended treatment. Of the ten treated patients, four experienced a longer progression-free survival under the targeted treatment than under their previous treatment.

Conclusions: One-third of patients with rare endocrine and neuroendocrine neoplasms who underwent CGP had a druggable alteration and received a treatment recommendation from the MTB. However, only 28.6% of these patients were treated accordingly. Our experience highlights the unmet medical need for targeted treatment options in patients with rare cancers.

Background: High-dose osimertinib shows modest anti-tumor activity and acceptable toxicity in patients with advanced non-small cell lung cancer (NSCLC) harboring an epidermal growth factor receptor exon 20 mutation (EGFRex20+). Plasma-derived circulating tumor DNA (ctDNA) is promising in monitoring responses and detecting resistance mechanisms to therapy.

Objective: We aimed to assess the concordance between variants detected in ctDNA to those found in corresponding tissue samples at baseline and progression, to analyze alterations in mutant ctDNA levels of EGFRex20+ variants as predictors of therapy response, and to identify resistance mechanisms to high-dose osimertinib as well as examine changes in mutant ctDNA levels of EGFRex20+ variants.

Patients and methods: Twenty-five patients with EGFRex20+ NSCLC received double dose (160 mg) osimertinib daily. Blood plasma was collected at baseline, 6 weeks after therapy start (T6), and at progression. ctDNA analysis was performed using the NGS Guardant360 CDx panel. The molecular profile at progression was compared with baseline/T6, and changes in ctDNA levels of the EGFRex20+ variants were linked to response or resistance.

Results: Collected ctDNA samples were analyzed retrospectively. Baseline ctDNA showed somatic alterations in 19/20 patients (95%) and the corresponding tumor biopsy NGS EGFRex20+ variant in 65%. Among 14 patients with profiling at all timepoints, there was no significant correlation between changes in mutant ctDNA levels and osimertinib response. At T6, nine patients showed decreased EGFRex20+ levels, with eight also showing tumor shrinkage. At disease progression, 9/14 (64%) patients had increased EGFRex20+ levels, correlating with tumor growth. Variants potentially associated with resistance were found in 11/18 patients (61%): single nucleotide variants (SNV, n = 14), insertions (n = 2), and gene fusions (n = 1). Mutations previously related to osimertinib resistance were found, including EGFR p.C797S (n = 1).

Conclusions: ctDNA analysis tracks variant dynamics and can identify resistance mechanisms in patients with EGFRex20+ NSCLC treated with high-dose osimertinib, offering valuable new insights.

Despite an evolving treatment landscape for people with metastatic castration-resistant prostate cancer, prognosis for this patient population remains poor. Prostate-specific membrane antigen positron emission tomography (PSMA PET) imaging may be used to identify patients with PSMA-positive (and no significant PSMA-negative) metastatic castration-resistant prostate cancer who could benefit from PSMA-targeted radioligand therapy. As the PSMA PET imaging and treatment landscape expands, there is a growing need for guidance and greater utilization of PSMA-targeted tracers and radioligand therapies to improve outcomes for patients with metastatic castration-resistant prostate cancer. This review discusses the current clinical considerations of PSMA PET, including the various imaging agents available and how best to identify patients eligible for PSMA PET imaging and subsequent PSMA-targeted radioligand therapy. This review also examines opportunities to mitigate discordant findings, as well as considerations around the standardization of reporting of PSMA PET imaging, key gaps in the evidence base, and guidance around the use of PSMA PET in clinical and research settings.