WU-KONG1B (ClinicalTrials.gov identifier: NCT03974022) is a multinational phase II, dose-randomized study to assess the antitumor efficacy of sunvozertinib in pretreated patients with advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations (exon20ins). Eligible patients with advanced-stage EGFR exon20ins NSCLC were randomly assigned by 1:1 ratio to receive sunvozertinib 200 mg or 300 mg once daily (200 and 300 mg-rand cohorts). After predefined interim analysis, additional patients were enrolled and treated with the 300 mg dose once daily. The primary end point was blinded independent review committee (IRC)-assessed confirmed objective response rate (cORR), and the key secondary end point was duration of response (DoR). Among 85, 89, and 107 efficacy-evaluable patients in 200 mg-rand, 300 mg-rand, and 300 mg-all (including randomly assigned and nonrandomized patients) cohorts, the cORRs were 45.9% (97.5% CI, 33.6% to 58.5%), 47.2% (97.5% CI, 35.1% to 59.5%), and 45.8% (97.5% CI, 34.8% to 57.0%), respectively, per IRC assessment. The predefined null hypothesis was rejected with statistical significance (P < .0001). Comparing 300 and 200 mg-rand cohorts, higher cORRs were observed in patients with baseline brain metastasis (52.4% v 28.6%) and previous amivantamab treatment (41.7% v 25%), as well as longer DoR (13.8 v 11.1 months). At 200 and 300 mg once daily, the most common treatment-related adverse events with grade ≥3 included diarrhea (2.2% v 18%), blood creatine phosphokinase increased (6.6% v 12.6%), and anemia (4.4% v 6.3%). Sunvozertinib is efficacious at both 200 and 300 mg once daily in treating platinum-pretreated patients with advanced EGFR exon20ins NSCLC. The treatment-related adverse events of sunvozertinib were consistent with an EGFR tyrosine kinase inhibitor, with a more favorable safety profile at 200 mg than 300 mg once daily.

Multiple myeloma (MM) is consistently preceded by monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). While these precursor conditions are asymptomatic, they are not entirely benign and carry a lifelong risk of progression to MM. Unlike other cancers defined by pathology, malignant transformation from MGUS or SMM to MM has so far relied on demonstration of clinical end-organ damage as morphology and cytogenetics cannot reliably distinguish them. In this study, using genomic data from 374 patients with MGUS or SMM (277 training, 97 validation), to our knowledge, we demonstrate for the first time the ability to identify malignant transformation in MGUS and SMM. We introduce the concept of genomic MM and genomic MGUS to differentiate the subsets of MGUS and SMM that are biologically malignant with genomic features indistinguishable from MM from the subset that is premalignant and unlikely to progress to malignancy. Importantly, we find that most SMM has biological features of malignant transformation indistinguishable from MM. As expected, this subset that we consider having genomic MM is associated with a high risk of progression to MM although some patients remained progression-free beyond 5 years. Conversely, 60% of MGUS and 10% of SMM have no evidence of malignant transformation (genomic MGUS), with no progression during follow-up. Integration of genomic features with the 2/20/20 International Myeloma Working Group model significantly improved the prediction of progression among genomic MM. These findings support the use of genomic criteria to refine the classification and the risk stratification in myeloma precursor conditions.

Data on bone health in patients with mild autonomous cortisol secretion (MACS) are limited and heterogenous. We sought to assess the prevalence of osteoporosis and symptomatic fragility fractures in patients with adrenal adenomas and hypercortisolism, and explore associations with the degree of cortisol excess and frailty. This multicenter cross -sectional study involved prospective enrollment of adults with nonfunctioning adrenal adenomas (NFA), MACS, Cushing syndrome (CS) and referent subjects without adrenal disorders during the study period (January 2019-September 2022). All participants completed a bone health questionnaire at enrollment and had dual-energy X-ray absorptiometry bone mineral density assessment within 12-months. Final analyses were adjusted for age, sex, body mass index, smoking status, alcohol use. Participants included 117 with NFA (median age 62 years, 80% women), 191 with MACS (median age 63 years, 74% women), 62 with CS (median age 50 years, 92% women), and 101 referent subjects (median age 59 years, 47% women). Both patients with CS (OR: 3.0, 95% CI: 1.1-8.3) and MACS (OR: 2.2, 95% CI: 1.9-4.9) had a higher prevalence of osteoporosis when compared to referents. Among patients with MACS, only those with post 1-mg dexamethasone suppression test (post-1mg-DST) cortisol > 83 nmol/L had a higher prevalence of osteoporosis when compared to referents (OR: 3.2, 95% CI: 1.4-7.5) and NFA (OR: 2.2, 95% CI: 1.1-4.4). For clinical fragility fractures, only patients with CS showed an increased prevalence when compared to referents (OR: 6.1, 95% CI: 1.7-26.4) and NFA (OR: 3.8, 95% CI: 1.3-11.2). Prevalence of clinical fragility fractures was similar to referents in patients with MACS (OR: 1.8, 95% CI: 0.6-6.9) and NFA (OR: 1.5, 95% CI: 0.4-6.1), and was not associated with post-1mg-DST cortisol or frailty in the MACS and NFA groups. Patients with CS, and those with MACS and post-1mg-DST cortisol > 83 nmol/L, exhibited a higher burden of osteoporosis. However, only CS was associated with an elevated risk of symptomatic fragility fractures.

PI3K/mTOR pathway activation drives oncogenesis and progression of many cancers. RMC-5552 is a bi-steric, mTORC1-selective inhibitor that potently inhibits phosphorylation of key mTORC1 substrates 4EBP1 and S6K, and exhibits selectivity for mTORC1 over mTORC2. Here, we report results from a first-in-human, dose-escalation study of RMC-5552 in patients with advanced solid tumors (NCT04774952). The safety, tolerability, pharmacokinetics, and preliminary activity of RMC-5552 (1.6-16 mg IV infusion weekly) were evaluated in 57 patients. The most common treatment-related adverse events were mucositis (49%), nausea (44%), and fatigue (42%). Consistent with mTORC1 selectivity, treatment-related hyperglycemia incidence was generally low (4%) and not dose limiting. Additionally, we tested potential prophylaxis with tacrolimus mouthwash (TM), which was predicted to block the mechanism of action of RMC-5552 locally and alleviate treatment-related oral mucositis. Between 8- to 12-mg dosing, mucositis was 65% without TM versus 31% with TM. In this study, the disease-control rate was 64%, and one patient with PTEN and PIK3CA-altered endometrial cancer had a complete response and treatment ongoing for >6 months as of the June 2024 data cut. Clearance of PI3K/mTOR pathway variants among circulating tumor DNA was observed. The success of TM-mediated prophylaxis and the clearance of selected variants in ctDNA are concordant with selective, on-mechanism, antitumor activity following RMC-5552 treatment. These data show that RMC-5552, the first bi-steric mTORC1-selective inhibitor in the clinic, is active at tolerable doses, and that selective inhibition of mTORC1 alleviates mTORC2-mediated hyperglycemia, overcoming a key limitation of prior mTOR inhibitors.

ABSTRACT Introduction Chronic myeloid leukemia in the chronic phase (CML-CP) has undergone therapeutic transformation with the advent of BCR::ABL1 tyrosine kinase inhibitors (TKIs), improving 10-year survival rates from 20% to ∼90%. These outcomes place increasing importance on maintaining quality of life (QoL), which can be compromised by adverse events (AEs) that may lead to decreased adherence or sub-therapeutic doses. Currently, there is no standardized definition of treatment intolerance, and treatment switches are based on individual physician practices. Methods A 13-member expert panel used a validated methodology (RAND/UCLA modified Delphi panel) to develop consensus on a definition of treatment intolerance in CML-CP. Panelists reviewed literature and provided 480 ratings on 96 unique patient scenarios that varied by TKI generation, line, and length of time on TKI treatment, frequency of AE interference on daily life, and TKI management strategies. Ratings were discussed at a meeting. Results After discussion, panelists agreed on 99% of scenarios. The group defined TKI treatment intolerance as patients whose AEs often interfered with daily activities, leading to TKI modifications. Panelists developed a tool to assess patient intolerance and recommendations for managing TKI therapy in the context of intolerance. Discussion Recognizing that treatment intolerance is influenced by laboratory findings, reported symptoms, and how patients experience their treatment, experts agreed on a patient-centered definition of TKI treatment intolerance in CML-CP. This definition represents a step forward in standardizing care for patients with CML-CP by presenting a balanced framework for managing TKI therapy, which will support shared decision-making.