Major Response Rate Research Articles

Clinical Characteristics, Treatment Approach and Long-Term Outcomes of 678 Patients with Symptomatic Waldenstrom's Macroglobulinemia: Comprehensive Insights from a Spanish Registry of IgM Gammapathies

Introduction The pathogenesis of Waldenstrom's macroglobulinemia (WM) involves the clonal expansion of lymphoplasmacytic B cells in bone marrow, producing monoclonal immunoglobulin M (IgM). The heterogeneity of clinical manifestations in this uncommon disease represents the treatment approach more challenging. Multicenter registries may help in improving health care and scientific research. PRAME is a Spanish national registry of WM and IgM-related disorders with comprehensive data collection, providing insights for a better understanding of WM. Methods This is a retrospective, multicenter study that included newly diagnosed symptomatic WM (SWM) patients, evaluated at (24) Spanish hospitals between 1990 and 2023. All patients had confirmed diagnoses of SWM according to the International Workshop Consensus. Data collection on patients' demographics and disease epidemiology, clinical characteristics, diagnosis, treatment approaches and outcomes were performed from patients' local medical files. Results From 1796 total patients included in the Spanish registry for IgM gammopathies, a total of 678 newly SWM patients were identified. The median age was 71(range 35-94) years, 37% of patients had aged ≥ 75 years and 63% were male. The most common symptom at diagnosis was anemia (43%), followed by B symptoms (30%). Fifteen percent had peripheral neuropathy (PN) as the first WM symptom (39% with sensitive motor PN). Hyperviscosity was only observed in 15%. The free light chain isotypes were mostly kappa (75.4%). Less than 5% of the total cohort, had an ECOG ≥3, at diagnosis. Among 403 patients, who had samples available for assessing MYD88L265P by quantitative allele-specific PCR, 75% were positive for the mutation. However, out of the 199 patients assessed for CXCR4(S388X) mutation, only 12% were positive. The first line of therapy was started in 98% of patients. Plasmapheresis was indicated in 10%, with a median number of 2 sessions. The most frequent indications for initiating the treatment were anemia (48%), B symptoms (13%), and neuropathy (9%). Symptoms related to IgM monoclonal and extramedullary involvement were seen in 15% (56% associated with hyperviscosity) and 11.3%, respectively. The main first-line treatment regimens received were: chlorambucil (37%), dexamethasone, rituximab and cyclophosphamide (DRC)(21%), rituximab monotherapy (13%), bendamustine/rituximab (BR) (9.1%), Bruton tyrosine kinase (BTK) inhibitors (7%), and bortezomib, dexamethasone and rituximab (BDR) (5.5%). The overall and major response rates (ORR and MRR) were 67% and 58%, respectively. (Table 1). The MRR was higher among patients who received BR as the first line of therapy (88%), with a 26% of complete response (CR) and 21% of very good partial responses (VGPR). The CR+VGPR rates with other common regimens were 17% for DRC, 9% for BDR and 21% for BTK inhibitors, respectively. With a median follow-up of 96 months (IQR, 43 to 192), the median overall survival (OS) was 8.7 years (95% confidence interval [CI]:7.3-10.1) and the median progression-free survival (PFS) was 6.8 years (95% CI:6.2-7.5) with no relevant improvement over the last years. (Figure 1) Conclusion In the current registry, we observed a high proportion of younger patients with good performance status at diagnosis. Among newly diagnosed SWM patients, BR demonstrated ongoing superiority as a front line of therapy, leading to deeper responses compared to other therapeutic schemes. There were no significant differences in OS between different times of diagnosis. This Spanish registry for SWM contributes to advancing knowledge and the continual enhancement of treatment strategies for WM.

Phase 2 Study of Dasatinib with and without Venetoclax in Patients with Early Chronic Phase Chronic Myeloid Leukemia (ECP-CML)

Background Treatment-free remission (TFR) is a therapeutic goal for patients with ECP-CML once patients maintain a deep molecular remission (DMR) on tyrosine kinase inhibitors (TKIs). Only a fraction of patients (pts) achieved sustained (3+ years) molecular remission with 4.0- to 4.5-log reduction (MR4.5). Preclinical studies showed that BCL-2 is a key survival factor for CML stem/progenitor cells. Therefore, the combination of TKIs and venetoclax, targeting BCR::ABL1 and BCL-2, has the potential to significantly improve DMR and subsequently the rates of TFR. The aim of this study is to evaluate the safety and efficacy of the combination. Methods Patients with ECP-CML or accelerated phase (AP; defined by clonal evolution only) were eligible; pts with < 1 month of prior TKI therapy were eligible. Pts received single-agent dasatinib 50 mg/d for the first 3 months. From Month 4 and onwards, venetoclax was administered from Days 1 to 14 each month concomitantly with dasatinib for a total of 3 years. The first 16 patients received venetoclax 200 mg/d, with a rapid ramp-up starting 50 mg on Day 1, then 100 mg on Day 2, then 200 mg daily on Day 3 and onwards. Due to neutropenia observed with continuous dose of venetoclax 200 mg/d, the protocol was ameded: from patient #17 and onwards, venetoclax was administered at 200 mg/d for 14 days per month and upon achievement of MR4.5, venetoclax was reduced to 100 mg/d for 7 days per month. After 3 years of combination, patients received single-agent dasatinib. TFR was offered after ≥ 3 years of DMR. The primary endpoint was the rate of major molecular response (MMR) by 12 months of the combination. The secondary endpoints were the 12-month rate of MR4.5 and the cumulative overall rate of MR4.5; the rates of MR4.5 at 6-, 12-, 18-, 24, and 36-months of the combination; the proportion of patients with sustained MR4.5 of 3 years and more; the TFR rate; overall survival; and the safety of the combination. Cumulative response rates were calculated with treatment failure as a competing event. Failure-free survival (FFS) was calculated from the initiation of therapy to loss of major cytogenetic response (MCyR), transformation to AP or blast phase, discontinuation of therapy for any reason except of TFR, or death. Results Sixty-five pts were enrolled and treated between April 2018 and August 2021. The median age at treatment initation was 46 years (range, 23-73) and 57% of the pts were females. Twenty-one (32%) pts had splenomegaly, 46 (71%) had low Sokal risk disease and 3 (5%) had high Sokal risk disease (Table 1). By 12 months of the combination, 85% of the pts had achieved MMR or deeper response. The median time to MMR, MR4, and MR4.5 were 6.2 months, 13 months, and 23.9 months from the time of TKI start, respectively. After a median follow-up of 25.7 months (range, 8.7-48.1), two pts discontinued therapy due to adverse events (GI intolerance, and pleural effusion); the 2 -year FFS was 96%. One pt switched TKI therapy due to the lack of 18-month complete cytogenetic response (CCyR); no loss of CCyR, transformation, or death was observed. We then compared the outcomes with the combination to the outcomes of 85 pts treated with single-agent dasatinib. From the start of TKI therapy, the 12-month cumulative MMR rates were 78% and 79% in the dasatinib single-agent and dasatinib + venetoclax groups, respectively. The cumulative 24-month rates of CCyR, MMR, MR4, and MR4.5 are summarized in Table 2. In the dasatinib single-agent group, 3 pts switched TKI therapy due to the lack of 12-month MCyR, 18-month CCyR, and the acquisition of ABL1 mutation (1 each); 3 pts switched TKI therapy due to loss of CCyR; 2 pts died during therapy (deaths unrelated to CML). Within one year of therapy, the incidence of grade 1/2 neutropenia (absolute neutrophil count, below lower range of normal to 1,000 x10 9/L) was 21% and 52% in the dasatinib single agent and dasatinib + venetoclax groups, respectively ( P<0.001); the incidence of grade 3/4 neutropenia (absolute neutrophil count, below 1,000 x10 9/L) was 8% and 17%, respectively ( P<0.001). There was no incidence of neutropenic fever in the dasatinib + venetoclax. Conclusion The combination of dasatinib 50 mg/d and venetoclax is safe and effective in pts with ECP-CML. With a median follow-up of 2 years, the cumulative resposne of dasatinib + venetoclax is similar to that of dasatinib single-agent without adding significant toxicities. Further follow-up is needed for the evaluation of TFR.

Lower-Initiating Dose of Bosutinib for Resistant or Intolerant to Prior Therapy Chronic Myeloid Leukemia Patients (BOGI trial): A Single-Arm, Multicenter, Phase II Trial

Introduction: The introduction of ABL1 tyrosine kinase inhibitors (TKIs) has markedly improved the survival outcomes in patients with chronic phase chronic myeloid leukemia (CML-CP). Second-generation TKIs are highly active for patients with newly diagnosed and resistant/intolerant CML-CP. Although bosutinib is generally safe, drug-related toxicities (DRTs) such as diarrhea or increased transaminase leading to treatment discontinuation, are often observed. The standard initial daily dosage of bosutinib is 400 mg for newly diagnosed or 500 mg for resistant/intolerant patients with CML-CP, whereas some experts suggest lower dose (200-300 mg) initiation is recommended to reduce adverse events (AEs). However, the safety and efficacy of lower dose initiation of bosutinib are unknown. Hence, we conducted a phase 2 study of BOsutinib Gradual Increase as a second/third-line treatment for CML-CP (BOGI trial, UMIN 000032282) to clarify whether a lower initiating dose of bosutinib (200 mg daily) would reduce discontinuation or interruption of treatment due to DRTs. Patients and methods We included CML patients who developed at least one line of treatment failure (resistant or intolerant), aged >18 years with an ECOG performance status of 0-2 and adequate organ function. After enrollment, the patients initiated 200 mg of bosutinib daily; subsequently, dose escalation was performed by 100 mg daily (up to 500 mg daily) every 2 weeks if no grade 3 or higher AEs occurred. BCR::ABL1 mRNA levels were measured by the standardized international scale at a central laboratory at 3, 6, 9, and 12 month since treatment initiation. The primary endpoint was the treatment discontinuation rate due to DRTs at 12 months. Secondary endpoints included the treatment interruption rate, mean bosutinib dosage, dosing days and relative dose intensity until 12 months, achievement of cytogenetic response (CCyR), cumulative rates of major molecular response (MMR) or deep molecular response (DMR). Sample size calculation was performed by research and biostatistics SWOG statistical tools (at null proportion = 0.32, alternative proportion = 0.14, one-sided α error = 5% and β error = 20%, power 80%) with the discontinuation rate of the previous Japanese phase 1/2 study of bosutinib as a reference (Nakaseko C, et al. Int J Hematol. 2015). Considering protocol deviations, sample size was 35 participants. Results Between Feb 4, 2019, and May 24, 2022, 35 patients enrolled from four Japanese hospitals. The median age was 61 years (range, 26 - 81 years); 19 patients were male and 16 were female and 16, 12, and 7 patients had low,intermediate, and high Sokal scores, respectively. Ten patients had hypertension, five had diabetes millitus, three had chronic heart disease, two had solid tumor, and one had cerebrovascular disease, respectively. Numbers of patients with previous TKIs were one for 19 (54%), two for 12 (34%) and three for 4 (11%), respectively and prior TKIs are imatinib (8, 23%), dasatinib (27, 77%), nilotinib (16, 46%) and bosutinib (1, 3%), respectively. In the intention to treat population, the bosutinib discontinuation rate at 12 months was 25.7% (95% CI, 15.6-39.3%) which is significantly lower than that of the previous report (v.s. 43.0%, p=0.019). Similarly, bosutinib discontinuation rate due to DRTs was 11.4% (95% CI, 5.2 - 23.2%), which is also significantly lower (v.s. 32%, p = 0.005). These results suggest lower initiating dose of bosutinib reduced bosutinib discontinuation rate due to DRTs, thus the primary endpoint was met. A total of 22 patients (62.9%) interrupted bosutinib at least once. Median bosutinib dosage, bosutinib dosing days and relative dose intensity until 12 months were 391.7 (204.9-477.3) mg/day, 351.0 (20-365) days and 78% (41-95), respectively. 28 patients (80.0%) achieved cytogenetic response (CCyR) at 6 months; cumulative incidence of MMR and DMR at 12 months were 23 (65.7%; 95%CI, 49.2-79.2%) and 15 (42.9%; 95%CI, 28.0-59.1%), indicating these secondary endpoints were comparable with the previous report. Grade 3 to 4 transaminase elevation was 20% which is comparable with the previous report (v.s. 29%, p=0.427), while a lower rate of diarrhea (3%; v.s. 25%, p=0.009) was notable. Conclusion The lower initiating dose followed by a gradual dose increase of bosutinib reduced the drug discontinuation rate due to severe DRTs, especially diarrhea, while efficacy was assured.

Flumatinib Versus Nilotinib for Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia

Introduction Tyrosine kinase inhibitors (TKIs) have considerably improved the long-term clinical outcomes in patients with chronic phase chronic myeloid leukemia (CML-CP). Most of these patients receive 1 st generation TKI imatinib as first-line therapy; however, an increasing number of patients are now receiving 2 nd generation TKIs as first-line therapy, because of the more potent BCR-ABL1 inhibition with proven efficacy in patients resistant or intolerant to imatinib. Flumatinib is a novel 2 nd generation BCR-ABL1 TKI with promising efficacy and manageable safety in newly diagnosed CML-CP. Compared to imatinib, patients treated with flumatinib have achieved significantly higher rates of 12-month major molecular response (MMR) and complete cytogenetic response were observed in patients with CML-CP and that too within a shorter time duration. Though there have been many studies comparing 2 nd generation TKIs vs imatinib in CML-CP, studies comparing clinical outcomes between different 2 nd generation TKIs are scarce. Here, we report the real-world effectiveness and safety of flumatinib and nilotinib in patients with newly diagnosed CML-CP. Methods In this study, adult patients (≥18 years old) with newly diagnosed Philadelphia chromosome-positive (Ph+) CML-CP who received either 300 mg nilotinib twice daily or 600 mg flumatinib once daily, were included, with a follow-up duration of roughly 3 years (NCT04739826). The primary endpoint was the rate of MMR at 12 months as defined by European LeukemiaNet 2020 recommendations (BCR-ABL1 transcript level ≤0.1% in peripheral blood on RT-PCR assay on International Scale [IS]).The secondary endpoints were the rate of early molecular response (EMR) at 3 months (BCR-ABL1 IS ≤10%), the rate of molecular response at 6 months (BCR-ABL1 IS ≤ 1%) and safety (adverse events [AEs] reports in accordance to Common Terminology Criteria for Adverse Events, version 4.03). Results A total of 446 patients were enrolled in the study between November 2020 and August 2022, of which 150 and 296 patients were enrolled in nilotinib and flumatinib groups, respectively. The baseline characteristics were comparable between the two groups (Table 1). No significant difference in the rate of MMR was observed at 12 months between nilotinib and flumatinib (78% vs 80%; P=0.68) . Similarly, no significant difference was observed in the rate of EMR at 3 months (85% vs 89%; P=0.26) and the rate of optimal molecular response at 6 months (93% vs 92%; P=0.70; BCR-ABL1 is ≤1%) between the two groups. The overall safety profile was similar between the two groups. However, hyperbilirubinemia (47% vs 7%), increased ALT (33% vs 12%), increased AST (24% vs 9%), rash (30% vs 18%) and anemia (19% vs 10%) were more frequent in nilotinib group than flumatinib group, whereas diarrhea was lower in nilotinib than flumatinib (2.7% vs 8.8%). The incidence rate of grade 3-4 AEs were reported to be 13% in nilotinib group and 10% in flumatinib group. The safety of flumatinib was more favorable compared to nilotinib in terms of hepatic toxicities, skin toxicities, etc. (Figure 1). Conclusion The efficacy of flumatinib is comparable to nilotinib in Chinese patients with newly diagnosed Ph+ CML-CP. The overall incidences of grade 3-4 AEs were also accessible for the two drugs, nevertheless, a few AEs inclusively hepatic toxicity, anemia and skin toxicity were remarkably lower with flumatinib intervention.

Evaluating Effectiveness and Safety of Flumatinib for Chronic Phase Chronic Myeloid Leukemia in (CML-CP) without Optimal Response (Warning, Failure) to Imatinib or/and Dasatinib

Introduction Flumatinib is a novel second-generation BCR-ABL1 targeted kinase inhibitors (TKI) with better efficacy and safety than first generation TKIs in first-line treatment of chronic myeloid leukemia in chronic phase (CML-CP). In the previous phase III study, newly diagnosed CML-CP patients receiving flumatinib achieved higher treatment responses and safety than imatinib. When it comes to the patients not achieving the optimal response to TKIs, flumatinib is potentially a better option, nonetheless the robust evidence is unavailable. This study reports the effectiveness and safety of switching to flumatinib in patients who have not achieved the optimal molecular response to imatinib or/and dasatinib. Methods This prospective, multicentre study enrolled Philadelphia Chromosome-Positive (Ph+) CML-CP patients aged ≥18 years and who failed to achieve the optimal response with imatinib or/and dasatinib between March 2021 to October 2022. All patients were treated with flumatinib 600 mg once a day and followed up to 24 months. The primary endpoint of the study was rate of major molecular response (MMR) at 12 months as defined by European LeukemiaNet 2020 recommendations (BCR-ABL1 transcript level ≤0.1% in peripheral blood on RT-PCR assay on International Scale [IS]) and safety was the secondary endpoint assessed with CTCAE 4.03 version. In addition, the optimal molecular response in either the warning or failure patients was evaluated at 3, 6 and 12 months respectively, after switching to flumatinib, and the difference in effectiveness was also analyzed from the available mutation subtypes. Results Overall, 94 patients with Ph+ CML-CP were included in the study. The median (range) age of the patients were 53 (19.0-84.0) years old and 61.7% of the patients were males. A total of 38 (40.4%) patients reported warning response from the previous TKIs whereas 56 (59.6%) of patients reported treatment failure to the previous TKIs. Seventy-seven (81.9%) patients have been treated with one TKI, either imatinib or dasatinib, and 17 (18.1%) have been treated with both prior to the study. Overall, 25 (54%) patients achieved MMR at 12-months follow-up compared to the baseline (Figure 1). The rates of optimal molecular response at 3- and 6-months were also improved compared to the baseline. The optimal molecular response was 76(88%) at 3 months, and 52(73%) at 6 months. Subgroup analysis with previous response to TKIs revealed that flumatinib improved the rates of optimal molecular response in both warning and failure groups. Switching to flumatinib from imatinib or/and dasatinib have been reported with an enhanced optimal molecular response in patients who experienced warning compared with those who had treatment failure after the TKIs with 38 (100%) vs 38 (79%), 29 (91%) vs 23 (59%) and 15 (68%) vs 10 (42%) at 3-, 6- and 12-months respectively (Figure 2). Similarly, the rates of optimal molecular response were improved in patients without mutations compared to those having mutations, 65 (90%) vs 9 (75%) at 3 months, 46 (77%) vs 5 (56%) at 6 months and 23 (59%) vs 1 (20%) at 12 months respectively. The most common adverse events (AEs) were diarrhea in 17 (18%), rash in 11 (12%), bloating in 11 (12%), and thrombocytopenia in 11 (12%) patients. Common hematological AEs of grade 3/4 were thrombocytopenia in 7 (7%), anemia in 3 (3%) and leucopenia in 1 (1%) patients. Conclusion For Ph+ CML-CP patients without the optimal molecular response in previous imatinib or/and dasatinib, flumatinib is a better alternative to the existing treatments. In addition, if the patients were switched to flumatinib earlier, the optimal response was achieved faster. The grade 3/4 AEs were mainly hematologically related, whereas the gastrointestinal events were mostly of grade 1-2.

Neoadjuvant tislelizumab combined with chemotherapy in locally advanced oral or oropharyngeal squamous cell carcinoma: a real-world retrospective study.

The treatment of locally advanced oral or oropharyngeal squamous cell carcinoma (LAOOPSCC) is surgery and radiotherapy or chemoradiotherapy but with unsatisfactory survival rate. Neoadjuvant programmed death-1 (PD-1) therapy are being used in several clinical trials. Therefore, in this retrospective study we aimed to determine the feasibility of neoadjuvant tislelizumab plus chemotherapy followed by surgery for LAOOPSCC. The clinical data of 33 patients with LAOOPSCC who received neoadjuvant PD-1 inhibitors and chemotherapy between April 2021 and October 2022 were retrospectively analyzed. Patients with stage III-IV LAOOPSCC received tislelizumab, albumin-bound paclitaxel, and cisplatin every 3 weeks (Q3W) for two cycles, followed by surgery and adjuvant radiotherapy or concurrent chemoradiotherapy. A median follow-up period was 20 months. The objective response rate (ORR) was 66.7%, with the major pathological response (MPR) rate at 54.5%, and the pathological complete response (pCR) rate was 33.3%. Sixteen patients underwent limited surgeries, and 15 patients were remitted from undergoing mandibulectomy and 9 patients were remitted from undergoing near total glossectomy or total glossectomy. A significant difference in the overall survival (OS) and disease-free survival (DFS) was observed in patients who achieved major pathological response (MPR) than who did not. The most common adverse events in neoadjuvant therapy were alopecia, decreased appetite or anorexia, leukopenia, and fatigue. Neoadjuvant PD-1 inhibitors combined with chemotherapy are feasible and safe, with a high pathological response and possible organ preservation in oral or oropharyngeal squamous cell carcinoma. However, further studies with a larger cohort of patients and longer follow-up period is required to strengthen our findings and evaluate the survival benefits of the treatment.

Orelabrutinib Monotherapy in Patients with Relapsed or Refractory Waldenström's Macroglobulinemia in a Single-Arm, Multicenter, Open-Label, Phase 2 Study: Long Term Follow-up Results

Background Orelabrutinib is a novel, small molecule, selective irreversible Bruton tyrosine kinase inhibitor, approved in China for the treatment of patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL). The previous publication of this study reported that orelabrutinib is highly active in R/R Waldenström's macroglobulinemia (WM), with a well-tolerated safety profile (EClinicalMedicine. 2022;52:101682). We present here the long-term results of this study. Methods This is a prospective, multicenter study of orelabrutinib in patients with WM who had at least one prior line of treatment (ClinicalTrials NO. : NCT04440059). Orelabrutinib was administered orally at a daily dose of 150 mg until disease progression or unacceptable toxicity. Genotyping using MYD88 L265P and CRCR4 S338X mutation were performed with qPCR assay. The primary endpoint was major response rate (MRR) assessed by the Independent Review Committee (IRC) according to IWWM-6 (Br J Haematol. 2013; 160: 171-176). Results Between August 2019 and December 2020, 66 R/R WM patients were assessed for eligibility. Forty-seven eligible patients were evaluated for efficacy at a median follow-up of 31.9 months (interquartile range: 28.0，36.5). As assessed by IRC, the MRR was 80.9%, and the overall response rate was 91.5%. The PFS rates was estimated as 72.1% at 36 months and the median PFS has not been reached. There is no significant difference in PFS across various MYD88 L265P and CRCR4 S338X genotype (P=0.69; Figure 1). The 30-months PFS rate in MYD88 L265P/CXCR4 NEG, MYD88 L265P/CXCR4 S338X, and MYD88 NEG/CXCR4 NEG were 86.2%, 75% and 75%, respectively. Most adverse events were Grades 1 or 2 (63.8%). The common grade 3 or higher adverse events occurred were neutropenia (10.6%), thrombocytopenia (8.5%), and pneumonia (6.4%). Treatment related serious adverse events were reported in 8.5% patients. Adverse events leading to discontinuation occurred in 4 patients (8.5%). One treatment-related death was reported (hepatitis B reactivation). Conclusions Results with longer follow-up continue to show that orelabrutinib has high, deep and durable response in patients with R/R WM. Data support the safety of long-term orelabrutinib treatment in R/R WM, with no new safety signals identified.

Sustained Efficacy and Safety with Asciminib (ASC) after Almost 4 Years of Median Follow-up from Ascembl, a Phase 3 Study of ASC Vs Bosutinib (BOS) in Patients (Pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) after ≥2 Prior Tyrosine Kinase Inhibitors (TKIs): An End of Study Treatment (EOS Tx) Update, Including Results from Switch Population

CONCLUSIONS CML requires chronic therapy, emphasizing the need for Txs that are characterized by high, durable efficacy and a low adverse event (AE) burden. ASC, the first BCR::ABL1 inhibitor Specifically Targeting the ABL Myristoyl Pocket (STAMP), demonstrated significantly superior efficacy and better safety/tolerability compared with BOS in pts with CML-CP who received ≥2 prior TKIs in the phase 3 ASCEMBL study. Major molecular response (MMR) rate was 25.5% with ASC vs 13.2% with BOS at wk 24, meeting the primary objective, and 37.6% vs 15.8% at wk 96, meeting the key secondary objective. Despite the longer duration of exposure to ASC, safety/tolerability remained consistently better with ASC vs BOS, with fewer all-grade and grade ≥3 AEs and AEs leading to Tx discontinuation observed. After a median follow-up of 3.7 y, we report EOS Tx results from ASCEMBL (cutoff: March 22, 2023). We also report the first available data from pts who experienced Tx failure on BOS and switched to ASC. Adults (aged ≥18 y) with CML-CP after ≥2 prior TKIs, with intolerance or lack of efficacy per 2013 ELN recommendations were randomized 2:1 to receive either ASC 40 mg twice daily or BOS 500 mg once daily. Pts who met Tx failure criteria per 2013 ELN while on BOS could switch to ASC and were analyzed separately. Pts who discontinued BOS due to intolerance could not switch. EOS will occur 5 y from when the last enrolled pt received first Tx dose. A total of 233 pts were randomized to ASC (n=157) or BOS (n=76). The most common reason for discontinuation was lack of efficacy in 40 (25.5%) pts on ASC and 28 (36.8%) on BOS. At the time of EOS Tx cutoff, Tx with ASC and BOS was ongoing in 77 (49.4%) and 8 (10.5%) pts, respectively; pts deriving benefit from study Tx at EOS TX, per investigator assessment, continued receiving posttrial access. MMR rate at wk 156 continued to be higher with ASC (33.8%) than with BOS (10.5%) (Figure 1). The difference after adjusting for baseline (BL) major cytogenetic response was 23.2%(95% CI, 13.1%-33.2%; 2-sided P<.001). The BCR::ABL1IS ≤1% rate at wk 156 in pts without this level of response at BL also continued to be higher with ASC (43.0%) than with BOS (11.1%). Despite the longer median duration (range) of exposure to ASC (156.0 [0.1-256.3] wk) vs BOS (30.5 [1.0-239.3] wk), safety/tolerability of ASC continued to be better compared with BOS and were consistent with previous analyses. Two new pts had AEs leading to Tx discontinuation since the wk 96 cutoff (1 pt on ASC reported pregnancy; 1 pt on BOS reported diarrhea), and rates remained lower with ASC vs BOS (8.3% vs 27.6%). The most frequent (≥10%) grade ≥3 AEs with ASC vs BOS were thrombocytopenia (22.4% vs 9.2%), neutropenia (18.6% vs 14.5%), diarrhea (0% vs 10.5%), and increased alanine aminotransferase (0.6% vs 14.5%). Most AEs occurred within the first 6 months (Figure 2). Exposure-adjusted incidence rates of arterial occlusive events (AOEs) with ASC decreased since the wk 96 cutoff, from 3.0 to 2.2 per 100 pt-y, and no new AOEs occurred with ASC, indicating that the risk of AOEs did not increase over time. Among pts who discontinued Tx due to lack of efficacy or disease progression, no new mutations occurred since the wk 96 cutoff. Of 28 pts who discontinued BOS for lack of efficacy, 25 switched to ASC. Almost all switch pts (96%) had BL BCR::ABL1IS >10% prior to switch. No switch pts achieved MMR at or by wk 48 post switch. However, at wk 48, 24% achieved BCR::ABL1IS ≤10% and 8% achieved BCR::ABL1IS ≤1%. The safety profile of ASC in switch pts was consistent with that in pts receiving ASC in the randomized period. Most frequent (≥10%) grade ≥3 AEs were neutropenia (32.0%) and thrombocytopenia (24.0%). AEs leading to Tx discontinuation occurred in 8.0% of switch pts. With almost 4 y of follow-up in ASCEMBL, ASC continued to show greater efficacy and better safety/tolerability than BOS in pts with CML-CP after ≥2 prior TKIs. The robust safety profile of ASC was sustained through each analysis in ASCEMBL (wk 24, wk 96, and EOS Tx), confirming that pts receiving ASC can maintain a high level of response and continue Tx without experiencing late-emerging AEs. Results in the switch population support the use of ASC early in the Tx paradigm. ASCEMBL EOS Tx results continue to strongly support ASC as the therapy of choice for pts with suboptimal responses and/or intolerance to ≥2 prior TKIs, allowing more pts to remain on Tx and achieve their Tx goals without needing to switch.

Flumatinib Versus Imatinib As a Frontline Therapy for Patients with Chronic Myeloid Leukemia in Chronic Phase: A Propensity Score Matching Study from Real-World Data

Background: Flumatinib mesylate, as a novel oral BCR-ABL1 tyrosine kinase inhibitor, is approved as a frontline therapy for chronic myeloid leukemia in chronic phase (CML-CP) in China since 2019. Mechanistically, with its structure of trifluoromethyl and pyridine flumatinib blocked BCR-ABL1 kinase autophosphorylation with much more potent activity than did imatinib and even showed higher efficacy than nilotinib against wild-type BCR-ABL1 kinase. Currently, there is still lacking the real-world effectiveness and safety of flumatinib in patients with CML. Methods: We retrospectively analyzed efficacy and safety of CML-CP patients (≥16 years) used flumatinib (600mg daily) or imatinib (400mg daily) as first-line treatment from 2020 to 2023, presenting a real-world comparison study. A propensity score (PS) matching was performed to adjust for Sokal risk score to compare the treatment efficacy, survival outcomes and safety of flumatinib and imatinib in a clinically well matched cohort. Results: PS matching resulted in 20 patients from each cohort being matched for Sokal risk scores. The median follow-up of the flumatinib-treated and imatinib-treated cohorts was 441 days and 487 days, respectively. In the intention-to-treat (ITT) population analysis, there is no differences between flumatinib and imatinib groups in 3-month early molecular response rate (85% vs. 80%, p = 0.677), 6-month major molecular response rate (MMR) (50% vs. 40%, p = 0.525) and 12-month MMR (55% vs. 50%, p = 0.752). In term of deep molecular response, more patients receiving flumatinib achieved molecular remission 4.5 (MR4.5) and molecular remission 4 (MR4.0) at 6 months (35% vs.0%, p = 0.004; and 45% vs. 5.0%, p = 0.003, respectively) and appeared to have higher 12-month MR4.5 and 12-month MR4.0 (45% vs.10%, p = 0.013; and 45% vs. 20%, p = 0.091, respectively; Table). During the follow-up period, treatment discontinuation occurred in 6 and 9 patients in flumatinib-treated and imatinib-treated cohorts respectively, including 2 and 3 patients due to drug resistance and 3 and 4 patients due to toxicity. The 2-year probability of event-free survival was 70% among the patients who received flumatinib and 47% among those who received imatinib ( p = 0.85), and the corresponding 2-year failure-free survival probabilities were 85% and 76%, respectively ( p = 0.77). Adverse events of edema, rash were more frequent in imatinib arm (any grade; 0% vs. 25%, p = 0.017; and 0% vs. 25%, p = 0.035, respectively), whereas alanine transaminase elevation appeared to be more frequent in flumatinib arm (any grade, 15% vs. 0%, p = 0.072). Of note, one patient receiving flumatinib had grade 3 QT prolongation and ventricular premature beat and was discontinued. Conclusions: The real-world data demonstrated that as a first-line treatment setting, flumatinib can bring patients with chronic phase CML higher rates of responses, and faster and deeper responses, indicating that flumatinib could be an alternative effective first-line treatment for CML-CP. The adverse events of flumatinib, such as cardiovascular events, abnormal liver function, and diarrhea, need to be given continuous concern in future studies.

ASC4KIDS: A Multicenter, Open-Label, Phase Ib/II Study to Determine the Dose and Safety of Asciminib in Pediatric Patients with Chronic Myeloid Leukemia in the Chronic Phase

Background Tyrosine kinase inhibitors (TKIs) are the standard of care for adult and pediatric patients with chronic myeloid leukemia in the chronic phase (CML-CP). More treatment options with improved efficacy and safety profiles are needed for pediatric patients. Asciminib is a first-in-class allosteric inhibitor of ABL (non-receptor tyrosine) kinases, specifically targeting the ABL myristoyl pocket (STAMP), and does not inhibit other protein kinases. Asciminib was approved by the US Food and Drug Administration (FDA) with subsequent approvals worldwide for patients aged ≥18 years with Philadelphia chromosome-positive (Ph+) CML-CP treated with ≥2 prior TKIs in October 2021. Asciminib 40 mg twice daily (bid) has demonstrated improved major molecular response rates (25.5% vs 13.2% at week 24) and a favorable safety profile compared with bosutinib 500 mg once daily (qd) in adult patients with Ph+ CML-CP in the phase 3 ASCEMBL study (NCT03106779). This study aims to characterize the pharmacokinetics (PK), long-term safety profile, and antileukemic effects of asciminib in pediatric patients and identify a pediatric formulation dose that will lead to asciminib exposure comparable to 80 mg qd or 40 mg bid in adult patients. Methods This multicenter, open-label study (NCT04925479) includes patients aged 1 to <18 years with Ph+ CML-CP, without a BCR::ABL1 T315I mutation, treated with ≥1 prior TKI. For the pediatric formulation group, at least 15 patients will be included in each of the two age groups (1 to <12 years and 12 to <18 years), consisting of Part 1, 2 and 3. The study started with an exploratory adult formulation group of Adolescent patients (aged 14 to <18 years, body weight ≥40 kg) treated with the adult formulation dose (40 mg bid or 80 mg qd tablet) under fasting conditions. The primary endpoint includes PK parameters; secondary endpoints include: hematologic and molecular responses, safety, and acceptability/palatability of the pediatric formulations. Part 1 (dose-determining cohort): 4 to 6 patients will receive the asciminib pediatric formulation bid (a mini-tablet of 1.3 mg/kg with food) to assess safety, and to assess if the exposure in pediatric patients is comparable to exposure with the adult formulation over the first 28 days (patients either from pediatric or adult categories). After the interim analysis, if a dose adjustment is required, an additional 4 to 6 patients will be assessed at an adjusted dose. Part 2 (expansion cohort, 40 mg bid regimen): 14 to 16 patients will receive the dose determined in part 1. The second interim PK and safety analysis will be conducted after all patients from parts 1 and 2 complete 28 days of treatment. Part 3 (expansion cohort, 80 mg qd regimen): 10 patients (5 from each age group) will receive the same total daily dose of asciminib qd. The PK, safety profile, and pharmacodynamic endpoints will be assessed for the bid regimen after all patients in parts 1 and 2 complete 52 weeks of treatment. The primary analysis for the combined bid and qd regimen will be performed after all patients complete 52 weeks of treatment (total treatment period: 5 years [ Figure]). A final analysis will be performed after all patients complete treatment. Patients who discontinue treatment early will be followed up for survival until the end of the study. There are 32 study sites open out of planned 35 study sites in 14 countries worldwide. The exploratory and the pediatric formulation groups recruited 4 patients and 9 patients, respectively, as of June 07, 2023, with a total of 13 patients in the study. The study is still recruiting. This study will determine a pediatric dose for asciminib and support a strategy of full extrapolation from adult data to use in the pediatric patients with CML-CP.

Asciminib (ASC) Once-Daily (QD) Dosing Demonstrates Comparable Tolerability and Efficacy to Twice-Daily (BID) Dosing: Results from the ASC in Monotherapy 4 CML (AIM4CML) Study in Patients (Pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

CONCLUSIONS ASC is the only approved BCR::ABL1 inhibitor that Specifically Targets the ABL1 Myristoyl Pocket, distinguishing it from other approved treatments that target the ATP binding site. In the phase III ASCEMBL trial (NCT03106779) ASC 40 mg BID was well tolerated and demonstrated superior efficacy vs bosutinib 500 mg QD in pts previously treated with ≥2 TKIs, with major molecular response (MMR; BCR::ABL1IS ≤0.1%) rates of 25.5% vs 13.2% at wk 24 and 37.6% vs 15.8% at wk 96. We present an interim analysis of the primary endpoint of the AIM4CML trial (NCT04666259), which was initiated to assess the safety, efficacy, and QD dosing of ASC in a similar population of pts with CML-CP. This is a multicenter, phase IIIb, open-label study of ASC in pts with CML-CP without the T315I mutation after ≥2 prior TKIs and pts with the T315I mutation after ≥1 prior TKI. Adults aged ≥18 years with CML-CP who had treatment failure with or intolerance of the most recent TKI were eligible. Pts without the T315I mutation were randomized to receive ASC 40 mg BID (cohort A) or 80 mg QD (cohort B). Results for pts with the T315I mutation who received ASC 200 mg BID (cohort C) will not be presented for this analysis. The primary endpoints include adverse events (AEs) and serious AEs by wk 24 in cohorts A and B, with additional safety and efficacy secondary endpoints. This study was not powered to detect statistical differences between cohorts. End of study is when the last pt completes 72 wks of treatment or discontinues prematurely. The numbers of enrolled pts in cohorts A, B, and C were 26, 27, and 3, respectively. This interim analysis included 42 pts randomized to cohort A (n=22) or cohort B (n=20), who reached 24 wks after cycle 1 day 1 of treatment by February 17, 2023. Most baseline characteristics in cohorts A and B were comparable, but median time since initial diagnosis and median baseline BCR::ABL1IS levels were longer and higher, respectively in cohort B (Table). Median duration of exposure was 23.1 (range, 2.7-72.3) wks in cohort A and 24.1 (range, 1.3-71.0) wks in cohort B. Prior to wk 24, treatment was discontinued in 7 and 4 pts in cohorts A and B, respectively. Reasons for discontinuation included physician decision (cohort A, n=4; cohort B, n=2), AEs (cohort A, n=2; cohort B, n=1), or pt decision (cohort A, n=1; cohort B, n=1). At the time of this interim analysis, discontinuation due to treatment failure was reported only in cohort B in 2 pts that discontinued due to physician decision. Cohorts A and B had comparable all-grade, grade 3, and grade 4 AEs. Treatment-emergent all-grade AEs occurring in ≥20% in cohorts A and B were fatigue (32% and 25%), headache (27% and 20%), abdominal pain (27% and 15%), rash (23% and 5%), dyspnea (23% and 10%), nausea (14% and 30%), hypertension (14% and 20%), cough (18% and 20%), and arthralgia (9% and 20%). While many pts had AEs requiring additional therapy, few had serious AEs, and similar numbers of pts in cohorts A and B had AEs leading to dose adjustments/interruptions and treatment discontinuation (Figure). One pt in cohort B had a fatal AE due to sepsis that was not attributed to study treatment. This trial is ongoing; data for the wk 24 primary endpoint for all enrolled pts will be available at the time of presentation. Pts with ≥1 molecular response assessment by wks 4, 12, and 24 were 18, 19, and 20 in cohort A, respectively, and 17, 17, and 18 in cohort B, respectively. The proportions of pts who maintained or achieved BCR::ABL1IS ≤1% by wks 4, 12, and 24 were higher in cohort B with 52.9%, 76.5%, and 88.9%, respectively than in cohort A with 50.0%, 63.2%, and 65.0%, respectively, likely due to higher baseline BCR::ABL1IS levels in cohort B (Table). MMR rates by wks 4, 12, and 24 were 33.3%, 42.1%, and 45.0% in cohort A and 23.5%, 47.1%, and 61.1% in cohort B, respectively. Deep molecular response (MR 4; BCR::ABL1IS ≤0.01%) rates by wks 4, 12, and 24 were 27.8%, 31.6%, and 30.0% in cohort A and 5.9%, 11.8%, and 27.8% in cohort B, respectively. This interim analysis of the AIM4CML trial further demonstrates the tolerability and efficacy of ASC and is among the first clinical reports on QD dosing of ASC in pts with CML-CP. Safety was comparable between the 80-mg QD and 40-mg BID doses, with both demonstrating safety profiles consistent with prior reports. Pts receiving ASC at both doses achieved and maintained molecular responses, which deepened over time. These results support the flexibility of QD dosing with ASC.

Great Debate: Chemoradiation Should be Added to Chemotherapy as a Neoadjuvant Treatment Strategy for Resectable Gastric Adenocarcinoma.

Most patients with resectable gastric cancer present with locally advanced disease and warrant neoadjuvant chemotherapy based on level 1 evidence. However, the incremental benefit of adding radiation to chemotherapy as a neoadjuvant treatment strategy for these patients is less clear. While awaiting the results of two ongoing randomized clinical trials attempting to specifically address this question (TOPGEAR and CRITICS-II), this article presents the debate between two gastric cancer surgery experts supporting each side of the argument on the use or omission of neoadjuvant radiation in this setting. On the one hand, neoadjuvant radiation may be better tolerated compared with modern triplet chemotherapy and may be associated with higher rates of major pathologic response. Additionally, there is evidence to suggest that radiation may offer a survival benefit when the tumor is located at the gastroesophageal junction or there is concern for a margin-positive resection. However, in the setting of adequate surgery, no survival benefit has been demonstrated by adding radiation to modern chemotherapy, likely reflecting the fact that death from gastric cancer is a result of distant recurrence, which is not addressed by local treatment such as radiotherapy. While awaiting the results of the TOPGEAR and CRITICS-II trials, this discussion of current evidence can facilitate the refinement of an optimal neoadjuvant therapy strategy in patients with resectable gastric cancer.

Neoadjuvant therapy with immune checkpoint inhibitors in operable nonsmall cell lung cancer.

In localized nonsmall cell lung cancer (NSCLC) systemic recurrences after surgery are common. Therefore, adjuvant or neoadjuvant chemotherapy is used. With the advent of immune checkpoint inhibitors (ICIs) in metastatic disease the question is whether ICIs can further improve the outcome. In several phase I/II trials, major pathological response (MPR) rates with several ICIs between 7% and 50% were seen. No major additional side effects occurred. In combination with chemotherapy CheckMate-816 randomized additional neoadjuvant nivolumab and achieved a high pathological complete response (pCR) rate and a better event-free survival (EFS) - without negatively influencing surgery. More randomized trials are performed with neoadjuvant immunochemotherapy and adjuvant treatment after surgery. In Keynote-671, pembrolizumab is used pre and postoperatively with a significantly higher EFS rate at 2 years (62.4% vs. 40.6%). Similar preliminary results are reported in the AEGEAN (durvalumab) and Neotorch (toripalimab) trials. Higher tumour stage and MPR, partly programmed cell death 1 ligand 1 (PD-L1) expression, tumour mutational burden (TMB) and circulating tumour DNA (ctDNA) are correlated with efficacy. Neoadjuvant immunochemotherapy improves MPR and EFS rates, especially in more advanced tumours and tumours expressing PD-L1 - without relevantly increasing toxicities. But further and longer evaluation is needed.

Efficacy and Safety of High-Dose Vitamin C Combined with Total Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer (HCCSC R02 Study).

Forpatients with locally advanced rectal cancer (LARC), the standard treatment is fluoropyrimidine (FU) -based neoadjuvant chemoradiotherapy (NCRT) combined with curative surgery. The CAO/ARO/AIO-04 trial and FORWARC trial reported that the addition of oxaliplatin to FU -based NCRT contributed to improve pathologic complete response (pCR), nevertheless, increased the acute therapeutic toxicity. Some studies showed that vitamin C (VitC) had potential benefits on anti-tumor therapy and anti-inflammatory response. Therefore, we conducted this HCCSC R02 study to explore the efficacy and safety of adding a high-dose intravenous VitC to mFOLFOX6/XELOX -based NCRT in LARC. HCCSCR02 study was designed as a prospective, single-center phase II trial, which including pts aged 18-75 years with stage II/III rectal adenocarcinoma, distance from anus ≤12cm. The enrollment criteria included: staged with MRI as cT3/cT4 or cN1/2, or mesorectal fascia involvement (MRF+), or difficult to preserve the anus. Patients with glucose-6-phosphate dehydrogenase enzyme(G6PD) deficiency were excluded. Pelvic intensity modulated radiation therapy (IMRT) was given in 45-50.4Gy/25-28 fractions. Concurrently, two cycles of chemotherapy (mFOLFOX6 or XELOX) were administered during IMRT, as well as intravenous VitC (24g) delivered daily after the end of each radiation therapy. Additional 2-3 cycles of mFOLFOX6 / XELOX were adopted between the completion of radiotherapy and surgery. The primary endpoint was pCR rate. The secondary endpoints included radiation-related toxicities, overall survival (OS) and disease-free survival (DFS). This study is still recruiting. From May 15, 2021 to Feb 8, 2023, 19 pts were recruited and finished all the scheduled NCRT, of which the proportion of cT4, cT3, cN2, cN1 were 31.6%, 63.2%, 52.6%, 36.8%, respectively. In addition, 10 pts (52.6%) were diagnosed as MRF+ initially, and 8 pts (42.1%) had a lower primary tumor(≤5cm) who were considered difficult for anal preservation before NCRT. All subjects enrolled were confirmed to be proficient mismatch repair (pMMR). As a result, 18 pts underwent a total mesorectal excision (TME) all with R0-resection, and 8 pts were evaluated as pCR (44.4%, 8/18, confidence interval: 0.246-0.663), 11 as major pathological response rate (MPR) (61.6%, 11/18), respectively. The anus preservation rate in patients with lower diseases was 87.5% (7/8). One case accepted a watch-and-wait strategy because of clinical complete response (cCR). Overall, grade 3 toxicities were observed in 4 pts, including 3 leucopenia (15.8%, 3/19), 2 neutropenia (10.5%, 2/19) and 1 diarrhea (5.3%, 1/19). No grade 4 adverse event was observed. The addition of high-dose VitC to the mFOLFOX6/XELOX-based NCRT in LARC showed a promising pCR, well tolerance, particularly low rate of diarrhea, thus warrants further investigation. NCT04801511.

SOX combined with sintilimab versus SOX alone in the perioperative management of locally advanced gastric cancer: a propensity score–matched analysis

ObjectivesTo evaluate the efficacy of SOX combined with a programmed cell death protein-1 (PD-1) inhibitor compared with SOX alone in the perioperative management of locally advanced gastric cancer and to explore biomarkers that may predict response to anti-PD-1 therapy.MethodsData of patients with clinical stage T3–4aN0–3M0 (IIb–III) gastric cancer were reviewed to create a primary database. Patients treated with perioperative SOX combined with sintilimab were included in Group A, while those treated with SOX alone were included in Group B. After one-to-one propensity score matching, pathological response and short-term survival outcomes were compared between the two groups. In addition, potential efficacy-related biomarkers were analyzed.ResultsBetween January 2018 and December 2022, a total of 150 patients were included in the analysis, with 75 patients in each group. The rates of pathological complete response (21.3% vs. 4.0%; P = 0.001) and major pathological response (45.3% vs. 22.7%; P = 0.003) in Group A were statistically higher than those in Group B. There was no significant difference in 1-year overall survival (92.8% vs. 92.0%; P = 0.392) and disease-free survival (88.9% vs. 88.0%; P = 0.357) between the two groups. Subgroup analysis of Group A showed that the pathological complete response (40.6% vs. 8.6%; P = 0.002) and major pathological response (65.6% vs. 28.6%; P = 0.002) rates were significantly higher in programmed death ligand-1-positive patients with a combined positive score of ≥ 5. A pathological complete response was achieved in 42.9% patients (3/7) with mismatch repair deficiency. For the two patients confirmed as Epstein-Barr virus-positive, one patient achieved a pathological complete response and the other achieved a major pathological response.ConclusionsThe adoption of SOX combined with a PD-1 inhibitor may improve the pathological response rate of patients with locally advanced gastric cancer, especially those with programmed death ligand-1 combined positive score ≥ 5, Epstein–Barr virus-positivity and mismatch repair deficiency. However, further prospective studies are still warranted to confirm the long-term survival benefit.

Neoadjuvant Immunotherapy and Non-Small Cell Lung Cancer: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

To systematically evaluate the effectiveness and safety of neoadjuvant immunotherapy for patients with non-small cell lung cancer (NSCLC). Randomized controlled trials of neoadjuvant immunotherapy in treating patients with NSCLC were comprehensively retrieved from electronic databases, eligible studies, previous systematic reviews and meta-analyses, guidelines, and conference abstracts. The meta-analysis was performed by the Stata/SE 12.0 software. Eleven randomized controlled trials were eventually included. The results of the meta-analysis showed that neoadjuvant immunochemotherapy significantly improved the objective response rate compared with neoadjuvant chemotherapy (CT; 62.46% vs 41.88%, P = 0.003), but the objective response rate of neoadjuvant double-immunotherapy was roughly comparable to that of neoadjuvant single-immunotherapy (15.74% vs 10.45%, P = 0.387). Major pathologic response (MPR) rate and pathologic complete response (pCR) rate of neoadjuvant immunochemotherapy and neoadjuvant double-immunotherapy were significantly superior to neoadjuvant CT alone and neoadjuvant single-immunotherapy, respectively. Compared with neoadjuvant CT alone, neoadjuvant immunochemotherapy increased the down-staging rate (40.16% vs 26.70%, P = 0.060), the surgical resection rate (83.69% vs 73.07%, P = 0.231), and R0 resection rate (86.19% vs 77.98%, P = 0.502), but there were no statistically significant differences. Neoadjuvant immunochemotherapy did not increase the postoperative complications rate than neoadjuvant CT alone (40.20% vs 41.30%, P = 0.920). In terms of safety, neoadjuvant immunochemotherapy and neoadjuvant double-immunotherapy did not increase the incidence of treatment-related adverse events (TRAEs) and the grade 3 or higher TRAEs. In summary, neoadjuvant immunochemotherapy had better clinical efficacy than neoadjuvant CT for patients with NSCLC. MPR rate and pCR rate of neoadjuvant immunochemotherapy and neoadjuvant double-immunotherapy were significantly superior to neoadjuvant CT and neoadjuvant single-immunotherapy, respectively, for patients with NSCLC, showing that MPR rate and pCR rate were probably considered as alternative endpoints for survival benefit. TRAEs were comparable between the corresponding groups. The long-term survival outcome of neoadjuvant immunotherapy for patients with NSCLC needs to be further confirmed to better guide clinical practice.

The long-term efficacy and safety of nilotinib in pediatric patients with CML: a 5-year update of the DIALOG study

AbstractThe efficacy and safety of nilotinib in pediatric patients with imatinib/dasatinib resistant/intolerant (R/I) or newly diagnosed (ND) Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP) was demonstrated in the phase 2, open-label DIALOG study. In this final analysis, long-term efficacy and safety are presented for patients who completed 66 cycles (of 28 days) of treatment with nilotinib (230 mg/m2 twice daily) or discontinued early. Overall, 59 patients were enrolled and 58 were treated (R/I, n = 33; ND, n = 25; median time on treatment: 60.5 and 51.9 months, respectively). In the R/I cohort, the cumulative major molecular response (MMR; BCR::ABL1 international scale [IS] ≤ 0.1%) rate was 60.6%, and no patients had a confirmed loss of MMR. Among ND patients, the best overall MMR rate was 76.0%; 3 patients had a confirmed loss of MMR. The cumulative molecular response MR4 (BCR::ABL1IS ≤ 0.01%) and MR4.5 (BCR::ABL1IS ≤ 0.0032%) rates by 66 cycles were 27.3% and 12.1% in the R/I cohort, and 56.0% and 44.0% in the ND cohort, respectively. The safety profile of nilotinib was consistent with those of earlier reports. No on-treatment deaths occurred. These long-term (up to ∼5 years) data support the efficacy and safety of nilotinib in pediatric patients with Ph+ CML-CP. This trial was registered at www.clinicaltrials.gov.uk as #NCT01844765.

Adverse outcomes for chronic myeloid leukemia patients with splenomegaly and low in vivo kinase inhibition on imatinib

Variability in the molecular response to frontline tyrosine kinase inhibitor (TKI) therapy in chronic myeloid leukemia may be partially driven by differences in the level of kinase inhibition induced. We measured in vivo BCR::ABL1 kinase inhibition (IVKI) in circulating mononuclear cells after 7 days of therapy. In 173 patients on imatinib 600 mg/day, 23% had low IVKI (<11% reduction in kinase activity from baseline); this was associated with higher rates of early molecular response (EMR) failure; lower rates of major molecular response (MMR), and MR4.5 by 36 months, compared to high IVKI patients. Low IVKI was more common (39%) in patients with large spleens (≥10 cm by palpation). Notably 55% of patients with large spleens and low IVKI experienced EMR failure whereas the EMR failure rate in patients with large spleens and high IVKI was only 12% (p = 0.014). Furthermore, patients with large spleen and low IVKI had a higher incidence of blast crisis, inferior MMR, MR4.5, and event-free survival compared to patients with large spleen and high IVKI and remaining patients. In nilotinib-treated patients (n = 73), only 4% had low IVKI. The combination of low IVKI and large spleen is associated with markedly inferior outcomes and interventions in this setting warrant further studies.

Neoadjuvant chemoimmunotherapy cycle number selection for non-small cell lung cancer and clinical outcomes: a real-world analysis.

Neoadjuvant chemoimmunotherapy is the optimal choice in the treatment of NSCLC; however, the optimal number of therapeutic cycles remains unclear. The primary aim of this study was to determine the optimal number of neoadjuvant therapeutic cycles in NSCLC. This study was a real-world clinical analysis that included patients who received neoadjuvant chemoimmunotherapy followed by surgery from January 2020 to August 2022. Patients were divided into two groups based on the number of therapeutic cycles: 2-cycle group and 3-4-cycles group. The primary endpoint was the major pathological response (MPR) rate. A total of 251 patients were included: 150 in the 2-cycle group and 101 in the 3-4-cycles group. Baseline characteristics were well-balanced between the groups. The MPR in the 2-cycle group was 57.3% and not significantly different from that of 57.4% in the 3-4-cycles group (p=0.529). Thirty-two patients (31.7%) in the 3-4-cycles group underwent surgery > 42 days after the final cycle of neoadjuvant therapy, significantly more than the 24 patients (16.0%) in the 2-cycle group (p=0.003). The incidence of adverse events related to neoadjuvant therapy was higher in the 3-4-cycles vs 2-cycle groups (72.3% versus 58.0%, respectively; p=0.021), while the 2-cycle group had a higher rate of postoperative morbidities (28.0% versus 12.9%, respectively; p=0.004). Additionally, for patients with ≤ 44.2% regression in diameter on computed tomography after two cycles of treatment, the MPR rate was higher in the 3-4-cycles vs 2-cycle group (47.3% versus 29.9%, respectively; p=0.048). For cases with programmed death-ligand 1 expression, regarding tumor proportion score ≤ 10%, 3-4 cycles of neoadjuvant treatment increased the MPR rate compared with 2 cycles (37.5% versus 9.5%, respectively; p=0.041). Our data support the positive role of chemoimmunotherapy in the neoadjuvant treatment of NSCLC. Extending to 3-4 cycles instead of 2 cycles of neoadjuvant chemoimmunotherapy may improve the safety of surgery and result in a lower incidence of postoperative morbidities; however, the MPR rate may not increase significantly. CT re-evaluation during treatment and PD-L1 expression at initial diagnosis are potential indicators to guide the choice of the number of therapeutic cycles.

466. ESOPHAGECTOMY AFTER NEOADJUVANT CHEMORADIATION THERAPY: DOES THE TIMING OF SURGERY INFLUENCE THE OUTCOME?

Abstract Background Multimodality treatment, either neoadjuvant chemoradiotherapy (nCRT) or perioperative chemotherapy (e.g., FLOT), and surgery, represents the standard of care for locally advanced, resectable cancer of the esophagus and esophago-gastric junction. The recommended interval between the ending of nCRT and surgery is between 6 and 8 weeks. A prolonged time to surgery (TTS) is associated with an increase in pathologic complete response (pCR) and survival in different malignancies, with a possible increase in surgical difficulty and postoperative complications. Materials and methods: A retrospective analysis was conducted on 154 patients with cT2-4aN0-(+), cT1bN+, M0 squamous cell (SCC) and adenocarcinoma (AC) cancer of the esophagus and esophagogastric junction (Siewert type 1) treated with nCRT and surgery between August 2017 and January 2022. Three groups were identified: patients operated within 10 (n = 37), between 10 and 12 (n = 48) and beyond 12 weeks (n = 69). Minimum follow-up period was six months. Results Demographic and clinical characteristics were comparable. Mean length of stay was 13.1, 15.6 and 16.5 days (p = 0.06) respectively. Incidence of postoperative complications and their severity were not different between groups. No postoperative deaths were observed. No difference in pCR was found. When analyzed by histology, a slight increase was evident in patients with SCC (33.3%, 43.5%, 39.4%; vs ADC 16%, 16%, 16.7%), though not statistically significant. Similar results were obtained for tumor regression grade, with an increase in major responses for SCC over time (Mandard 1–2: SCC 50%, 61%, 62%; ADC 60%, 64%, 58%). No difference in overall survival was observed. Conclusions Esophagectomy performed more than 10 weeks after the end of chemoradiation therapy was not associated with an increase in postoperative morbidity. We observed, though, a trend towards longer hospital stays. The rate of major pathological response seems to increase over time after completion of chemoradiation therapy, but only for squamous histotype. Larger studies are required to corroborate these findings.