Ruxolitinib, a potent Janus kinase 1/2 inhibitor, resulted in rapid and durable improvements in splenomegaly and disease-related symptoms in the 2 phase III COMFORT studies. In addition, ruxolitinib ...was associated with prolonged survival compared with placebo (COMFORT-I) and best available therapy (COMFORT-II). We present a pooled analysis of overall survival in the COMFORT studies using an intent-to-treat analysis and an analysis correcting for crossover in the control arms. Overall, 301 patients received ruxolitinib (COMFORT-I, n=155; COMFORT-II, n=146) and 227 patients received placebo (n=154) or best available therapy (n=73). After a median three years of follow up, intent-to-treat analysis showed that patients who received ruxolitinib had prolonged survival compared with patients who received placebo or best available therapy hazard ratio=0.65; 95% confidence interval (95%CI): 0.46-0.90; P=0.01; the crossover-corrected hazard ratio was 0.29 (95%CI: 0.13-0.63). Both patients with intermediate-2- or high-risk disease showed prolonged survival, and patients with high-risk disease in the ruxolitinib group had survival similar to that of patients with intermediate-2-risk disease in the control group. The Kaplan-Meier estimate of overall survival at week 144 was 78% in the ruxolitinib arm, 61% in the intent-to-treat control arm, and 31% in the crossover-adjusted control arm. While larger spleen size at baseline was prognostic for shortened survival, reductions in spleen size with ruxolitinib treatment correlated with longer survival. These findings are consistent with previous reports and support that ruxolitinib offers a survival benefit for patients with myelofibrosis compared with conventional therapies. (clinicaltrials.gov identifiers: COMFORT-I, NCT00952289; COMFORT-II, NCT00934544).
Myelofibrosis (MF) is associated with a variety of burdensome symptoms and reduced survival compared with age-/sex-matched controls. This analysis evaluated the long-term survival benefit with ...ruxolitinib, a Janus kinase (JAK)1/JAK2 inhibitor, in patients with intermediate-2 (int-2) or high-risk MF.
This was an exploratory analysis of 5-year data pooled from the phase 3 COMFORT-I and -II trials. In both trials, patients could cross over to ruxolitinib from the control group (COMFORT-I, placebo; COMFORT-II, best available therapy). All continuing patients in the control groups crossed over to ruxolitinib by the 3-year follow-up. Overall survival (OS; a secondary endpoint in both trials) was evaluated using pooled intent-to-treat data from patients randomized to ruxolitinib or the control groups. OS was also evaluated in subgroups stratified by baseline anemia and transfusion status at week 24.
A total of 528 patients were included in this analysis; 301 were originally randomized to ruxolitinib (COMFORT-I, n = 155; COMFORT-II, n = 146) and 227 to control (n = 154 and n = 73, respectively). The risk of death was reduced by 30% among patients randomized to ruxolitinib compared with patients in the control group (median OS, 5.3 vs 3.8 years, respectively; hazard ratio HR, 0.70 95% CI, 0.54-0.91; P = 0.0065). After correcting for crossover using a rank-preserving structural failure time (RPSFT) method, the OS advantage was more pronounced for patients who were originally randomized to ruxolitinib compared with patients who crossed over from control to ruxolitinib (median OS, 5.3 vs 2.3 years; HR ruxolitinib vs RPSFT, 0.35 95% CI, 0.23-0.59). An analysis of OS censoring patients at the time of crossover also demonstrated that ruxolitinib prolonged OS compared with control (median OS, 5.3 vs 2.4 years; HR ruxolitinib vs censored at crossover, 0.53 95% CI, 0.36-0.78; P = 0.0013). The survival benefit with ruxolitinib was observed irrespective of baseline anemia status or transfusion requirements at week 24.
These findings support ruxolitinib treatment for patients with int-2 or high-risk MF, regardless of anemia or transfusion status. Further analyses will be important for exploring ruxolitinib earlier in the disease course to assess the effect on the natural history of MF.
ClinicalTrials.gov identifiers, NCT00952289 and NCT00934544 .
Ruxolitinib is a potent Janus kinase (JAK) 1/JAK2 inhibitor that has demonstrated rapid and durable improvements in splenomegaly and symptoms and a survival benefit in 2 phase 3 trials in patients ...with myelofibrosis. Ruxolitinib was well tolerated and effectively reduced splenomegaly and symptom burden in Asian patients with myelofibrosis in the Asian multinational, phase 2 Study A2202. We present a subset analysis of Japanese patients (
n
= 30) in Study A2202. At data cutoff, 22 patients were ongoing; 8 discontinued, mainly due to adverse events (
n
= 4). At week 24, 33 % of patients achieved ≥35 % reduction from baseline in spleen volume; 56.0 % achieved ≥50 % reduction from baseline in total symptom score, as measured by the 7-day Myelofibrosis Symptom Assessment Form v2.0. The most common adverse events were anemia (63 %), thrombocytopenia (40 %), nasopharyngitis (37 %), decreased platelet counts (30 %), and diarrhea (30 %). Dose reductions or interruptions due to hemoglobin decreases were more frequent in Japanese patients; no loss of efficacy and no discontinuations due to hematologic abnormalities were observed. Ruxolitinib was well tolerated in Japanese patients and provided substantial reductions in splenomegaly and myelofibrosis-related symptoms similar to those observed in the overall Asian population and phase 3 COMFORT studies.
TPS1129 Background: Substantial improvement in survival outcomes has been achieved with cyclin-dependent kinase (CDK) 4/6 inhibitors plus endocrine therapy (ET) in patients with hormone ...receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) advanced/metastatic breast cancer (BC); however, resistance to this therapy ultimately occurs. PF-07220060 is an oral, highly potent, selective, next generation inhibitor of CDK4 with sparing of CDK6. A first-in-human phase 1/2a study evaluated PF-07220060 (300/400 mg BID) plus ET in patients with HR+/HER2− advanced/metastatic BC who progressed on a prior CDK4/6 inhibitor plus ET (n = 26). At the data cutoff date of November 1, 2022, in patients with measurable disease (n = 21), 6 (29%) had confirmed objective response (OR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, and 11 (52%) had a clinical benefit response (CBR). Of all patients (n = 26), median progression-free survival (PFS) was 24.7 weeks, and 8 (31%) patients continued treatment without progression for 60 or more weeks (1). Methods: This international (29 countries; 356 proposed sites), phase 3, open-label, randomized, parallel-group clinical trial will evaluate whether PF-07220060 plus fulvestrant improves clinical outcomes compared with the investigator-chosen therapies in adult female and male patients with HR+/HER2− advanced/metastatic BC with progression after prior therapy of CDK4/6 inhibitor plus a nonsteroidal aromatase inhibitor.Key eligibility criteria include advanced/metastatic BC with measurable disease or non-measurable bone-only disease, documented HR+/HER2− status, and progressive disease/recurrence during or within 12 months after the last dose of prior CDK4/6 inhibitor given in the advanced or adjuvant setting, respectively. One additional prior line of approved treatment in the advanced setting targeting ESR1, PIK3CA, AKT1, PTEN, or BRCA is allowed. Approximately 500 patients will be randomly assigned (1:1) to receive PF-07220060 (orally and continuously in a 28-day cycle) plus fulvestrant (intramuscular injection on days 1 and 15 of cycle 1 and then on day 1 of each cycle thereafter) or investigator’s choice of fulvestrant alone or everolimus plus exemestane, which must be declared before randomization. The primary endpoint is PFS by blinded independent central review, which is defined as the time from the date of randomization to the date of first documented disease progression, as determined per RECIST v1.1, or death due to any cause, whichever occurs first. Secondary objectives include overall survival, OR, duration of response, CBR, safety, patient-reported outcomes, and pharmacokinetics. 1. Yap. JCO. 2023;41:3009. Clinical trial information: NCT06105632 .
Purpose
ENESTfreedom is evaluating treatment-free remission (TFR) following frontline nilotinib in patients with chronic myeloid leukemia (CML) in chronic phase. Following our primary analysis at 48 ...weeks, we here provide an updated 96-week analysis.
Methods
Attempting TFR required ≥ 3 years of nilotinib, a molecular response of MR
4.5
BCR-ABL1
≤ 0.0032% on the International Scale (
BCR-ABL1
IS
), and sustained deep molecular response (DMR) during a 1-year consolidation phase. Patients restarted nilotinib following loss of major molecular response (MMR;
BCR-ABL1
IS
≤ 0.1%).
Results
Ninety-six weeks after stopping treatment (3.6-year median prior nilotinib duration), 93 of 190 patients (48.9%) remained in TFR. Of 88 patients who restarted nilotinib following loss of MMR, 87 regained MMR and 81 regained MR
4.5
by the data cut-off. Ninety-six-week TFR rates were 61.3, 50.0, and 28.6% in patients with low, intermediate, and high Sokal risk scores at diagnosis, respectively. Patients consistently in MR
4.5
during consolidation had higher TFR rates (50.6%) than patients with ≥ 1 assessment without MR
4.5
during consolidation (35.0%). In a landmark analysis, 96-week TFR rates for patients with MR
4.5
, MR
4
(
BCR-ABL1
IS
≤ 0.01%) but not MR
4.5
, and MMR but not MR
4
at TFR week 12 were 82.6, 23.1, and 0%, respectively. There were no reports of disease progression or death due to CML; overall adverse event frequency decreased following TFR. Within the follow-up period, TFR did not adversely affect disease outcomes.
Conclusions
These results demonstrate the feasibility and durability of TFR following frontline nilotinib and emphasize the importance of sustained DMR for TFR.
Preclinically, AKT kinase inhibition restores drug sensitivity in platinum-resistant tumors. Here the pan-AKT kinase inhibitor afuresertib was given in combination with paclitaxel and carboplatin ...(PC) in patients with recurrent platinum-resistant epithelial ovarian cancer (PROC) and primary platinum-refractory ovarian cancer (PPROC).
Part I was a combination 3+3 dose escalation study for recurrent ovarian cancer. Patients received daily continuous oral afuresertib at 50-150 mg/day with intravenous paclitaxel (175 mg/m
) and carboplatin (AUC5) every 3 weeks for six cycles followed by maintenance afuresertib at 125 mg/day until progression or toxicity. Part II was a single-arm evaluation of the clinical activity of this combination in recurrent PROC (Cohort A) or PPROC (Cohort B). Patients received oral afuresertib at the MTD defined in Part I in combination with PC for six cycles, followed by maintenance afuresertib. Primary endpoints were safety and tolerability of afuresertib in combination with PC (Part I, dose escalation), and investigator-assessed overall response rate (ORR) as per RECIST version 1.1 (Part II).
Twenty-nine patients enrolled into Part I, and 30 into Part II. Three dose-limiting toxicities of grade 3 rash were observed, one at 125 mg and two at 150 mg afuresertib. The MTD of afuresertib in combination with PC was therefore identified as 125 mg/day. The most common (≥50%) drug-related adverse events observed in Part I of the study were nausea, diarrhea, vomiting, alopecia, fatigue, and neutropenia and, in Part II, were diarrhea, fatigue, nausea, and alopecia. The Part II ORR in the intention to treat patients was 32% 95% confidence interval (CI), 15.9-52.4 by RECIST 1.1 and 52% (95% CI, 31.3-72.2) by GCIG CA125 criteria. Median progression-free survival was 7.1 months (95% CI, 6.3-9.0 months).
Afuresertib plus PC demonstrated efficacy in recurrent PROC with the MTD of afuresertib defined as 125 mg/day.
Peripheral neuropathy is a common toxicity associated with tubulin-targeted chemotherapeutic agents. This Phase II study compares the incidence and severity of neuropathy associated with eribulin ...mesylate or ixabepilone in metastatic breast cancer (MBC). The primary objective was to assess the incidence of neuropathy; the study was designed to detect a difference in neuropathy rate of 35 % for eribulin versus 63 % for ixabepilone (odds ratio 0.316, 80 % power, 0.05 two-sided significance level). Eligibility criteria included: MBC; prior taxane therapy; at least one chemotherapy for advanced disease; no or minimal pre-existing neuropathy (Grade 0 or 1). The intent-to-treat population comprised 104 patients randomized (1:1) to eribulin mesylate (1.4 mg/m
2
, 2–5 min intravenous on days 1 and 8) or ixabepilone (40 mg/m
2
, 3 h intravenous on day 1) on a 21-day cycle. 101 patients in the safety population received a median of 5.0 eribulin and 3.5 ixabepilone cycles. Incidence of neuropathy (any grade) was 33.3 and 48.0 %, and peripheral neuropathy was 31.4 and 44.0 % for eribulin and ixabepilone, respectively. After controlling for pre-existing neuropathy and number of prior chemotherapies, these differences were not significant. Compared with ixabepilone, fewer patients receiving eribulin discontinued treatment due to neuropathy (3.9 vs. 18.0 %) or adverse events (AEs) in general (11.8 vs. 32.0 %). Time to onset of neuropathy was 35.9 weeks for eribulin and 11.6 weeks for ixabepilone, and time to resolution was 48 versus 10 weeks, respectively; other AEs were comparable. Objective responses were 15.4 versus 5.8 % and clinical benefit rates were 26.9 versus 19.2 %. In conclusion, after controlling for pre-existing neuropathy and number of prior chemotherapies, the differences in the incidence of neuropathy with eribulin and ixabepilone were not statistically significant. Onset of neuropathy tended to occur later with eribulin and resolve later.
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