Patients with myelofibrosis who were treated with ruxolitinib, a JAK1 and JAK2 inhibitor, showed significant responses with respect to spleen size and quality of life. No effect on overall survival ...was seen, but one third of the patients assigned to the best available therapy could not be evaluated.
Myelofibrosis, which can present as a primary disease or can evolve from polycythemia vera or essential thrombocythemia,
1
is characterized by marrow fibrosis, progressive anemia, and extramedullary hematopoiesis, manifested primarily as splenomegaly. Severe constitutional symptoms (e.g., night sweats and weight loss), pruritus, fatigue, and sequelae of splenomegaly are common.
2
The median survival from the time of diagnosis is 4 years for patients with intermediate-2–risk disease and 2 years for patients with high-risk disease.
3
Apart from allogeneic stem-cell transplantation, treatment is palliative and does not address the characteristic abnormality identified in myelofibrosis, a dysregulation of Janus kinase (JAK)–mediated cytokine and growth-factor signal . . .
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).
Ruxolitinib is a potent Janus kinase (JAK)1/JAK2 inhibitor that has demonstrated rapid reductions in splenomegaly and marked improvement in disease-related symptoms and quality of life in patients ...with myelofibrosis (MF). The present analysis reports the 3-year follow-up (median, 151 weeks) of the efficacy and safety of Controlled Myelofibrosis Study With Oral Janus-associated Kinase (JAK) Inhibitor Treatment-II (the COMFORT-II Trial), comparing ruxolitinib with the best available therapy (BAT) in 219 patients with intermediate-2 and high-risk MF. In the ruxolitinib arm, with continued therapy, spleen volume reductions of ≥35% by magnetic resonance imaging (equivalent to approximately 50% reduction by palpation) were sustained for at least 144 weeks, with the probability of 50% (95% confidence interval CI, 36-63) among patients achieving such degree of response. At the time of this analysis, 45% of the patients randomized to ruxolitinib remained on treatment. Ruxolitinib continues to be well tolerated. Anemia and thrombocytopenia were the main toxicities, but they were generally manageable, improved over time, and rarely led to treatment discontinuation (1% and 3.6% of patients, respectively). No single nonhematologic adverse event led to definitive ruxolitinib discontinuation in more than 1 patient. Additionally, patients randomized to ruxolitinib showed longer overall survival than those randomized to BAT (hazard ratio, 0.48; 95% CI, 0.28-0.85; log-rank test, P = .009). This trial was registered at clinicaltrials.gov as #NCT00934544.
Key Points
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Background: Neuregulin 1 (NRG1) fusion proteins have recently been identified as oncogenic drivers in diverse cancers with high unmet medical need. We recently reported promising ...responses in patients with cancers harboring NRG1 fusions treated with the bispecific antibody MCLA-128 (Schram 2019). The objective of this study was for the first time to quantitatively summarize the frequency of tumors harboring NRG1 fusions reported in the published literature. Methods: Neuregulin 1 (NRG1) fusion proteins have recently been identified as oncogenic drivers in diverse cancers with high unmet medical need. We recently reported promising responses in patients with cancers harboring NRG1 fusions treated with the bispecific antibody MCLA-128 (Schram 2019). The objective of this study was for the first time to quantitatively summarize the frequency of tumors harboring NRG1 fusions reported in the published literature. Results: Out of 212 articles identified in the literature as of 31-Jul-2019, 37 met the inclusion criteria and were abstracted. 13 different tumor types were identified as harboring NRG1 fusions including 5 tumor (sub)types which met the criteria for frequency meta-analysis (Table 1). NRG1 fusions were most frequent in pancreatic adenocarcinoma (3.3%, 95% confidence intervals (CI): 0.3-28.7%; apparent enrichment in KRAS WT) and NSCLC (0.8% 95% CI: 0.3-2.7%) with an enrichment in invasive mucinous adenocarcinoma (9.8%, 95% CI: 4.7-19.6%). Statistically significant heterogeneity was observed indicating substantial variation across studies in each analysis. For tumor types that did not meet the criteria for meta-analysis (uterine, renal cell, ovarian, colorectal, head and neck, bladder, prostate and sarcoma) the reported frequency of NRG1 fusions was typically less than 1%. Conclusions: NRG1 fusions are present across a wide range of different solid tumor types, most frequently in NSCLC and PDAC. NRG1 fusion-driven cancers represent a potential tumor-agnostic therapeutic target. The advent of new treatment options and increased genomic testing will allow a more precise estimation of the frequency of NRG1 fusions in cancer. Table: see text
The JAK1/JAK2 inhibitor ruxolitinib produced significant reductions in splenomegaly and symptomatic burden and improved survival in patients with myelofibrosis (MF), irrespective of their JAK2 ...mutation status, in 2 phase III studies against placebo (COMFORT-I) and best available therapy (COMFORT-II). We performed a comprehensive mutation analysis to evaluate the impact of 14 MF-associated mutations on clinical outcomes in 166 patients included in COMFORT-II. We found that responses in splenomegaly and symptoms, as well as the risk of developing ruxolitinib-associated anemia and thrombocytopenia, occurred at similar frequencies across different mutation profiles. Ruxolitinib improved survival independent of mutation profile and reduced the risk of death in patients harboring a set of prognostically detrimental mutations (ASXL1, EZH2, SRSF2, IDH1/2) with an hazard ratio of 0.57 (95% confidence interval: 0.30-1.08) vs best available therapy. These data indicate that clinical efficacy and survival improvement may occur across different molecular subsets of patients with MF treated with ruxolitinib.
•Improvements in splenomegaly and symptoms in patients receiving ruxolitinib occurred regardless of the mutations that were present.•Ruxolitinib relieved the negative impact of prognostically detrimental mutations in myelofibrosis patients from the COMFORT-II study.
Proportional hazards are a common assumption when designing confirmatory clinical trials in oncology. This assumption not only affects the analysis part but also the sample size calculation. The ...presence of delayed effects causes a change in the hazard ratio while the trial is ongoing since at the beginning we do not observe any difference between treatment arms, and after some unknown time point, the differences between treatment arms will start to appear. Hence, the proportional hazards assumption no longer holds, and both sample size calculation and analysis methods to be used should be reconsidered. The weighted log‐rank test allows a weighting for early, middle, and late differences through the Fleming and Harrington class of weights and is proven to be more efficient when the proportional hazards assumption does not hold. The Fleming and Harrington class of weights, along with the estimated delay, can be incorporated into the sample size calculation in order to maintain the desired power once the treatment arm differences start to appear. In this article, we explore the impact of delayed effects in group sequential and adaptive group sequential designs and make an empirical evaluation in terms of power and type‐I error rate of the of the weighted log‐rank test in a simulated scenario with fixed values of the Fleming and Harrington class of weights. We also give some practical recommendations regarding which methodology should be used in the presence of delayed effects depending on certain characteristics of the trial.
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Background: The WNT and EGFR signaling pathways are oncogenic and mitogenic drivers in CRC and other cancers. MCLA-158 is an ADCC enhanced human IgG1 cLC bispecific antibody ...identified from functional screening of CRC patient (pt)-derived organoids (PDO). MCLA-158 exposure leads to EGFR degradation in LGR5+ cancer and exhibits potent growth inhibition of RASmut and wt CRC PDOs, while minimal inhibition is observed in non-tumoral PDOs. Blockade of metastasis initiation was seen in preclinical in vivo models. MCLA-158 also demonstrated tumor regression or stasis in esophageal squamous (6/6) and gastric adenocarcinoma (6/8) PDX models selected for LGR5 and EGFR expression. Methods: Metastatic CRC pts progressing after oxaliplatin, irinotecan and fluoropyrimidines, and EGFR monoclonal antibodies if RASwt, received MCLA-158 IV every 2 weeks (q2w; 4-week cycle) in a phase I study. Safety, efficacy (per RECIST 1.1), PK and ADA were assessed. WNT and EGFR pathway components were evaluated in tumor tissue. EGFR pathway mutations (ctDNA) and soluble EGFR (sEGFR) were assessed in blood. PDOs were derived from baseline biopsies and assessed for MCLA-158 responsiveness. Results: As of 7 September 2020, 33 pts were treated over 11 dose levels (5 to 1500 mg, flat dose). At enrollment, median age was 58 years (range 35-76), ECOG PS 0/1:22/11, and 15 pts were RASmut. Pts had a median of 3 metastatic sites (range 1-12) with a median of 4 prior lines of therapy (range 1-10). A median of 2 MCLA-158 cycles (range 1-6) were administered. No dose limiting toxicity occurred. Infusion-related reactions were the most common AEs (67% of pts), occurred mostly in cycle 1 (21/22 pts), and were manageable. Other common related AEs included rash acneiform (36%), diarrhea (15%), pyrexia (9%) and asthenia/fatigue (9%). Related AEs were mostly mild or moderate; G3 related AEs were IRRs (4 pts; 12%), diarrhea and hypophosphatemia (1 pt each). The RP2D (1500 mg) was selected based on safety, PK and receptor occupancy prediction. MCLA-158 exhibited target-mediated clearance with proportional PK from 750 mg (t
1/2
~80 h at 1500 mg). Low ADA titers were seen in 3/23 pts, with no effect on PK. Target saturation is predicted at steady state serum trough levels. No clinical responses were observed during dose escalation. No/low baseline tumor EGFR expression (0-1+ IHC) was observed in 17/30 pts and non-elevated sEGFR levels ( < 4 ng/mL) in 18/22 pts. More than 1 activating mutation in EGFR signaling pathway genes were identified in ctDNA from 10/20 pts. 1/4 PDOs had > 30% growth inhibition with MCLA-158 ex vivo. MCLA-158 activity on PDOs correlated negatively with the presence of EGFR pathway resistance-mutations. Conclusions: Dual EGFR/LRG5 blockade with MCLA-158 was well tolerated, and the RP2D was 1500 mg IV q2w. Enrollment of pts with gastric and other non-CRC cancers at the RP2D continues in the expansion phase. Clinical trial information: NCT03526835.
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