Increased Blood Creatine Phosphokinase Research Articles

Phase 2 Trial of Single-Agent Cobimetinib for Adults with Histiocytic Neoplasms

Background: Histiocytic neoplasms (HN) are clonal hematopoietic disorders characterized by diverse mutations in the mitogen-activated protein kinase (MAPK) pathway. BRAF inhibition is highly effective for patients with HN harboring the BRAFV600E mutation, and implementation of BRAF inhibitors transformed management of BRAFV600E-mutated Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis (LCH). No standard or approved therapies existed, however, for patients with HN lacking the BRAFV600E mutation. Efficacy of mitogen-activated protein kinase (MEK) inhibition for HN harboring various MAPK pathway mutations has been observed in case reports and series. We present here results from 26 patients treated in a phase 2 trial of single-agent cobimetinib for adults with HN (NCT02649972). The data were submitted to the Food and Drug Administration (FDA) in a supplemental new drug application for cobimetinib, and FDA approval was granted in October, 2022. Methods: This is an open-label phase 2 trial of cobimetinib 60mg daily for patients with (1) BRAFV600-wildtype (wt) histiocytosis or (2) BRAFV600-mutant histiocytosis intolerant or without access to BRAF inhibitor therapy. Eligible patients were age 16 or older, had histologic confirmation of HN diagnosis, ECOG 0 to 3, multi-system HN or HN refractory to conventional (i.e. chemotherapeutic or immunosuppressive) therapy or single-system HN deemed unlikely to benefit from conventional therapy, and with disease measurable by positron emission tomography (PET) Response Criteria (PRC). Patients were eligible with any tumor mutation or with no identified tumor mutation. The primary endpoint was overall response rate (complete metabolic response + partial metabolic response; ORR) by PRC. Secondary endpoints included safety (CTCAE 4.0), duration of response (DoR) and progression-free survival (PFS) as determined by modified PERCIST, overall survival (OS), and response rate by RECIST. Data cut-off was March 28, 2019 for efficacy evaluation, and safety follow-up cut-off was September 28, 2019. Results: Twenty-six patients (13 ECD, with Rosai-Dorfman disease [RDD], 4 with LCH, 2 with juvenile xanthogranuloma [JXG], 3 with mixed histiocytosis) with a median age of 50.5 were analyzed. Six patients had BRAFV600E-mutant disease, one of these with additional mutations in KRAS and NRAS. Of the remaining 20, 15 had non-BRAFV600 MAPK pathway mutations (4 KRAS [one of them with ARAF mutation as well], 6 MEK1, 1 MEK2, 1 RAF1, 1 ARAF, 2 non-V600 BRAF mutations, and 5 had no mutation identified). Twenty-six patients were evaluable for safety, 24 for PRC, 19 for RECIST. Response rates are listed in Table 1 and PRC responses are presented in Figure 1. The ORR by PRC was 83.3% (95% CI 62.62-95.26), in the PRC-evaluable population. Responses were observed across MAPK mutations, histiocytosis subtypes and tumor genotypes. By BRAFV600 status, in PRC-evaluable population, the ORR for BRAFV600E-mutant disease was 100% (95% CI 47.82-100), and for BRAFV600-wt disease was 78.9% (95% CI 54.43-93.95). Median DoR was 31.1 months (95% CI 16.8-NE) in the PRC-evaluable population. ORR by RECIST was 63.2% (95% CI 38.36-83.71), in the RECIST-evaluable population. Three patients died on study, none related to cobimetinib. Grade 3 or 4 toxicities in >10% of patients included decreased lymphocyte count (19%), increased blood creatine phosphokinase (12%), decreased ejection fraction (12%), hypokalemia (12%), hyponatremia (12%), acute kidney injury (12%) and dyspnea (12%). Conclusions: Cobimetinib demonstrates robust efficacy in HN irrespective of underlying MAPK pathway mutation, including BRAF-wt and BRAFV600-mutant HN. Safety of cobimetinib in this patient population was consistent with the known safety profile.

Phase 1b study of HS-10241 combined with almonertinib in pre-treated advanced non-small cell lung cancer (NSCLC) harboring EGFR mutation.

e21134 Background: MET gene amplification is one of the most frequent acquired resistance mechanisms following prior EGFR-TKI monotherapy. HS-10241, an oral and highly selective MET-TKI, may contribute to overcoming common acquired MET-based resistance mechanisms. Here, we reported the preliminary safety and efficacy data of HS-10241 with almonertinib in treatment of advanced NSCLC with EGFR mutation. Methods: This Ph1b study (NCT05430386) was composed of dose escalation part (Part 1) and dose expansion part (Part 2). In Part 1, patients (pts) with EGFR-mutated advanced NSCLC upon disease progression on EGFR-TKI received HS-10241 (BID) plus almonertinib (110 mg QD), and HS-10241 was escalated at 200 mg and 300 mg using a rolling six design. Based on the available data of Part 1, an expansion cohort was opened at HS-10241 300 mg BID with almonertinib 110mg QD to enroll pts with EGFR mutation centrally confirmed and MET-amplification detected by central FISH (MET gene copy number[GCN] ≥5 and/or MET:CEP7 signal ratio ≥2). Results: As of 16 December 2022, 10 pts in part 1, 4 pts at 200 mg and 6 pts at 300 mg HS-10241, and 35 pts in part 2 were enrolled into this study. Of these pts, 13 (28.9%) pts received previous treatment with 1st or 2nd-generation but no 3rd-generation EGFR TKI, 15 (33.3%) pts received 3rd-generation EGFR-TKI only and 15 (33.3%) pts received both 1st/2nd and 3rd-generation EGFR TKIs, whether or not they received treatment with chemotherapy. Only one dose-limiting toxicity (grade 2 Nausea with grade 2 vomiting leading to discontinuation≥14 days) was reported in the cohort with HS-10241 300 mg. The MTD was not reached. Treatment-emergent adverse events (TEAEs) occurred in 41/45 (91.1%) pts. The most common TEAEs (≥ 20%) were increased AST, increased ALT, vomiting, nausea, increased blood creatine phosphokinase, thrombocytopenia, decreased appetite, and increased GGT. Among all the pts, 22 pts with EGFR mutation regardless of the MET gene status were evaluable for efficacy, 12 of which achieved partial response (response rate 54.5%; 8 confirmed PR), and 7 had stable disease (SD). Of the 13 pts who had centrally confirmed EGFR mutation and MET-amplification (6 with GCN ≥10, and 7 with GCN ≥5 but < 10), 8 had PR (response rate 61.5%; 5 confirmed PR), and 4 had SD. Among the 8 pts achieving PR, there were 4 with GCN ≥10, and 4 with GCN ≥5 but < 10.Moreover, 9 of the 13 pts received both 1st/2nd and 3rd-generation EGFR-TKI and there were 6 PRs (response rate 66.7%;3 confirmed PR) and 2 SDs. Pharmacokinetics analysis showed low risk of potential drug-drug interactions on HS-10241 combined with almonertinib. Conclusions: HS-10241 in combination with almonertinib was well tolerated, and showed encouraging antitumor activity in treatment of advanced NSCLC with EGFR mutation and MET amplification following prior EGFR-TKI, whether MET GCN ≥10 or MET GCN ≥5 but < 10. Clinical trial information: NCT05430386 .

Efficacy and safety of tunlametinib in patients with advanced NRAS-mutant melanoma: A multicenter, open-label, single-arm, phase 2 study.

9510 Background: NRAS-mutant melanoma is an aggressive subtype with worse prognosis. However, no targeted therapy has been approved to date worldwide. Tunlametinib (HL-085), a novel, potent, selective, oral small-molecule MEK1/2 inhibitor, has showed a favorable pharmacokinetics profile, acceptable tolerability and encouraging antitumor activity in the phase 1 study (BMC Med. 2023 Jan 4;21(1):2). Methods: This is an ongoing, multicenter, open-label, single-arm, phase 2 pivotal registration study. Patients (pts) with NRAS-mutant unresectable stage III or IV melanoma were enrolled and received tunlametinib 12 mg orally twice daily. A historical control of objective response rate (ORR) of 10% was predefined for sample size estimation (100 pts, assuming loss to follow-up rate of 5%) and efficacy evaluation. The primary endpoint was the confirmed ORR per RECIST v1.1 assessed by independent radiology review committee. Results: A total of 100 pts were enrolled. All pts were included in the safety analysis set and 95 pts were included in the full analysis set (FAS) for efficacy analysis. At cut-off date (August 17, 2022), median follow-up was 7.9 months (95% CI: 6.6, 9.8). In the FAS, the median age was 58.0 years (range: 24 to 84). Sixty-four pts (67.4%) had received prior immunotherapy (PD-1/PD-L1 inhibitor). Fifty-six pts (58.9%) were acral melanoma, 16 (16.8%) mucosal melanoma and 12 (12.6%) skin melanoma. Fourteen pts (14.7%) were stage III and 81 (85.3%) stage IV. The most frequent NRAS mutation types were Q61R (40.0%), Q61K (29.5%) and G12D (9.5%). Confirmed ORR was 34.7% (95%CI: 25.3%, 45.2%). Median progression-free survival was 4.2 months (95%CI: 3.5, 5.6), overall survival was immature, and 1-year survival rates was 57.2% (95% CI, 44.7%, 67.8%). Subgroup analysis showed that, in pts who had previously received immunotherapy, the confirmed ORR was 39.1% (95% CI: 27.1%, 52.1%). The most frequent treatment related adverse events (TRAEs) were increased blood creatine phosphokinase (CK), diarrhea, peripheral oedema, facial oedema and increased aspartate aminotransferase. Grade ≥3 TRAEs occurred in 68 pts (68.0%), of which 38.0% (38/100) were increased blood CK. Most of pts with CK elevation are asymptomatic and can be managed by dose interruption or reduction without permanent treatment discontinuation. No treatment-related death was reported. Conclusions: Tunlametinib was well tolerated and demonstrated encouraging treatment response rate in pts with advanced NRAS-mutant melanoma. These results indicate that tunlametinib could be a promising treatment option for NRAS-mutant melanoma, even for those immunotherapy failed pts. Clinical trial information: NCT05217303 .

A multicenter, open-label, single-arm phase 1/2 study to evaluate the safety and efficacy of FCN-159 in pediatric participants with neurofibromatosis type 1.

10023 Background: Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disease characterized by multiple progressive tumor and non-tumor manifestations, with abnormal activating MAPK pathway. Plexiform neurofibromas (PN) presents in 20-50% of NF1 patients (pts) and may cause serious complications. Selumetinib was approved for pediatric pts with NF1-related PN in US and EU, but therapeutic options remain limited in China. FCN-159 is a highly potent selective anti-tumorigenic inhibitor of MEK1/2, potentially effective in NF1-related PN. Methods: This multi-center, open-label phase1/2 clinical trial is the first-in human study to assess safety and efficacy in pediatric pts with NF1-related PN. The primary objective was to determine the dose limiting toxicity (DLT) and recommended phase 2 dose (RP2D) in the dose escalation, followed by a dose expansion phase 2 to evaluate safety and efficacy. The starting dose in pediatric pts was determined according to the adults in the dose-escalation phase (previously published in ASCO 2022, abstract no. 3011). Here, we first present the safety and efficacy results in pediatric participants. Results: As of data cut-off (November 21, 2022), 65 pts were enrolled, 19 pts in phase 1 and 45 pts in phase 2. A dose of 4 mg/m2 (10 pts) and 5 mg/m2 (9 pts) were evaluated in phase 1 and no DLT was observed. Pediatric pts in the 5 mg/m2 cohort achieved similar exposure to the 8 mg adult cohort. AUC simulation from population PK model at different BSA ranges were also similar to the adults of 8 mg. Therefore, the RP2D was determined to be 5 mg/m2.Treatment-emergent adverse events (TEAEs) were reported in 62 pts (95.4%). Common TEAEs (≥ 20%) were mouth ulcer (43.1%), sinus arrhythmia (36.9%), upper respiratory tract infection (35.4%), folliculitis (21.5%), paronychia (21.5%), and increased blood creatine phosphokinase (20%). 5 pts (7.7%) experienced grade ≥3 treatment-related AEs (TRAEs), including 2 pts (2/10, 10%) in the 4 mg/m2 group and 3 pts (3/55, 5.5%) in the 5 mg/m2 group. Grade 3 TRAEs were increased aspartate aminotransferase (1.5%), electrocardiogram QT prolongation (1.5%), folliculitis (3.1%), and dermatitis acneiform (1.5%). No grade ≥ 4 TRAEs were observed. 2 pts (3.1%) reported treatment-related serious adverse events (one case of rhabdomyolysis and dermatitis acneiform each). TEAEs led to dose interruption (26.2%), and discontinuation (1.5%). No reported TEAE led to dose reduction or death. Of the 19 pts with at least one tumor assessment data after baseline, 8 (42%) pts had partial response, 11 (57.8%) with stable disease and none with disease progression. The median DOR could not be evaluated. Conclusions: Overall, FCN-159 was well-tolerated and demonstrated promising anti-tumor activity in pediatric participants with NF1-related PN. Long-term efficacy and safety follow-up are ongoing. Clinical trial information: NCT04954001 .

Integrated efficacy and safety of brigatinib in patients with ALK TKI-naive advanced ALK+ NSCLC in the ALTA-1L and J-ALTA studies.

9078 Background: Brigatinib demonstrated efficacy and manageable safety in patients (pts) with anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI)-naive ALK+ non-small cell lung cancer (NSCLC) in phase 3 (ALTA-1L) and phase 2 (J-ALTA) trials. We present results of integrated efficacy and safety analyses of ALTA-1L and J-ALTA. Methods: ALTA-1L (NCT02737501) and J-ALTA (NCT03410108; conducted in Japan) were open-label, multicenter studies in pts with advanced or metastatic ALK+ NSCLC. Pts in ALTA-1L and in part 3 of J-ALTA were ALK TKI-naive. Stable or asymptomatic brain metastases were allowed in both studies. Pts received brigatinib 180 mg qd (7-day lead-in at 90 mg). Primary endpoints were blinded independent review committee (IRC)-assessed progression-free survival (PFS) in ALTA-1L and IRC-assessed 12-month PFS in the J-ALTA ALK TKI-naive cohort (both per RECIST v 1.1). Secondary endpoints included IRC-assessed objective response rate (ORR), duration of response, intracranial ORR, intracranial PFS, overall survival, and safety. Pooled efficacy and safety data from both studies are presented. Results: The pooled analysis population included 169 pts (ALTA-1L, N = 137; J-ALTA ALK TKI-naive cohort, N = 32). Median follow-up overall was 35.8 months (last pt last contact: ALTA-1L, January 2021; J-ALTA, July 2021). Most (66%) pts were aged < 65 years, 24% had baseline brain metastases, 95% had stage IV disease at study entry, and 21% had received prior chemotherapy for locally advanced or metastatic disease. With brigatinib treatment, median PFS by IRC was 29.3 months (95% CI, 23.9‒44.7). The confirmed ORR was 79% (95% CI, 72‒85%), with 36 complete responses and 97 partial responses. Median duration of response was 38.1 months (95% CI, 22.9‒not reached). Median overall survival was not reached; the 3-year survival rate was 74% (95% CI: 66‒80%; 84 pts at risk). Intracranial ORR and intracranial PFS will be presented. Grade 3/4 treatment-emergent adverse events were reported in 74% of pts; the most common were increased blood creatine phosphokinase (31%), hypertension (18%), and increased lipase (16%). Any grade interstitial lung disease/pneumonitis was reported in 12 (7%) of pts. Adverse events led to treatment discontinuation in 11% of pts. Conclusions: Brigatinib treatment demonstrated clinically meaningful systemic and intracranial efficacy in this integrated analysis of pts with ALK TKI-naive advanced or metastatic ALK+ NSCLC in the ALTA-1L or J-ALTA trials. Safety results were consistent with the known profile for brigatinib, with no new safety findings. Clinical trial information: NCT02737501 ; NCT03410108 .

Efficacy and safety of baricitinib in Japanese patients with autoinflammatory type I interferonopathies (NNS/CANDLE, SAVI, And AGS)

BackgroundThis study evaluated the efficacy and safety of baricitinib (Janus kinase-1/2 inhibitor), in adult and pediatric Japanese patients with Nakajo-Nishimura syndrome/chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (NNS/CANDLE), stimulator of interferon genes-associated vasculopathy with onset during infancy (SAVI), or Aicardi-Goutières syndrome (AGS).MethodsA Phase 2/3, multicenter, open-label study (NCT04517253) was conducted across 52 weeks. Primary efficacy endpoint assessed the change in mean daily diary score (DDS) from baseline to the end of primary treatment period. Other efficacy endpoints included change in mean DDS to the end of maintenance period, daily corticosteroid use, Physician’s Global Assessment of Disease Activity (PGA) scores, and daily symptom-specific score (DSSS) from baseline to primary and maintenance treatment periods. All treatment-emergent adverse events (TEAEs) that occurred postdosing were recorded.ResultsOverall, 9 patients (5 with NNS, 3 with SAVI, and 1 with AGS) were enrolled; 55.6% were females, mean age was 26 years, and mean corticosteroid use/weight was 0.2 mg/kg. At the end of primary treatment period, mean DDS decreased from baseline in patients with NNS/CANDLE (0.22) and SAVI (0.21) and increased in the patient with AGS (0.07). At the end of maintenance treatment period, mean DDS decreased from baseline in patients with NNS/CANDLE (0.18) and SAVI (0.27) and increased in the patient with AGS (0.04). Mean percent corticosteroid use decreased by 18.4% in 3 out of 5 patients with NNS/CANDLE and 62.9% in 1 out of 3 patients with SAVI. Mean PGA score decreased from baseline in patients with NNS/CANDLE (1.60), SAVI (1.33), and AGS (1.0), and mean DSSS improved from baseline. All patients reported ≥ 1 TEAE. Frequently reported AEs included BK polyomavirus detection (3; 33.3%), increased blood creatine phosphokinase (2; 22.2%), anemia (2; 22.2%), and upper respiratory tract infection (2; 22.2%). Three (33.3%) patients reported serious adverse events, 1 of which was related to study drug. One patient with SAVI died due to intracranial hemorrhage, which was not related to study drug.ConclusionBaricitinib may offer a potential therapeutic option for patients with NNS/CANDLE, SAVI, and AGS, with a positive benefit/risk profile in a vulnerable patient population with multiple comorbidities.Trial registrationNLM clinicaltrials.gov, NCT04517253. Registered 18 August 2020.

Efficacy and safety of tafolecimab in Chinese patients with heterozygous familial hypercholesterolemia: a randomized, double-blind, placebo-controlled phase 3 trial (CREDIT-2)

BackgroundHeterozygous familial hypercholesterolemia (HeFH) is largely underdiagnosed and undertreated in China where few patients achieved recommended target levels of low density lipoprotein cholesterol (LDL-C). We conducted the first randomized, placebo-controlled clinical trial in Chinese patients with HeFH to assess the efficacy and safety of tafolecimab, a novel fully human proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibody.MethodsPatients diagnosed with HeFH by Simon Broome criteria and on a stable lipid-lowering therapy for at least 4 weeks were randomized 2:2:1:1 to receive subcutaneous tafolecimab 150 mg every 2 weeks (Q2W), tafolecimab 450 mg every 4 weeks (Q4W), placebo Q2W or placebo Q4W in the 12-week double-blind treatment period. After that, participants received open-label tafolecimab 150 mg Q2W or 450 mg Q4W for 12 weeks. The primary endpoint was the percent change from baseline to week 12 in LDL-C levels. Secondary endpoints included proportion of participants achieving ≥50% LDL-C reductions and proportion of participants with LDL-C <1.8 mmol/L at week 12 and 24, the change from baseline to week 12 in non-high density lipoprotein cholesterol (non-HDL-C), apolipoprotein B and lipoprotein(a) levels, as well as the change from baseline to week 24 in lipid levels.ResultsIn total, 149 participants were randomized and 148 received at least one dose of the study treatment. At week 12, tafolecimab treatment induced significant reductions in LDL-C levels (treatment difference versus placebo [on-treatment estimand]: −57.4% [97.5% CI, −69.2 to −45.5] for 150 mg Q2W; −61.9% [−73.4 to −50.4] for 450 mg Q4W; both P <0.0001). At both dose regimens, significantly more participants treated with tafolecimab achieved ≥50% LDL-C reductions or LDL-C <1.8 mmol/L at week 12 as compared with corresponding placebo groups (all P <0.0001). Meanwhile, non-HDL-C, apolipoprotein B and lipoprotein(a) levels were significantly reduced in the tafolecimab groups at week 12. The lipid-lowering effects of tafolecimab were maintained till week 24. During the double-blind treatment period, the most commonly-reported adverse events in the tafolecimab groups included upper respiratory tract infection, increased blood creatine phosphokinase, increased alanine aminotransferase, increased aspartate aminotransferase and hypertension.ConclusionsTafolecimab administered either 150 mg Q2W or 450 mg Q4W yielded significant and persistent reductions in LDL-C levels and showed a favorable safety profile in Chinese patients with HeFH.Trial registrationClinicalTrials.gov, NCT04179669.

Overall survival with first-line atezolizumab in combination with vemurafenib and cobimetinib in BRAFV600 mutation-positive advanced melanoma (IMspire150): second interim analysis of a multicentre, randomised, phase 3 study

Primary analysis of the phase 3 IMspire150 study showed improved investigator-assessed progression-free survival with first-line atezolizumab, vemurafenib, and cobimetinib (atezolizumab group) versus placebo, vemurafenib, and cobimetinib (control group) in patients with BRAFV600 mutation-positive melanoma. With a median follow-up of 18·9 months (IQR 10·4-23·8) at the primary analysis, overall survival data were immature. Here, we report the results from the second, prespecified, interim overall survival analysis. The multicentre, double-blind, placebo-controlled, randomised, phase 3 IMspire150 study was done at 108 academic and community hospitals in 20 countries. Patients aged 18 years or older with previously untreated unresectable stage IIIc or stage IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible for inclusion. Patients were randomly assigned (1:1) to receive either atezolizumab (840 mg intravenously on day 1 and 15) or placebo plus vemurafenib (960 mg or 720 mg twice daily orally) and cobimetinib (60 mg once daily orally; 21 days on and 7 days off) in 28-day cycles. Atezolizumab and placebo were added to treatment regimens from cycle two onwards. Randomisation was done centrally (Durham, NC, USA) based on a permuted block randomisation scheme (block size of 4) using an interactive web-based response system and was stratified by geographical region and baseline lactate dehydrogenase concentration. Overall survival was analysed in the intention-to-treat population and safety was analysed in all patients who received at least one dose of study drug according to actual treatment received. The primary endpoint was investigator-assessed progression-free survival, which was previously reported. Here, we report the second, prespecified, interim overall survival analysis, which was planned after about 270 overall survival events had occurred. The trial is ongoing, but is no longer enrolling patients, and it is registered with ClinicalTrials.gov, NCT02908672. Between Jan 13, 2017, and April 26, 2018, 514 patients (median age 54 years [IQR 43-63]; 299 [58%] men and 215 [42%] women) were enrolled in the trial and randomly assigned to the atezolizumab group (256 [50%] patients) or the control group (258 [50%] patients). At the data cutoff (Sept 8, 2021), 273 patients had died (126 in the atezolizumab group and 147 in the control group). Median follow-up was 29·1 months (IQR 10·1-45·4) for the atezolizumab group versus 22·8 months (10·6-44·1) for the control group. Median overall survival was 39·0 months (95% CI 29·9-not estimable) in the atezolizumab group versus 25·8 months (22·0-34·6) in the control group (HR 0·84 [95% CI 0·66-1·06]; p=0·14). The most common adverse events of any grade in the atezolizumab group were blood creatine phosphokinase increased (123 [53%] of 231 patients), diarrhoea (116 [50%]), and pyrexia (115 [50%]). The most common adverse events of any grade in the control group were diarrhoea (157 [56%] of 280 patients), blood creatine phosphokinase increased (135 [48%]), and rash (119 [43%]). The most common grade 3-4 adverse events were increased lipase (54 [23%] of 231 patients in the atezolizumab group vs 62 [22%] of 280 patients in the control group), increased blood creatine phosphokinase (51 [22%] vs 50 [18%]), and increased alanine aminotransferase (32 [14%] vs 26 [9%]). Serious adverse events were reported in 112 (48%) patients in the atezolizumab group and 117 (42%) patients in the control group. Grade 5 adverse events were reported in eight (3%) patients in the atezolizumab group versus six (2%) patients in the control group. Two grade 5 adverse events (hepatitis fulminant and hepatic failure) in the atezolizumab group were considered to be associated with the triplet combination, and one event in the control group (pulmonary haemorrhage) was considered to be associated with cobimetinib. Additional follow-up of the IMspire150 trial showed that overall survival was not significantly improved with atezolizumab, vemurafenib, and cobimetinib compared with placebo, vemurafenib, and cobimetinib in patients with BRAFV600 mutation-positive advanced melanoma. Results of the final analysis are awaited to establish whether a significant improvement in overall survival can be achieved with long-term treatment with this triplet combination versus vemurafenib plus cobimetinib. F Hoffmann-La Roche.

Updated Results from an Open-Label Phase 1/2 Study of Favezelimab (anti-LAG-3) Plus Pembrolizumab in Relapsed or Refractory Classical Hodgkin Lymphoma

Background: PD-1 inhibitors play a key role in the treatment of relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL) but improving upon current treatment responses remain of clinical interest. Lymphocyte-activation gene 3 (LAG-3) is involved in T-cell regulation and is commonly coexpressed with PD-1 on anergic T cells. Dual blockade of PD-1 and LAG-3 has demonstrated antitumor activity leading to US Food and Drug Administration approval for the treatment of patients with unresectable or metastatic melanoma. Favezelimab (MK-4280), a humanized IgG4 LAG-3 inhibitor, plus pembrolizumab (anti-PD-1) is being investigated in the multicohort phase 1/2 MK-4280-003 efficacy and safety study (NCT03598608) in patients with R/R hematologic malignancies. Initial results from the MK-4280-003 study demonstrated promising antitumor activity and acceptable safety in anti-PD-1-naive patients with R/R cHL (cohort 1) (Johnson NA, et al. J Clin Oncol. 2022;40(16_suppl):7516). Updated results from cohort 1 after additional follow-up are presented. Methods: Part 1 was the safety lead-in phase to determine the recommended phase 2 dose (RP2D) followed by a dose-expansion phase (part 2). Eligible patients in cohort 1 had R/R cHL after autologous stem cell transplantation (ASCT) or were ineligible for ASCT, and had no prior anti-PD-1 therapy. Part 1 included patients from all cohorts who received escalating doses (per modified toxicity probability index interval design) of pembrolizumab IV 200 mg Q3W and favezelimab IV 200 mg or 800 mg Q3W. In part 2, patients received pembrolizumab plus favezelimab at the established RP2D (800 mg Q3W) for ≤35 cycles (~2 years). CT scans were performed every Q12W and PET scans at Weeks 12 and 24 to assess response by investigator review per the IWG 2007 criteria. Adverse events (AE) were graded per the NCI CTCAE, v4.0. The primary end points were safety and RP2D. Objective response rate (ORR) was a secondary end point. Duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were exploratory end points. Results: Among the 30 patients enrolled in cohort 1, the median age was 40.5 years, 53% had ECOG PS 0, and 80% had ≤3 prior lines of therapy. At database cutoff (May 03, 2022), 6 (20%) patients had completed 2 years of study treatment and 13 (43%) patients had discontinued (9 progressive disease; 4 AEs); 4 (13%) patients discontinued due to treatment-related adverse events [TRAEs]); 11 (37%) patients had treatment ongoing at the time of database cutoff. No deaths were treatment-related. Among the 26 patients (87%) who had TRAEs; the most common (≥10%) were hypothyroidism (27%); infusion-related reaction (23%), fatigue (20%); pruritus and headache (17% each), chills (13%); arthralgia, hyperthyroidism, maculopapular rash, myalgia, nausea and pyrexia (10%, each). Grade 3 or 4 TRAEs occurred in 7 patients (23%); including 1 (3%) event each of thrombocytopenia, enterocolitis, fatigue, autoimmune hepatitis, increased blood creatine phosphokinase, increased amylase, increased lipase, organizing pneumonia, and maculopapular rash. Of 3 patients who received hematopoietic stem cell transplantation after completion of study treatment, 1 had a grade 3 or 4 AE unrelated to study treatment (increased blood bilirubin) that resolved. After a median follow-up of 15.5 months, 22 patients had objective response (ORR, 73% [95% CI, 54-88]; complete response, 9 [30%]; partial response, 13 [43%]). Of 29 patients (97%) who received a postdose scan, 28 had a baseline reduction in target lesions and 23 (79%) had ≥50% reduction from baseline (Figure). Median DOR was not reached (NR; range, 2.6-28.8+ months); 7 patients (56%) had response ≥12 months. Median PFS was 19.4 months (95% CI, 8.5-NR); 12-month PFS rate was 62%. Median OS was NR (95% CI, NR-NR); 12-month OS rate was 96%. Conclusion: After additional follow-up, favezelimab plus pembrolizumab combination therapy continued to demonstrate sustained antitumor activity and acceptable safety in anti-PD-1-naive patients with R/R cHL. Further studies comparing the activity of this combination to that of single-agent pembrolizumab would be of clinical benefit. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Brigatinib in Japanese patients with tyrosine kinase inhibitor-naive ALK-positive non-small cell lung cancer: first results from the phase 2 J-ALTA study

BackgroundWe evaluated the safety and efficacy of the anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) brigatinib in Japanese patients with TKI-naive ALK-positive non-small cell lung cancer (NSCLC) from the phase 2, open-label, single-arm, multicenter J-ALTA study.MethodsIn the TKI-naive cohort of J-ALTA, the primary end point was independent review committee (IRC)-assessed 12-month progression-free survival (PFS). Secondary end points included objective response rate (ORR), intracranial response, overall survival (OS), and safety.ResultsThe data were cut approximately 12 months after last patient enrollment. Thirty-two patients with ALK TKI-naive ALK-positive NSCLC were enrolled (median age [range], 60.5 [29–85] years; median duration of follow-up, 14.2 [3.2–19.3] months; median treatment duration, 13.8 [0.4–19.3] months). IRC-assessed 12-month PFS was 93.0% (90% confidence interval (CI) 79.2–97.8%); ORR, 96.9% (95% CI 83.8–99.9%), 12-month OS, 96.9% (95% CI 79.8–99.6%), and median OS was not reached. Of five patients with measurable baseline CNS metastases, two had partial intracranial response. The most common treatment-emergent adverse events were increased blood creatine phosphokinase (81%), hypertension (59%), and diarrhea (47%). Grade ≥ 3 adverse events occurred in 91% of patients; pneumonitis was reported in 3 (9%) patients.ConclusionsIn the J-ALTA TKI-naive cohort, brigatinib demonstrated clinically meaningful efficacy consistent with the international phase 3 study. The safety profile in Japanese patients was consistent with previous studies. Brigatinib is an important first-line option for Japanese patients with ALK-positive NSCLC.Clinical registrationNCT03410108

Safety and efficacy of pralsetinib in RET fusion–positive non-small-cell lung cancer including as first-line therapy: update from the ARROW trial

RET fusions are present in 1%-2% of non-small-cell lung cancer (NSCLC). Pralsetinib, a highly potent, oral, central nervous system-penetrant, selective RET inhibitor, previously demonstrated clinical activity in patients with RET fusion-positive NSCLC in the phase I/II ARROW study, including among treatment-naive patients. We report an updated analysis from the ARROW study. ARROW is a multi-cohort, open-label, phase I/II study. Eligible patients were ≥18 years of age with locally advanced or metastatic solid tumours and an Eastern Cooperative Oncology Group performance status of 0-2 (later 0-1). Patients initiated pralsetinib at the recommended phase II dose of 400 mg once daily until disease progression, intolerance, consent withdrawal, or investigator's decision. The co-primary endpoints (phase II) were overall response rate (ORR) by blinded independent central review and safety. Between 17 March 2017 and 6 November 2020 (data cut-off), 281 patients with RET fusion-positive NSCLC were enrolled. The ORR was 72% [54/75; 95% confidence interval (CI) 60% to 82%] for treatment-naive patients and 59% (80/136; 95% CI 50% to 67%) for patients with prior platinum-based chemotherapy (enrolment cut-off for efficacy analysis: 22 May 2020); median duration of response was not reached for treatment-naive patients and 22.3 months for prior platinum-based chemotherapy patients. Tumour shrinkage was observed in all treatment-naive patients and in 97% of patients with prior platinum-based chemotherapy; median progression-free survival was 13.0 and 16.5 months, respectively. In patients with measurable intracranial metastases, the intracranial response rate was 70% (7/10; 95% CI 35% to 93%); all had received prior systemic treatment. In treatment-naive patients with RET fusion-positive NSCLC who initiated pralsetinib by the data cut-off (n= 116), the most common grade 3-4 treatment-related adverse events (TRAEs) were neutropenia (18%), hypertension (10%), increased blood creatine phosphokinase (9%), and lymphopenia (9%). Overall, 7% (20/281) discontinued due to TRAEs. Pralsetinib treatment produced robust efficacy and was generally well tolerated in treatment-naive patients with advanced RET fusion-positive NSCLC. Results from the confirmatory phase III AcceleRET Lung study (NCT04222972) of pralsetinib versus standard of care in the first-line setting are pending.

Abstract CT537: A phase 2, multicenter, randomized, double-blind trial of maintenance therapy with FLT3 inhibitor gilteritinib (ASP2215) in patients with FLT3/ITD AML (GOSSAMER study)

Abstract Background: Patients with acute myeloid leukemia (AML) in remission are at high risk of relapse, warranting remission-prolonging therapy. Gilteritinib is the first FMS-like tyrosine kinase 3 (FLT3) inhibitor approved as monotherapy in FLT3-mutated relapsed/refractory AML. The aim of the study was to compare relapse-free survival (RFS) in patients with FLT3/internal tandem duplication AML in first complete remission who received gilteritinib or placebo. Method: In this phase 2, double-blind trial, patients were randomized 2:1 to gilteritinib (120 mg) or placebo once daily for up to 2 years, beginning after completion of induction/consolidation (I/C) therapy. RFS, defined as time from randomization date until the date of documented relapse or death from any cause was assessed via independent review committee adjudication (primary efficacy endpoint). Overall survival (OS) was defined as the time from date of randomization until date of death from any cause. Survival and treatment-emergent adverse events (TEAEs) were assessed 30 days after treatment discontinuation, and every 3 months thereafter. Due to a slow accrual rate, this trial (NCT02927262) was changed from a planned phase 3 to phase 2 based on the reduction in sample size. Results: 124 patients were screened and 98 were randomized (gilteritinib 63, placebo 35) and are included in the full analysis set (FAS), of whom 32 (gilteritinib 20, placebo 12) completed 2 years of treatment. The safety analysis set (SAF) comprised 97 patients (gilteritinib 62, placebo 35) who had received ≥1 dose of study drug. In the FAS, relapse occurred in 31/63 (49.2%) gilteritinib- and 20/35 (57.1%) placebo-treated patients; 3/63 (4.8%) gilteritinib-treated patients died without relapse. RFS was not significantly improved with gilteritinib vs placebo (hazard ratio [HR] 0.738, 95% confidence interval [CI] 0.407-1.336; 1-sided stratified log-rank p-value 0.163). Median RFS was 24.02 months for gilteritinib and 15.84 months for placebo. OS in the FAS was not significantly different between treatments (gilteritinib 21/63, [33.3%], placebo 11/35 [31.4%]; HR 1.130, 95% CI 0.540-2.364; 1-sided stratified log-rank p-value 0.627). Median OS was not reached in either arm. TEAEs in the SAF occurred in 58/62 (93.5%) gilteritinib- and 33/35 (94.3%) placebo-treated patients including, respectively, 51/62 (82.3%) and 20/35 (57.1%) drug-related TEAEs and 10/62 (16.1%) and 3/35 (8.6%) serious drug-related TEAEs. The most common TEAEs were increased blood creatine phosphokinase (gilteritinib 18/62 [29.0%], placebo 1/35 [2.9%]) and thrombocytopenia (gilteritinib 12/62 [19.4%], placebo 4/35 [11.4%]). Conclusion: Gilteritinib showed improved RFS versus placebo, but the difference was not statistically significant. There were no new safety findings in the gilteritinib arm. Citation Format: Mark D. Minden, Jacob M. Rowe, Emmanuel Gyan, Kohmei Kubo, Nahla Hasabou, David Delgado, Wensheng He, Stanley C. Gill, Jason E. Hill, Ramon Tiu. A phase 2, multicenter, randomized, double-blind trial of maintenance therapy with FLT3 inhibitor gilteritinib (ASP2215) in patients with FLT3/ITD AML (GOSSAMER study) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT537.

MOTION: A randomized, phase 3, placebo-controlled, double-blind study of vimseltinib (DCC-3014) for the treatment of tenosynovial giant cell tumor.

TPS11590 Background: Tenosynovial giant cell tumor (TGCT) is a rare, locally aggressive neoplasm that occurs in the synovium of joints, bursae, or tendon sheaths. TGCT is caused by upregulation of the colony-stimulating factor 1 (CSF1) gene, resulting in aberrant CSF1 expression and the recruitment of CSF1 receptor (R)-dependent inflammatory cells. Resection is the primary treatment, but nonsurgical treatment options are necessary for patients with symptomatic TGCT not amenable to surgical resection. Vimseltinib is an oral switch control TKI specifically designed to selectively and potently inhibit CSF1R. In a Phase 1/2 study in patients with TGCT, vimseltinib showed encouraging antitumor activity with an overall objective response rate (ORR) of 42% in the cohort receiving 30 mg twice weekly (recommended phase 2 dose; Gelderblom et al, ESMO 2021 Poster). Vimseltinib was also well tolerated, and the majority of the common (≥15%) treatment-emergent adverse events (TEAEs) were Grades 1–2. Among these common TEAEs, the only Grade 3–4 event in the Phase 2, twice-weekly, 30-mg cohort was increased blood creatine phosphokinase (CPK); however, this elevated CPK was not associated with any symptoms (Gelderblom et al, ESMO 2021 Poster). Phase 1/2 efficacy and safety data support further development of vimseltinib; here, we describe the ongoing Phase 3 study for patients with TGCT not amenable to surgical resection. Methods: MOTION (NCT05059262) is a Phase 3, randomized, placebo-controlled, double-blind study that aims to evaluate the efficacy and safety of vimseltinib for the treatment of TGCT not amenable to surgical resection. Participants must be at least 18 years of age and have histologically confirmed and symptomatic TGCT for which surgical resection will potentially cause worsening functional limitation or severe morbidity. Prior CSF1R therapy is not permitted (previous imatinib and nilotinib is allowed). In Part 1 of the study, eligible participants will be randomized 2:1 to receive either vimseltinib 30 mg twice a week or matched placebo for 24 weeks. The primary outcome measure is ORR assessed by central read using Response Evaluation Criteria in Solid Tumors version 1.1 at 25 weeks. Secondary outcome measures include ORR per tumor volume score, range of motion, and patient-reported outcomes. Participants assigned to placebo in Part 1 will have the option to receive vimseltinib in Part 2, a long-term treatment phase in which participants will receive open-label vimseltinib. This international study plans to randomize 120 participants and is currently enrolling. Clinical trial information: NCT05059262.

7MO Oritinib (SH-1028) a third-generation EGFR tyrosine kinase inhibitor in locally advanced or metastatic NSCLC patients with positive EGFR T790M: Results of a single-arm phase II trial

Oritinib (SH-1028) is a third-generation EGFR-TKI selectively targeting both sensitive EGFR and EGFR T790M mutations. Herein, we report the efficacy and safety of oritinib in EGFR T790M-positive advanced NSCLC patients from the phase II study (NCT03823807). Eligible patients were locally advanced or metastatic NSCLC patients aged ≥ 18 years, with centrally confirmed EGFR T790M mutation. Patients with asymptomatic, stable CNS metastases were eligible into the study. Oritinib 200 mg was given orally once daily until disease progression or unacceptable toxicity. Primary efficacy endpoint was objective response rate (ORR). Secondary efficacy endpoints included disease control rate (DCR), progression-free survival (PFS), duration of response (DOR) and overall survival (OS). Between December 2019 and March 2021, 228 patients were enrolled and 227 patients received at least one dose of oritinib. The median age of 227 patients was 62 years old, 57.3% of patients were female and 24.7% received systemic chemotherapies. At data cutoff (September 17, 2021), 137 of 227 patients achieved confirmed partial responses with ORR of 60.4% (95% CI: 42.4%, 68.8%) by IRaC. The DCR was 92.5% (88.3%, 95.6%), the mPFS was 12.6 months (95% CI: 9.7, 15.3), the mDOR was 12.5 months (95% CI: 11.2, NA) and the mOS was immature. The most common (≥10%) treatment-emergent adverse events (TEAEs) included diarrhea (45.4%), increased blood creatine phosphokinase (26.0%), anaemia (20.3%), decreased white blood cell count (15.4%), decreased appetite (15.0%), increased blood creatine phosphokinase isoenzyme (13.2%), nausea (13.2%), vomiting (13.2%), increased serum creatine (12.8%), upper respiratory tract infection (12.3%), increased aspartate aminotransferase (11.9%), cough(11.9%), decreased platelet count (11.0%), constipation (10.6%). Grade≥3 TEAEs included increased blood creatine phosphokinase (4.0%), hypertension (3.1%), death (2.6%), diarrhea (2.2%). No interstitial lung disease were reported. Oritinib demonstrated potential clinical benefit and tolerable in advanced NSCLC patients with EGFR T790M mutation.

Neoadjuvant cemiplimab for resectable hepatocellular carcinoma: a single-arm, open-label, phase 2 trial

Surgical resection of early stage hepatocellular carcinoma is standard clinical practice; however, most tumours recur despite surgery, and no perioperative intervention has shown a survival benefit. Neoadjuvant immunotherapy has induced pathological responses in multiple tumour types and might decrease the risk of postoperative recurrence in hepatocellular carcinoma. We aimed to evaluate the clinical activity of neoadjuvant cemiplimab (an anti-PD-1) in patients with resectable hepatocellular carcinoma. For this single-arm, open-label, phase 2 trial, patients with resectable hepatocellular carcinoma (stage Ib, II, and IIIb) were enrolled and received two cycles of neoadjuvant cemiplimab 350 mg intravenously every 3 weeks followed by surgical resection. Eligible patients were aged 18 years or older, had confirmed resectable hepatocellular carcinoma, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate liver function. Patients were excluded if they had metastatic disease, if the surgery was not expected to be curative, if they had a known additional malignancy requiring active treatment, or if they required systemic steroid treatment or any other immunosuppressive therapy. After resection, patients received an additional eight cycles of cemiplimab 350 mg intravenously every 3 weeks in the adjuvant setting. The primary endpoint was significant tumour necrosis on pathological examination (defined as >70% necrosis of the resected tumour). Secondary endpoints included delay of surgery, the proportion of patients with an overall response, change in CD8+ T-cell density, and adverse events. Tumour necrosis and response were analysed in all patients who received at least one dose of cemiplimab and completed surgical resection; safety and other endpoints were analysed in the intention-to-treat population. Patients underwent pre-treatment biopsies and blood collection throughout treatment. This trial is registered with ClinicalTrials.gov (NCT03916627, Cohort B) and is ongoing. Between Aug 5, 2019, and Nov 25, 2020, 21 patients were enrolled. All patients received neoadjuvant cemiplimab, and 20 patients underwent successful resection. Of the 20 patients with resected tumours, four (20%) had significant tumour necrosis. Three (15%) of 20 patients had a partial response, and all other patients maintained stable disease. 20 (95%) patients had a treatment-emergent adverse event of any grade during the neoadjuvant treatment period. The most common adverse events of any grade were increased aspartate aminotransferase (in four patients), increased blood creatine phosphokinase (in three), constipation (in three), and fatigue (in three). Seven patients had grade 3 adverse events, including increased blood creatine phosphokinase (in two patients) and hypoalbuminaemia (in one). No grade 4 or 5 events were observed. One patient developed pneumonitis, which led to a delay in surgery by 2 weeks. This report is, to our knowledge, the largest clinical trial of a neoadjuvant anti-PD-1 monotherapy reported to date in hepatocellular carcinoma. The observed pathological responses to cemiplimab in this cohort support the design of larger trials to identify the optimal treatment duration and definitively establish the clinical benefit of preoperative PD-1 blockade in patients with hepatocellular carcinoma. Regeneron Pharmaceuticals.

Efficacy of Aumolertinib (HS-10296) in Patients With Advanced EGFR T790M+ NSCLC: Updated Post-National Medical Products Administration Approval Results From the APOLLO Registrational Trial

IntroductionAumolertinib (formerly almonertinib; HS-10296) is a novel third-generation EGFR tyrosine kinase inhibitor (TKI) with revealed activity against EGFR-sensitizing mutations and EGFR T790M mutation. MethodsPatients with locally advanced or metastatic NSCLC who developed an EGFR T790M mutation after progression on first- or second-generation EGFR TKI therapy were enrolled in this registrational phase 2 trial of aumolertinib at 110 mg orally once daily (NCT02981108). The primary end point was objective response rate (ORR) by independent central review. ResultsA total of 244 patients with EGFR T790M-positive NSCLC were enrolled. The ORR by independent central review was 68.9% (95% confidence interval [CI]: 62.6–74.6). The disease control rate was 93.4% (95% CI: 89.6–96.2). The median duration of response was 15.1 months (95% CI: 12.5–16.6). The median progression-free survival was 12.4 months (95% CI: 9.7–15.0). Among 23 patients with assessable central nervous system (CNS) metastases, the CNS-ORR and CNS-disease control rate were 60.9% (95% CI: 38.5–80.3) and 91.3% (95% CI: 72.0–98.9), respectively. The median CNS-duration of response was 12.5 months (95% CI: 5.6–not reached). Treatment-related adverse events of more than or equal to grade 3 occurred in 16.4% of the patients, with the most common being increased blood creatine phosphokinase level (7%) and increased alanine aminotransferase level (1.2%). The relative dose density of aumolertinib was 99.2% in this study. ConclusionsAumolertinib is an effective and well-tolerated third-generation EGFR TKI for patients with EGFR T790M-positive advanced NSCLC after disease progression on first- and second-generation EGFR TKI therapy. On the basis of these findings, aumolertinib was approved in the People’s Republic of China for patients positive for EGFR T790M NSCLC.

Safety and efficacy of teriflunomide in paediatric multiple sclerosis (TERIKIDS): a multicentre, double-blind, phase 3, randomised, placebo-controlled trial

Therapeutic options for children with multiple sclerosis are scarce. Teriflunomide is approved in more than 80 countries for the treatment of adults with relapsing multiple sclerosis. The TERIKIDS study examined the safety and efficacy of teriflunomide in children with relapsing multiple sclerosis. The TERIKIDS trial was a multicentre, phase 3, double-blind, parallel-group, randomised, placebo-controlled study conducted at 57 clinical centres in 22 countries in Asia, Europe, the Middle East, North Africa, and North America. The trial enrolled patients aged 10-17 years, diagnosed with relapsing multiple sclerosis and with at least one relapse in the year preceding screening or at least two relapses in the 2 years preceding screening. Patients were randomly assigned (2:1) to oral teriflunomide (dosage equivalent to 14 mg in adults) or matching placebo, using an interactive web and voice response system, for up to 96 weeks. Personnel in all sites and all patients were masked to study treatment in the double-blind period. Early entry into a subsequent 96-week open-label extension phase was possible before the end of the double-blind period for patients with confirmed clinical relapse or high MRI activity (at least five new or enlarged T2 lesions at week 24, followed by at least nine new or enlarged T2 lesions at week 36, or at least five new or enlarged T2 lesions at weeks 36 and 48, or at weeks 48 and 72). The primary endpoint was time to first confirmed clinical relapse by the end of the double-blind period. Key secondary imaging endpoints were number of new or enlarged T2 lesions and number of gadolinium-enhancing lesions per MRI scan. Efficacy endpoints were analysed in the intention-to-treat population, and safety was assessed in all patients randomly assigned to treatment and exposed to the double-blind study medication. This study is registered with ClinicalTrials.gov (trial number NCT02201108) and is closed to recruitment, but an additional optional open-label extension is ongoing. Between July 24, 2014, and the date of last patient visit on Oct 25, 2019, 185 patients were screened for eligibility, 166 (90%) were enrolled, and 109 were randomly assigned teriflunomide and 57 were randomly assigned placebo. 102 (94%) of 109 and 53 (93%) of 57 completed the double-blind period. Switch to the ongoing open-label extension because of high MRI activity was more frequent than anticipated in the placebo group (14 [13%] of 109 patients in the teriflunomide group vs 15 [26%] of 57 in the placebo group), decreasing the power of the study. After 96 weeks, there was no difference in time to first confirmed clinical relapse with teriflunomide compared with placebo (hazard ratio 0·66, 95% CI 0·39-1·11; p=0·29). Teriflunomide reduced the number of new or enlarged T2 lesions versus placebo by 55% (relative risk 0·45, 95% CI 0·29-0·71; p=0·00061), and the number of gadolinium-enhancing lesions by 75% (relative risk 0·25, 0·13-0·51; p<0·0001). Adverse events occurred in 96 (88%) patients in the teriflunomide group and 47 (82%) patients in the placebo group; serious adverse events occurred in 12 (11%) patients in the teriflunomide group and 6 (11%) patients in the placebo group. Nasopharyngitis, upper-respiratory-tract infection, alopecia, paraesthesia, abdominal pain, and increased blood creatine phosphokinase were more frequent with teriflunomide than with placebo. During the double-blind phase, four patients in the teriflunomide group had pancreatic adverse events (two with acute pancreatitis and two with pancreatic enzyme elevation), of which three events led to treatment discontinuation. No significant difference in time to first confirmed clinical relapse was found, possibly because more patients than expected switched from the double-blind to the open-label treatment period because of high MRI activity. Key secondary imaging analyses and a prespecified sensitivity analysis of probability of relapse or high MRI activity suggest that teriflunomide might have beneficial effects in children with relapsing multiple sclerosis by reducing the risk of focal inflammatory activity. Sanofi.

Effectiveness, adherence and safety of evolocumab in a Swiss multicenter prospective observational study

Abstract Background/Introduction Achievement of low LDL-C-levels and adherence to lipid lowering therapy (LLT) is essential to prevent recurrent cardiovascular (CV) events. However, most patients (pts) with acute coronary syndromes don't maintain LDL-C levels within guideline recommendations beyond 1 year. Practical solutions to increase long-term adherence to LLT are needed. Purpose To describe pts receiving evolocumab (evo) and drug adherence in a real-world clinical setting. Methods We enrolled adults ≥18 years with confirmed atherosclerotic cardiovascular disease (ASCVD) or at high CV risk, and elevated LDL-C levels despite maximally tolerated statin therapy. Physicians in clinical practice prescribed evo according to Swiss reimbursement limitations. At baseline (BL), all pts used evo; some were already on PCSK9i treatment (PCSK9i pre-treated), others were newly initiated on evo (PCSK9i naïve); planned follow-up was 12 months. The web-based mHealthAlert system was offered to support pts' therapy management. The primary outcome was cholesterol levels at BL and after 3, 6 and 12 months of evo therapy. Results All 100 enrolled pts completed 12 months follow-up. For BL characteristics see Table. 81% had a history of at least one CV event and 55% had ≥2 previous CV events; 3% had familial hypercholesterolemia. At BL, 71% had a history of statin-related muscle symptoms, 44% had documented statin use, 65% were PCSK9i pre-treated and 35% were PCSK9i naïve; overall median LDL-C was 1.9 mmol/L. In PCSK9i naive pts, median LDL-C at enrolment was 3.5 mmol/L and fell by a mean of 2.1 mmol/L (60% reduction) within 3 months of evo initiation; this reduction was maintained over 12 months. The 2016 ESC/EAS LDL-C goals (&amp;lt;1.8 mmol/L) were attained at least once over 12 months by 74% of pts while 69% attained the 2019 goals (&amp;lt;1.4 mmol/L). In PCSK9i pre-treated pts, LDL-C remained stable during evo treatment; 79% and 74% attained the 2016 and 2019 goals, respectively, at least once over 12 months. Goal attainment was higher in pts receiving combination therapy of evo ± statin ± ezetimibe (Figure). Overall, 89% of pts self-reported full adherence to evo. Adverse events were reported in 30% of pts, two events in one pt were considered serious (increased blood creatine phosphokinase and myopathy) and three pts discontinued evo due to adverse events. Conclusion In Swiss clinical practice, evo was mainly used in high CV risk pts with statin-related muscle symptoms and severe CV disease. In this population, adherence to evo and low LDL-C levels were maintained over one-year. Among pts using evo either in mono- or combination therapy, the majority attained guideline recommended LDL-C levels. However, goal attainment was higher in pts using evo in combination with other LLT, especially with regards to LDL-C &amp;lt;1.4 mmol/L. Effectiveness and safety of evo in real-world clinical practice was comparable to that found in randomized, controlled clinical trials. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Study 20150245 was funded by Amgen Switzerland AG

Safety of Janus kinase (JAK) inhibitors in the short-term treatment of atopic dermatitis.

Atopic dermatitis (AD) is a chronic heterogeneous condition characterized by erythematous, pruritic, and inflamed skin. Janus kinase (JAK) inhibitors are a new class of drugs that target proteins in the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. These drugs can be administered orally or topically to inhibit signaling of the JAK-STAT pathway and minimize the production of proinflammatory cytokines. The efficacy and safety of JAK inhibitors have been investigated in phase 2 and 3 clinical trials for AD. The safety of new medications, which are immunosuppressive by nature, is of utmost concern for the prescriber and patient alike. Herein we summarize the safety results of clinical trials using oral abrocitinib, upadacitinib, and baricitinib, as well as topical ruxolitinib and delgocitinib for the treatment of AD. The most prevalent (2-5% occurrence rate) treatment-emergent adverse events from oral JAK inhibitor use in AD were nausea, upper respiratory tract infection, headache, herpes zoster, herpes simplex, acne, increased blood creatine phosphokinase levels, and decreased platelet counts. Topical JAK inhibitors were not associated with systemic effects. All studies reported that JAK inhibitors were well tolerated in patients with AD in comparison with the control group. While the use of JAK inhibitors in patients suffering from AD is very promising, trials reported to date are of short duration (maximum 16 weeks), and more information on the long-term safety of these novel agents is required.

Initial results from a dose finding study of TNO155, a SHP2 inhibitor, in adults with advanced solid tumors.

3005 Background: SHP2 transduces signals from activated receptor tyrosine kinases to downstream pathways including MAPK. TNO155 is a selective, allosteric, oral inhibitor of SHP2. Methods: CTNO155X2101 (NCT03114319) is an ongoing first-in-human, open-label dose escalation/expansion trial of TNO155 in adults with advanced solid tumors. The primary objective is to characterize the safety and tolerability of TNO155 and identify regimen(s) for future study. Secondary assessments included pharmacokinetics, pharmacodynamics, and preliminary clinical efficacy. Here we present data from TNO155 single agent escalation. Results: As of 10/26/2020, 118 patients received TNO155 in variable schedules: once (QD; 1.5–70 mg; n = 55) or twice daily (BID; 30–50 mg; n = 25) in a 2 weeks on/1 week off (2w/1w) cycle; or QD in a 3w/1w cycle (30–60 mg; n = 32), or continuously (40 or 50 mg QD; n = 6). The most common cancer diagnoses treated were colorectal (54%), gastrointestinal stromal tumor (16%), non-small cell lung (12%), and head &amp; neck (8%). The median number of prior antineoplastic therapies was 4 (range 1–10). Overall 109 patients (92%) have discontinued study treatment, 94 (80%) for progressive disease and 6 (5%) for adverse events (AEs). TNO155 showed rapid absorption (median day 1 Tmax ̃1.1 hours), an effective median T½ of ̃34 hours, and near dose-proportional exposure at day 14 (power model: AUCτ beta = 1.09 [90% CI 1.02–1.16]). AEs were mostly Grade 1/2 and generally consistent with on-target effects of SHP2 inhibition. The most common treatment-related AEs (all grades) were increased blood creatine phosphokinase (n = 33, 28%), peripheral edema (n = 31, 26%), diarrhea (n = 31, 26%), and acneiform dermatitis (n = 27, 23%). The most common treatment-related Grade ≥3 AEs were decreased platelets (n = 5, 4%), increased aspartate aminotransferase, diarrhea, and decreased neutrophils (each n = 4, 3%). The best observed response was stable disease (SD) per RECIST 1.1, reported in 24 (20%) patients, with a median duration of SD of 4.9 months (range 1.7–29.3). Evidence of SHP2 inhibition, as measured by change in DUSP6 expression by qPCR in paired pre- vs. on-treatment tumor samples, was seen in the majority of patients treated with TNO155 doses ≥20 mg/day (≥25% reduction, 38/42 [90%]; ≥50% reduction, 25/42 [60%]). Analysis of tumor whole-transcriptome RNA sequencing data is ongoing. Conclusions: TNO155 shows favorable pharmacokinetic properties and promising early safety and tolerability data at doses with evidence of target inhibition. The optimal dose using several schedules is still under evaluation. Studies of TNO155 in combination with other agents, including nazartinib (mutant-selective EGFR inhibitor[i]), adagrasib (KRAS G12Ci), spartalizumab (anti-PD-1 antibody), ribociclib (CDK4/6i), and dabrafenib (BRAFi) with LTT462 (ERKi), are ongoing (NCT03114319, NCT04330664, NCT04000529, NCT04294160). Clinical trial information: NCT03114319.