Second-line Tyrosine Kinase Inhibitors Research Articles

Real-Life Data of Bosutinib Treatment for Chronic Myeloid Leukemia: The Multi-Center Experience of the Gruppo Di Miglioramento Sicilia-Calabria

Background and rationale: Bosutinib is a second generation tyrosine kinase inhibitor (TKI), which has been indicated in Italy in the second line of CML treatment, since 2014. Thanks to its safety profile, bosutinib is frequently chosen as an advanced line of treatment in fragile patients. We collected retrospective data from patients treated with bosutinib in any line of TKI therapy, in order to study the role that this drug has in real-life, compared to clinical trials in terms of treatment line, dosage, toxicity and efficacy. Patients and methods: We collected data from65 chronic phase CML patients treated with bosutinib between 2015-08-18 and 2023-04-27, followed at 12 Haematology centers in Sicily and Calabria. Of these patients, 42 (64.6%) were male, and had a median follow-up of 29 months (range 1-96). Mean age at diagnosis was 62, and mean age at bosutinib start was 67. Median therapies prior bosutinib treatment was 2. Fourtyfour patients (67.7%) had cardiovascular comorbidities (CV) at diagnosis: 37 patients (55%) had at least one cardiovascular risk factor: in particular, arterial hypertension in 31 patients (70.4%), dyslipidaemia in 10 patients (22.7%), diabetes mellitus in 14 patients (31.8%), obesity (grade 3) in 2 patients (4.5%); 7 patients (10.7%) had already experienced an acute cardiovascular or cerebrovascular event. Finally, only 12 patients (18.4%) had no comorbidity at diagnosis. Mean age at the start of bosutinib for CV-risk patients was 70 years. Among 44 patients with CV risk before starting bosutinib, 38 patients were still alive (86.4%) at last follow-up. Fifteen patients with CV risk discontinued bosutinib (34%), while none presented new CV events during treatment. In terms of efficacy, however, in patients with CV risk, the median molecular response, at the last follow-up, is MR2. Results: Thirty-eight patients (58.5%) discontinued bosutinib, while 27 (41.5%) were still on treatment at the time of the last follow-up. Of the 38 patients who discontinued bosutinib, 5 discontinued due to resistance (13.8%) and 19 due to intolerance (50%). Of these 19 intolerant patients, only 1 patient discontinued bosutinib due to CV event (heart failure) and only 1 patient discontinued due to gastrointestinal toxicity (grade 3 diarrhea). Most reported toxicities were as follows: Skin Toxicity 3 pt 5%Perpheral edema 2 pt 3%Hepatototoxicity 2 pt 3% In the efficacy evaluation, early-suspenders (bosutinib treatment duration < 6 months) were, therefore, cut out, 55 patients (84.6%) were evaluated in this sub-analysis, 34 (61.8%) male and 21 (38.2%) female. Median age in this subanalysis is 67 years. Bosutinib was second-line treatment in 35 cases (63.6%), third-line therapy in 15 cases (27.3%), fourth-line therapy in 4 cases (7.3%). Overall, 35 patients assumed bosutinib as a second-line TKI: 22 of them were from the 1L-imatinib group (62.9%), while 13 were from the 2nd generation TKI-1L group (37.1%). Of the 22 1L-imatinib and 2L-bosutinib patients, 56.1% reached MR3 or deeper during bosutinib treatment and 38.1% reached MR4.5 or deeper. Of the 13 patients in 1L-2genTKI 2L-bosutinib group, 61.5% reached at least MR3, while 15.4% reached MR4.5 or MR5. Drop-out rate was similar between the two groups. Conclusion Bosutinib revealed to be safe in patients with CML in 2 nd and further lines of treatment, especially in terms of cardiotoxicity, even in subjects with a high CV risk at treatment initiation. Furthermore, our data revealed as most patients are currently treated with a lower dose of bosutinib than standard (median dosage 302 vs 500 mg a day), obtaining good response rates in 2 nd and further lines. Subsequent eventual dose increase is evaluated on the basis of the molecular response.

Incremental Healthcare Resource Utilization and Costs Associated with Non-Optimal Treatment in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Treated with Tyrosine Kinase Inhibitors (TKI) in Early Lines of Therapy in the United States (US)

Introduction: TKIs are the standard of care for CML-CP. Although effective TKI options are available in early lines of therapy of CML, patients may experience intolerance or resistance to TKI leading to non-optimal treatment (NOPT). This retrospective cohort study assessed the incremental healthcare resource utilization (HRU) and medical costs associated with NOPT in patients with CML treated in first-line (1L) or second-line (2L) TKI therapy in the US. Methods: Adult patients with CML who received 1L TKI therapy with imatinib, dasatinib, nilotinib, or bosutinib (1L cohort), and those who received 2L TKI therapy with imatinib, dasatinib, nilotinib, bosutinib, or ponatinib (2L cohort), in 2012 or later, were selected from the OptumInsight Clinformatics database (01/2007-06/2022). Patients were required to have ≥2 years of continuous health plan coverage post-1L/2L initiation (1L/2L index date). Patients were classified in NOPT subgroup if they met one of the following criteria: 1) treatment discontinuation/switch within the first 6 months post-index, or 2) temporary treatment interruption and/or dose reduction within the first 6 months post-index followed by treatment discontinuation within the first 12 months post-index, or 3) low treatment adherence (proportion of days covered [PDC] ≤50%). Patients were classified in the reference (REF) subgroup if they met one of the following criteria: 1) high treatment adherence (PDC >90%) and no treatment discontinuation, 2) high treatment adherence (PDC >90%) and treatment discontinuation occurring more than 12 months post-index. All-cause HRU (inpatient [IP] admissions, outpatient [OP] visits, and emergency department [ED] visits) and associated medical costs (2022 USD) were measured during the 2 years post-index and reported per-patient-per-year (PPPY). Incremental HRU and costs of NOPT (vs. REF) were estimated using multivariable Poisson regressions and two-part models (adjusted for age, gender, race, region, health plan type, time from CML diagnosis to index date, and Darkow Disease Complexity Index), respectively. Adjusted incidence rate ratios (IRR) and mean cost differences (Δ) were reported along with p-value, estimated using bootstrap technique. All analyses were conducted separately in the 1L and 2L cohorts. Results: Of 2,043 patients that initiated 1L TKI therapy in 2012 or later, 197 patients were included in NOPT subgroup (median age: 69 years; 52.3% female; 68.5% White) and 284 in REF subgroup (median age: 62 years; 40.1% female; 74.6% White). Patients in NOPT subgroup had 80% more IP admissions (adjusted IRR=1.8; p <0.001) with twice more IP days (adjusted IRR=2.0; p=0.024), 30% more OP visits (adjusted IRR=1.3; p=<0.001) in the first 2 years post-index, as compared to REF subgroup. Consistently, patients in NOPT subgroup had higher medical costs (adjusted Δ=$13,551 PPPY; p=0.012) mainly driven by higher IP costs (adjusted Δ =$5,989 PPPY; p=0.028) along with numerically higher OP costs (adjusted Δ=$5,483 PPPY; p=0.060) in the first 2 years post-index, as compared to REF subgroup ( Figure 1). Of 586 patients that initiated 2L TKI therapy in 2012 or later, 69 patients were included in NOPT subgroup (median age: 67 years; 60.9% female; 76.8% White) and 72 in REF subgroup (median age: 68 years; 51.4% female; 69.4% White). Patients in NOPT subgroup had 3 times more IP admissions (adjusted IRR=3.1; p <0.001) with almost 7 times more IP days (adjusted IRR=6.7; p<0.001), 80% more ED visits (adjusted IRR=1.8; p=0.036), and numerically more OP visits (adjusted IRR=1.2; p=0.056) in the first 2 years post-index, as compared to REF subgroup. Consistently, patients in NOPT subgroup had higher medical costs (adjusted Δ=$30,962 PPPY; p=0.008) mainly driven by higher OP costs (adjusted Δ=$8,380 PPPY; p=0.016) and higher ED costs (adjusted Δ=$4,332 PPPY; p=0.012) along with numerically higher IP costs (adjusted Δ=$14,063 PPPY; p=0.100) in the first 2 years post-index, as compared to REF subgroup ( Figure 1). Conclusions: In this study of patients with CML-CP non-optimal treatment resulting in early treatment discontinuation/switch or dose interruptions/reduction in the first 6 months from treatment initiation or low adherence with the currently approved TKIs in 1L and 2L therapy for CML was associated with significant incremental economic burden. This highlights the need for more tolerable therapeutic options early in the treatment course.

Safety and Efficacy of Second-Line TKI Plus Anti-PD1 in Metastatic Non-Clear Cell Renal Cell Carcinoma: A Real-World Study

ObjectivesGuidelines recommend clinical trials or tyrosine kinase inhibitor (TKI) as the first-line option for systemic therapy for non-clear cell renal cell carcinoma (nccRCC) with limited efficacy. However, the preferred subsequent options remain unclear when patients progress after first-line treatment. This study aimed to evaluate the efficacy and safety of anti-PD-1 plus TKI therapy as the second-line regimen in nccRCC. Patients and MethodsWe conducted a retrospective analysis of patients with metastatic nccRCC who failed first-line TKI therapy between October 2011 and September 2020. The baseline characteristics of the patients and adverse events (AEs) were collected. Efficacy measures included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). ResultsThe current study enrolled 65 patients, with a median age of 48 (interquartile 37–60) years. Among all patients, 21 received TKI monotherapy while 44 patients received combination therapy (TKI plus anti-PD1). The ORR and DCR for the whole cohort were 38.5% and 56.9%, respectively. ORR (50.0% vs. 14.3%, P = .006) and DCR (70.5% vs. 28.6%, P = .001) were improved in the combination group compared with the TKI group. The overall second-line PFS was 7.7 (95% CI: 6.1-9.3) months and OS was 25.2 (19.5-30.8) months. Patients receiving combination therapy had a longer PFS compared with those receiving TKI monotherapy [median PFS (95% CI): 9.2 (5.9-12.4) vs. 5.4 (2.6-8.2) m, Log-rank P = .002]. The incidence of treatment-related AEs of grade 3 or higher was comparable between the 2 groups (56.8% vs. 52.4%). ConclusionAnti-PD-1 plus TKI therapy appeared effective and safe in the treatment of patients with metastatic nccRCC who progressed after first-line TKIs.

Which Second-Line Tyrosine Kinase Inhibitor(s) for Chronic Myeloid Leukemia?

In patients with chronic myeloid leukemia who require second-line tyrosine kinase inhibitor therapy, many options exist. These treatments include alternate generation tyrosine kinase inhibitors and in some cases consideration of allogeneic transplant. Although efficacious, each tyrosine kinase inhibitor possesses distinct side effects and pharmacological profiles that prevent a generalizable treatment approach. Furthermore, there is limited head-to-head trial data that would suggest the superiority of one tyrosine kinase inhibitor over another to help guide treatment decisions in specific clinical settings. Therefore, we treat each patient independently. A patient's treatment plan must be personalized by a variety of clinical factors to optimize response and tolerability. Our general approach is to first examine the reason for treatment failure, which may be due to either intolerance or relapse. Second, we consider the age and patient's comorbidities such as lung disease, diabetes, or cardiovascular disease. In patients who have inadequate responses, we analyze the patient's BCR-ABL1 mutational profile, which is beneficial if that patient harbors a specific tyrosine kinase inhibitor responsive mutation, such as T315I. Using these steps, we can provide a generalizable approach to choosing the appropriate second-line tyrosine inhibitor for chronic myeloid leukemia.

Beyond atezolizumab plus bevacizumab in patients with advanced hepatocellular carcinoma: overall efficacy and safety of tyrosine kinase inhibitors in a real-world setting.

In patients with advanced hepatocellular carcinoma (HCC) progressing after atezolizumab and bevacizumab, the optimal therapeutic sequence is still unclear and no second-line agent has proven its efficacy. The aim of this retrospective multicenter real-world cohort study was to provide an evaluation of the efficacy and safety of the use of second-line tyrosine kinase inhibitors (TKIs) in this population. All patients with advanced HCC, treated in first-line setting by atezolizumab-bevacizumab, and who received at least one dose of treatment with TKI were included in this study. All the data were retrospectively collected from medical records. The primary outcome was progression-free survival (PFS). Secondary outcomes were overall survival (OS), overall global survival (OGS), and safety. A total of 82 patients were included in this study. Patients were assigned to the regorafenib group (n = 29, 35.4%) or other TKI (sorafenib n = 41, lenvatinib n = 8, or cabozantinib n = 4) group (n = 53). PFS was not significantly different between the two groups [2.6 versus 2.8 months, HR 1.07 (95% CI: 0.61-1.86), p = 0.818]. Median PFS rates were 2.6, 4.4, and 2.8 months in sorafenib-, lenvatinib-, and cabozantinib group, respectively. OS was statistically different between the regorafenib group and other TKI group [15.8 versus 7.0 months, HR 0.40 (95% CI: 0.20-0.79), p = 0.023]. When adjusting on confounding factors, there was still a difference in OS favoring the regorafenib group (adjusted hazard ratio 0.35, p = 0.019). OGS of patients who received regorafenib was improved compared to other TKI [18.6 versus 15.0 months, HR 0.42 (95% CI: 0.22-0.84), p = 0.036]. Twenty percent of patients had grade 3 and none had grade 4 or 5 adverse events. In patients who experienced disease progression and fit for a third-line treatment, 80% and 50% received cabozantinib in regorafenib group and other TKI group, respectively. Efficacy of any TKI in the second-line setting was not affected by atezolizumab-bevacizumab treatment as first-line therapy. The safety profile in the second-line setting was consistent with the results shown in pivotal studies. PFS rates of patients were similar, regardless of TKI type. Regorafenib was associated with better OS and OGS rates compared to other TKI. These data need to be confirmed in prospective comparative studies.

Second-Line Therapy Tyrosine Kinase Inhibitor for Chronic Phase Chronic Myeloid Leukemia Resistant to Imatinib

Since the era of tyrosine kinase inhibitor (TKI) therapy, there has been an increase in the median survival of chronic myeloid leukemia. Nevertheless, nowadays there were several cases of chronic myeloid leukemia that are resistant to the first-line TKIs, so that several second-line TKIs were introduced. Assessment of the therapeutic response was performed using a complete peripheral blood examination, bone marrow aspiration cytogenetic examination, and quantitative BCR-ABL examination. The treatment failure criteria were applied based on the ELN criteria. In selecting the second line TKI should be based on the results of mutation analysis and consider the safety profile of the second line therapy. This paper will discuss the recommendations for second-line therapy TKI, adjusted to the resources in Indonesia.

A review of the therapeutic role of the new third-generation TKI olverembatinib in chronic myeloid leukemia.

Several tyrosine kinase inhibitors (TKIs) have been developed as targeted therapies to inhibit the oncogenic activity of several tyrosine kinases in chronic myeloid leukemia (CML), acute lymphoid leukemia (ALL), gastrointestinal stromal tumor (GIST), and other diseases. TKIs have significantly improved the overall survival of these patients and changed the treatment strategy in the clinic. However, approximately 50% of patients develop resistance or intolerance to imatinib. For second-generation TKIs, approximately 30%-40% of patients need to change therapy by 5 years when they are used as first-line treatment. Clinical study analysis showed that the T315I mutation is highly associated with TKI resistance. Developing new drugs that target the T315I mutation will address the dilemma of treatment failure. Olverembatinib, as a third-generation TKI designed for the T315I mutation, is being researched in China. Preliminary clinical data show the safety and efficacy in treating CML patients harboring the T315I mutation or who are resistant to first- or second-line TKI treatment. Herein, we review the characteristics and clinical trials of olverembatinib. We also discuss its role in the management of CML patients.

Outcome of Third-Line Tyrosine Kinase Inhibitors in Patients with Chronic Myeloid Leukemia in Chronic Phase: A Propensity Score Analysis

Background: Tyrosine Kinase Inhibitors (TKI) dramatically improve survival in patients with chronic myeloid leukemia in chronic phase (CML-CP). However, patients may develop intolerance of or resistance to TKI therapy over years. Given multiple effective therapies available, the optimal selection of third-line therapy is not clear. The aim of this study is to evaluate the outcomes of third-line TKI therapy in patients with CML-CP. Methods: We retrospectively combined patient-level data of third-line TKI therapy in the clinical trials of PACE and OPTIC studies with patients who received third-line TKI therapy at our institution. Given equivalent outcomes between second-generation TKIs (2G-TKI), we compared the outcomes of patients between 2G-TKI and ponatinib as third-line TKI therapy. Patients with T315I mutations were excluded in our study given the known resistance to all the 2G-TKI therapies. Multiple imputations was performed for missing covariates to reduce bias. Univariate and multivariate Cox regression analysis was performed for survival to identify prognostic factors with a p-value cutoff of 0.05 from univariate to multivariate analysis. One-to-one propensity score matching was performed with a caliper of 0.200, using matching covariates with age at the time of third-line therapy, gender, race, comorbidity, prior TKI therapy, the duration of prior TKI therapy, best prior response during the front-line and second-line TKI therapy, body mass index, white blood cell count, platelet count, percentages of basophils and blasts in peripheral blood, and BCR::ABL1 levels on the international scale. Progression-free survival (PFS) was defined from the start of third-line TKI therapy to the time of loss of major cytogenetic response during the study, progression to accelerated phase or blast phase at any time, death from any cause at any time, or the date of last follow-up; overall survival (OS) was defined as the start of third-line TKI therapy to death from any cause or the date of last follow-up. The Kaplan-Meier method was used for survival with the log-rank test and a significance p-value level of 0.05. Results: We identified 354 patients who received third-line TKI therapy [204 patients (58%) from our institution; 63 patients (18%) from the PACE study; 87 (25%) patients from the OPTIC study] with a median follow-up of 46 months (Table 1). Among them as third-line TKI therapy, 173 patients received 2G-TKI [69 patients (19%), dasatinib; 64 patients (18%), nilotinib; 40 patients (11%), bosutinib], and 181 patients received ponatinib (51%). Overall, the median age at the time of third-line TKI therapy was 54 years (range, 18-87). Prior to third-line TKI therapy, 313 patients (88%) received imatinib; 156 patients (44%), dasatinib; 161 patients (45%), nilotinib; 35 patients (10%), bosutinib. The overall median BCR::ABL1 level was 16.3% on the international scale at the time of third-line TKI therapy. Patients who received ponatinib had higher rates of non-ischemic cardiovascular comorbidity, shorter total duration of prior TKI therapies, higher percentage of basophiles in peripheral blood, and higher levels of BCR::ABL1 on the international scale. Propensity score matching minimized the baseline covariates and identified 96 patients at each group with a median follow-up of 46 months after propensity score matching. There is a tendency of deeper response with ponatinib at baseline BCR::ABL1 levels of >1-10% and >0.1-1% before and after propensity score matching. Using pre-matched data, multivariate Cox regression showed older age at the time of third-line TKI therapy and higher BCR::ABL1 levels as adverse prognostic factors for survival ; the third-line ponatinib therapy was associated with favorable survival [P=0.003; hazard ratio (HR), 0.435; 95% confidence internal (CI), 0.253-0.748]. The 4-year PFS rates were 58% and 75% in the 2G-TKI and ponatinib group, respectively, before matching (P<0.001); the 4-year PFS rates were 78% and 89%, respectively, after matching (P=0.0099). The 4-year OS rates were 57% and 80% in the 2G-TKI and ponatinib group, respectively, before matching; the 4-year OS rates were 78% and 87%, respectively, after matching (Figure 1). Conclusion: Third-line ponatinib therapy is optimal selection for patients with CML-CP who failed prior 2 TKI therapies in the absence of T315I mutation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Addition of tyrosine kinase inhibitors (TKIs) in patients (pts) with unresectable hepatocellular carcinoma (HCC) who progress on first-line immunotherapy (IO).

e16193 Background: Atezolizumab plus bevacizumab is now standard first-line therapy for advanced HCC. Early phase trials in HCC and phase III trials in other solid tumors testing IO and TKI have shown greater antitumor activity with the combination than with either agent alone. Cancer and vascular endothelial cells release VEGF, which not only increases angiogenesis, promoting tumor growth, but also induces an immunosuppressive tumor microenvironment (TME). Preclinical studies suggest that TKIs with anti-VEGF activity have immunomodulatory potential, enabling the infiltration and activation of effector T cells to the TME. Experimental models of HCC with combination of IO plus TKI also reverted immune escape mechanisms mediated by β-catenin, Wnt, and TGFβ activation and by Treg or neutrophil infiltration. At our institution, pts who were treated with IO alone in the front line often had a TKI added on progression of disease (PD). We aimed to evaluate whether the addition of a TKI could rescue IO failure. Methods: We conducted an IRB-approved retrospective chart review of pts with unresectable HCC at Mount Sinai Health System who received IO from 1/2017 to 6/2021 and who subsequently received a TKI on PD. We assessed the objective response rate (ORR), median progression-free survival (mPFS) and overall survival (mOS). Follow-up CT/MRI imaging studies were conducted every 2-3 months after addition of TKI. Results: Of 277 pts who received first-line IO during the study period, 46 evaluable pts subsequently had TKIs added to IO upon PD. Pts were predominantly male (37/46), with median age 63 years, and 38 had cirrhosis. Etiologies of HCC were as follows: 9 HBV, 22 HCV, 15 alcohol-related, 7 NASH-associated. All pts received first-line nivolumab. TKIs added were lenvatinib (44/46) and sorafenib (2). At the start of IO, most pts (31/46) had Child Pugh class A liver disease and performance status ECOG 0 (31/46). TKIs were added upon PD and after a median of 5.8 months (range 2.1-28.1 months) from IO initiation. ORR of IO plus TKI was 15% (7/46; 2 complete responses and 5 partial responses). 16 pts had stable disease, and 13 had PD. Among the 11/46 pts who initially responded to first-line IO, 2 achieved a response with TKI. There were 5 responses among the 35/46 non-responders to first-line IO. TKI-related grade 3-4 adverse events, including liver toxicity, rash, and encephalopathy, led to discontinuation in 7/46 pts. mOS after adding TKI was 9.5 months (95% CI: 6.1-13.7) and mPFS was 5.4 months (95% CI: 3.6-9.7). The mOS and mPFS of adding TKI after PD did not differ between IO initial responders and non-responders. Overall, mOS from IO initiation was 17.6 months (95% CI: 14.5-24.4). Conclusions: Adding a TKI after PD on single agent IO in pts with advanced HCC did not add a signal of clinical benefit compared with reported outcomes from second-line TKIs alone.

Hepatic metastases in gastrointestinal stromal tumors: oncologic outcomes with curative-intent hepatectomy, resection of treatment-resistant disease, and tyrosine kinase inhibitor therapy alone.

Hepatic resection for metastatic GIST (mGIST) is often performed with either curative-intent or for tyrosine kinase inhibitor (TKI)-resistant lesions. The efficacy of hepatectomy for treatment-resistant lesions (TRL) is uncertain. We reviewed patients with liver-mGIST treated from 2003 to 2018. Oncologic outcomes including overall (OS), post-operative progression-free survival (PFS), and post-progression OS were evaluated using Kaplan-Meier and Cox proportional hazards modeling. We identified n=91 patients; 31 (34%) underwent curative-intent hepatectomy, 60 (66%) were initially managed with TKI alone, and 17 (19%) had resection of a TRL. The median follow-up for resected patients was 102 months (range 5-209 months) with 23 (25%) managed with a major hepatectomy. Patients having curative-intent hepatectomy had 72% 10-year OS following diagnosis of liver-mGIST, compared with 58% (P=0.50) for TRL resection and 41% (P=0.01) for non-resected patients. Curative-intent hepatectomy (HR 0.39, P=0.03) and age (HR 1.04, P=0.004) were independently associated with 10-year OS, but not TRL resection. TRL resection was not associated with improved post-progression OS compared to second-line TKI therapy (HR 0.61, P=0.21). Curative-intent hepatectomy is associated with improved OS in liver-mGIST. The oncologic benefit of resecting treatment-resistant liver-mGIST compared to second-line TKI therapy alone remains unclear in the era of multi-line TKI therapy.

Efficacy of second-line ICIs combined with TKIs among patients with metastatic renal cell carcinoma: a real-world study.

Aim: To evaluate the efficacy of immune checkpoint inhibitors (ICIs) plus tyrosine kinase inhibitors (TKIs) as second-line treatment in patients withmetastatic renal cell carcinoma (mRCC). Patients & methods: Baseline and follow-up data from patients withmRCCtreatedwith second-line ICIs plus TKIs or TKIs alone from a single institution were retrospectively gathered. Results: A total of 110 patients were included. The objective response rate was higher among patients treatedwith ICIs plus TKIs than those treatedwith TKIs alone (36.5vs 12.1%;p=0.002). Treatment withICIs plus TKIs was associated with longer progression-free survival(15.0 vs 9.0months;p=0.009) and overall survival (not reachedvs 16.0months;p=0.018) than TKI monotherapy. The survival rates at 2 (83.0vs 74.4%;p=0.426) and 3years (58.1vs 47.5%;p=0.214) between the two groups were not statistically different. Notably, patients with certain clinicopathological features tended to gain more survival benefits with combined therapy. Conclusion: ICIs plus TKIsshowed superior progression-free survival time and tumor response rate over TKIs alone as second-line treatment in patients with mRCC. Future randomized prospective trials are necessary to validate these preliminary findings.

Efficacy of tyrosine kinase inhibitors (TKI) after combination ipilimumab plus nivolumab (I/N) in metastatic clear cell renal cell carcinoma (ccmRCC) patients: Results from the Canadian Kidney Cancer Information System (CKCis).

346 Background: The use of I/N is a proven first-line option for patients with intermediate/poor IMDC prognostic criteria. The use of vascular endothelial growth factor inhibitors such as sunitinib have shown activity in the treatment of ccmRCC, but their effectiveness post I/N needs better characterization. This study aims to demonstrate the efficacy of sunitinib, and other TKI agents post I/N in ccmRCC in a real world setting. Methods: Patients with ccmRCC who had received I/N and were subsequently treated with TKI between Jan 1, 2011 and December 31, 2019 were identified from CKCis. Time to treatment failure (TTF – time from start of first subsequent TKI to discontinuation for any reason) and overall survival (OS) – time from first subsequent TKI to death) were calculated using the Kaplan-Meier method. Cox regression was performed to adjust for IMDC criteria. RECIST criteria was used to determine best overall response (ORR) of TKI radiographically. Results: 64 patients were treated with TKI post I/N. Characteristics and outcomes are listed in the table. Of the second-line TKI patients, 51 received sunitinib, 10 received pazopanib and 3 received other TKI. Reasons for second-line TKI discontinuation are: 28% toxicity, 34% progression, 7% other reasons while 31% remain on treatment. Median follow-up time was 12.9m. ORR for second-line TKI overall and second-line sunitinib was 30.0% and 29.4%, respectively. Conclusions: These data show that TKI are active after I/N in ccmRCC. TTF may underestimate PFS due to the large number of patients discontinuing treatment for toxicity and not progression. Efficacy of second-line TKI post I/N in this dataset is similar that of first-line sunitinib from recent randomized phase III trials, suggesting that there may be no significant loss of TKI activity after having received first-line I/N. Overall, these data support the use of TKI after I/N.[Table: see text]

Efficacy and Safety Results from Ascembl, a Multicenter, Open-Label, Phase 3 Study of Asciminib, a First-in-Class STAMP Inhibitor, Vs Bosutinib in Patients with Chronic Myeloid Leukemia in Chronic Phase after ≥2 Prior Tyrosine Kinase Inhibitors: Update after 48 Weeks

Efficacy and Safety Results from Ascembl, a Multicenter, Open-Label, Phase 3 Study of Asciminib, a First-in-Class STAMP Inhibitor, Vs Bosutinib in Patients with Chronic Myeloid Leukemia in Chronic Phase after ≥2 Prior Tyrosine Kinase Inhibitors: Update after 48 Weeks

Economic Model to Evaluate the Cost-Effectiveness of Second-Line Nilotinib Versus Dasatinib for the Treatment of Philadelphia Chromosome-Positive Chronic Myeloid Leukemia (CML-CP) in Italy.

ObjectiveThe aim of this study was to evaluate the cost effectiveness of second-line nilotinib versus dasatinib for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML-CP) patients who are intolerant or resistant to imatinib and can transition to treatment-free remission (TFR).MethodsA partitioned survival model was developed to compare the cost effectiveness of nilotinib versus dasatinib. The model was developed from the Italian healthcare payer perspective and included the following health states: on second-line tyrosine kinase inhibitor (TKI), off second-line TKI, accelerated phase/blastic crisis, TFR, and death. Progression-free and overall survival curves were derived from patient-level data that compared nilotinib and dasatinib as second-line therapy in CML-CP patients who were resistant or intolerant to imatinib. Drug costs, healthcare costs, and adverse event costs were based on real-world evidence and publicly available databases. Cost effectiveness was estimated over a 40-year time horizon. Scenario analyses were performed by adjusting time horizon, TFR parameters, costs, and utilities.ResultsSecond-line nilotinib resulted in greater time spent in TFR (0.91 life-years), increased quality-adjusted life-years (QALYs) (1.89), increased life-years (2.16), and decreased per-patient costs (− 38,760 €). Therefore, nilotinib was strongly dominant compared with dasatinib in the base-case analysis. Nilotinib remained strongly dominant in most scenario analyses including shorter time horizon, exclusion of TFR, and varying TKI drug costs.ConclusionsWhile the model showed that nilotinib treatment of imatinib-intolerant or resistant CML-CP patients was more effective and less costly than dasatinib treatment, there is considerable uncertainty in the findings.Supplementary InformationThe online version contains supplementary material available at 10.1007/s41669-021-00286-3.

Spectrum of BCR-ABL Mutations and Treatment Outcomes in Ethiopian Imatinib-Resistant Patients With Chronic Myeloid Leukemia.

PURPOSEDespite the successes achieved in chronic myeloid leukemia (CML) with tyrosine kinase inhibitor (TKI) therapy, resistance remains an obstacle. The most common mechanism of resistance is the acquisition of a point mutation in the BCR-ABL kinase domain. Few studies have reported African patients with CML in regard to such mutations. We here report the types of BCR-ABL mutations in Ethiopian imatinib-resistant patients with CML and their outcome.PATIENTS AND METHODSPatients with CML with a diagnosis of imatinib resistance who were tested for BCR-ABL mutation between 2014 and September 2019 were included.RESULTSA total of 962 cases of CML on imatinib therapy were reviewed and 164 cases of failure were found. Of these, only 31 cases (19%) had mutation analysis performed. Most cases (94%) were secondary failures. At the time of CML diagnosis, the median age was 33 years and the majority presented with features of advanced-phase disease. Of the 31 patients, 22 mutations were found (65%). The types of mutations detected were as follows: non–P-loop mutations 36% (11), P-loop mutations 13% (four), and alternatively spliced BCR-ABL variants 23% (seven). The splice variant frequently detected was BCR-ABL35INS (20%). Twenty-six of the 31 patients (84%) were switched to second-line TKIs, whereas in four patients (13%), imatinib dose escalation was done. Overall, the outcome revealed that 16 patients (52%) were alive with complete hematologic response, whereas 12 patients (39%) had died. All patients who expressed BCR-ABL135INS were treated with second-line TKIs, and two of them (33%) had died because of disease progression.CONCLUSIONIn Ethiopia, CML affects the young and point mutations were frequently detected in imatinib-resistant patients. BCR-ABL1 35INS was also prevalent and associated with disease progression.

Treatment Characteristics and Deep Molecular Response in Chronic Phase - Chronic Myeloid Leukemia Patients Treated with Second-Line Nilotinib or Dasatinib: A Multi-Country Retrospective Chart Review Study

BackgroundAchievement of deep molecular response (i.e., MR4.5, BCR-ABL1 ≤0.0032% on international scale, or 4.5-log reduction) is an important goal of tyrosine kinase inhibitor (TKI) treatment for patients (pts) with chronic myeloid leukemia (CML). Pts achieving a sustained MR4.5 are potential candidates for treatment-free remission. However, data on MR4.5 after TKI therapy outside of clinical trial setting are limited, especially in second-line TKI treatment setting.ObjectiveThis study aims to describe pt and treatment characteristics by regions and investigate frequency and time to achieving MR4.5 in pts with chronic phase (CP)-CML treated with second-line nilotinib or dasatinib in 10 countries, categorized into two regions, Europe [France, Germany, Italy, Netherlands]/Australia and Latin America - LATAM [Argentina, Brazil, Chile, Colombia, and Mexico]).MethodsOnline physician panel approach was used to recruit oncologists (N=172) globally to conduct physician-based chart reviews. To increase the representativeness of physician sample, each physician was allowed to review up to four patients, and was instructed to select these pts via randomization scheme. Eligible pts were diagnosed with CP-CML at age ≥18 years, initiated second-line nilotinib or dasatinib between 1/1/11 and 7/1/15, and had ≥12 months of follow-up since initiating the first-line or second-line TKI. A multivariate Fine and Gray's extension of Cox proportional hazards model was used to assess time to first recorded MR4.5 for nilotinib vs dasatinib as second-line therapy. The model accounted for competing-risk event of TKI resistance and random effect of country clustering of data, and was adjusted for age, gender, Sokal risk score at CML diagnosis, prior hydroxyurea use, first-line TKI agent (1st vs 2nd generation TKI), first-line TKI treatment duration, and reasons for first-line TKI discontinuation. Adjusted hazard ratios (HR) and 95% confidence intervals (CI) were reported.ResultsThe study included 285 pts treated with nilotinib (N=138[48%]) or dasatinib (N=147[52%]) as second-line TKI, including 111 nilotinib and 117 dasatinib pts from Europe/Australia (80%), and 27 nilotinib and 30 dasatinib pts from LATAM (20%). Median follow-up time was 19.5 and 18.9 months for nilotinib and dasatinib in both regions, respectively. In Europe/Australia, 85% of pts had received imatinib as first-line TKI, and in LATAM, 96% (Table 1). In Europe/Australia, 85% of pts discontinued first-line TKI due to ineffectiveness (per treating physician) and 16% due to toxicity; corresponding percentages were 79% and 23% in LATAM. Median (range) age at second-line TKI initiation was 58 (18-88) years in Europe/Australia vs 49 (22-77) in LATAM. In Europe/Australia, more second-line nilotinib (21%) than dasatinib (10%) pts had high-risk Sokal score at CML diagnosis. Compared to Europe/Australia, more pts in LATAM had a high-risk Sokal score in both the nilotinib (30%) and dasatinib (27%) cohorts.The raw proportion of pts achieving first recorded MR4.5 by 24 months of second-line TKI therapy was 34% for nilotinib and 31% for dasatinib. After controlling for country clustering effects and baseline covariates, adjusted multivariate Cox model showed that nilotinib was associated with a significantly higher rate of achieving MR4.5 (HR=1.37, 95% CI [1.12, 1.67], p<0.01) than dasatinib. Additionally, high-risk Sokal score was significantly inversely associated with achieving MR4.5 (HR=0.34, 95% CI [0.14, 0.81], p=0.01) while discontinuing first-line TKI due to resistance (HR=0.57, 95% CI [0.30, 1.08], p=0.08) reached borderline statistical significance at the two-sided α-level of <0.10 (Figure 1). MR4.5 outcome will be reported by regions in the presentation.ConclusionThis retrospective chart review study shows some variations in pt and treatment characteristics across regions. A significant percentage of second-line TKI pts can reach MR4.5 after failure to first-line TKI. In addition, this study suggests that second-line nilotinib may be associated with a higher rate of MR4.5 than dasatinib in this setting. Given its retrospective and observational nature, our results should be taken with caution as this study is susceptible to unmeasured confounding and biases. Rigorous clinical assessment in a prospective setting is needed to conclusively compare rates of achieving MR4.5 in ptstreated with nilotinib versus dasatinib. [Display omitted] DisclosuresCortes:ARIAD: Consultancy, Research Funding; Teva: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Sun Pharma: Research Funding; BMS: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Huynh:Novartis Pharmaceuticals Corporation: Research Funding. Mendelson:Novartis Pharmaceuticals Corporation: Employment. Brandt:Novartis Pharmaceuticals Corporation: Employment. Dalal:Novartis Pharmaceuticals Corporation: Employment. Dersarkissian:Novartis Pharmaceuticals Corporation: Research Funding; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding. Cortina:Novartis Pharmaceuticals Corporation: Employment. Narkhede:Novartis Pharmaceuticals Corporation: Research Funding. Duh:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding; Novartis Pharmaceuticals Corporation: Research Funding.

Response and Outcomes of Third-Line Tyrosine Kinase Inhibitor Therapy on Patients with Chronic Phase Chronic Myeloid Leukemia

Response and Outcomes of Third-Line Tyrosine Kinase Inhibitor Therapy on Patients with Chronic Phase Chronic Myeloid Leukemia

Outcomes after Sequential Tyrosine Kinase Inhibitors Treatment in Chronic Phase Chronic Myeloid Leukemia

Introduction: Tyrosine kinase inhibitors (TKIs) made great success in chronic myeloid leukemia (CML) treatment. However, TKIs often need to be changed due to not only adverse events but also suboptimal response or treatment failure. Currently, 5 TKIs, imatinib (IM), dasatinib (DAS), nilotinib (NIL), bosutinib (BOS), and ponatinib (PON) are approved for CML, and the sequential TKI treatment outcomes has not been well studied. Thus, we sought to evaluate outcomes of CP CML in an era where several TKIs are available.Method: Record of CP-CML who were referred to Winship Cancer Center between January 2005 and April 2016 were reviewed. We excluded patients who did not initiate TKI as first-line within 6 months after diagnosis.Results: A total 206 patients were included and followed up median 48.8 (1.4-190.1) months. Clinical characteristics were summarized in table 1. Age at diagnosis was 50 (11-88), and male/female was 105/101. Risk scores was calculated in 110 patients (53.4%), and low/(intermediate)/high of Sokal, Hasford, and EUTOS were 64/27/19, 66/38/6, and 95/15, respectively. Four-teen patients (6.8%) showed additional chromosomal abnormality at initial diagnosis. A total 76 patients (36.9%) were treated with one TKI, 73 (35.4%) were 2 TKIs and rest of them (27.7%), more than 3 TKIs (3 TKIs, n=33; 4 TKIs, n=17; 5 TKIs, n=7). Eight-teen patients (8.7%) reused same TKIs in different treatment lines. IM was the most frequently used in 1st line treatment (n=145, 70.4%), DAS in 2nd line treatment (n=68, 52.3%), NIL in 3rd line treatment (n=21, 32.3%), and PON in 4th and 5th line treatment (n=11, 36.7%, and n=4, 40%), respectively. Reason for switching TKIs or discontinuation included resistant (49.8%), intolerance or adverse event (43.5%), and others (insurance, clinical trial, or reason are not available, 6.7%). ABL domain mutation were tested in 71 (34%) patients, and mutations were detected in 25 patients (35%). Nine patients had more than one mutation, and T315I were detected in 36% of them (n=9).Median 39.0 (3.8-119.8) months after diagnosis, 19 (9.2%) were progressed to advanced phase (AP, n=6; myeloid BC (MBP), n=4; lymphoid BP (LBP), n=9). Eight patients underwent allogeneic HSCT due to TKI failure (n=2), presence of T315I mutation (n=1), persistent neutropenia after imatinib (n=1), and progression to LBP (n=3) and AP (n=1), and 1 did autologous HSCT due to progression to MBP with CSF involvement. Ten patients were expired because of complication of allogenic HSCT (n=3), refractory disease (n=6) and acute myocardial infarction (n=1).Estimated cumulative PFS at 5- and 10-year were 92% and 81%, and OS at 5- and 10-year were 94% and 87% respectively. Fifteen patients of progressed patients were treated with median 1.5 (1-3) more TKIs after disease progression, number of used TKIs for PFS and for OS are not same. According to number of used TKI, PFS rates were not different between groups (Figure 1A, p=0.051), but OS rate were different (Figure 1B, p=0.002). OS at 10 years of 1 TKI was 100% (n=76), 2TKI, 82% (n=73), 3TKIs, 87% (n=33), 4 TKIs, 75% (n=16), and 5TKIs, 55% (n=7), respectively. In univariate analysis, female (p=0.008), ABL kinase mutation (p<0.001), optimal response at 3, 6, and 12 months were related PFS (p<0.001, p=0.002, and 0.037, respectively) (Figure 2 A, C, and E), and Hasford (p<0.001), EUTOS (p=0.047), optimal response at 3 and 6 months (p=0.002 and 0.013) predicted OS. (Figure 2 B and D). Age, race, Sokal score, additional chromosomal abnormality, and 1st line TKI (IM vs newer generation TKIs) did affect neither PFS nor OS.Conclusion: In the era of multiple TKIs, 63% of CP-CML patients were treated more than one TKIs. The best OS was observed in patients tolerating and responding to first and second-line TKI, but OS of 5 TKIs treated patients at 10 years were still 55%, showing potential for long term survival. PFS and OS can be predicted by early molecular response. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Cytogenetic and Molecular Responses after 2 Years of Tyrosine Kinase Inhibitor (TKI) Treatment in Simplicity, an Observational Study of Chronic-Phase Chronic Myeloid Leukemia (CP-CML) Patients (Pts) in Routine Clinical Practice

Abstract Introduction: Data on clinical response and factors associated with response in CP-CML outside clinical trials are limited.SIMPLICITY (NCT01244750) is an ongoing observational study of CP-CML pts in routine clinical practice receiving first-line (1L) imatinib (IM), dasatinib (DAS) or nilotinib (NIL) in the US and Europe. This analysis aims to describe the factors associated with achievement of complete CyR (CCyR) and major MR (MMR). Methods: Clinical response after start of 1L TKI was assessed by CyR (karyotype or FISH) and MR (only tests by PCR on the international scale were included) as determined by the treating physician. Proportions of patients achieving CCyR and MMR between 30 days and either 12 or 24 months (mos) are presented; data at specified time points will be provided at presentation. Logistic regression models were used to identify factors associated with CCyR and MMR by 12 and 24 mos after 1L TKI initiation. Results: By March 03 2017, 1242 pts were enrolled prospectively in SIMPLICITY, receiving IM (n=416), DAS (n=418) or NIL (n=408); 55% were male. The median (interquartile range; min-max) age of pts at initiation of 1L TKI was 57 (46-68; 18-91) years; 35% of pts were treated in Europe, 65% in the US; 53% at academic centers and 47% at community practices. Numbers of pts followed by 3, 6, 12 and 24 months were 1233, 1224, 1195 and 1121, respectively. Of pts followed 12% (n=151), 31% (n=384), 44% (n=522) and 51% (n=567) had documented CyR testing by 3, 6, 12 and 24 mos; 23% (n=285), 55% (n=672), 72% (n=857) and 84% (n=937) of pts had documented MR testing by 3, 6, 12 and 24 mos; and 7% (n=82), 19% (n=231), 32% (n=379) and 42% (n=475) of pts had documented testing by both CyR and MR by 3, 6, 12 and 24 mos. Proportions of pts remaining on their 1L TKI declined with duration of follow-up. Of pts with documented CyR testing, 93% (n=141), 93% (n=356), 89% (n=464) and 85% (n=484) had remained on their 1L TKI by 3, 6, 12 and 24 mos, respectively. Of pts with documented MR testing, 93% (n=266), 91% (n=610), 85% (n=728) and 78% (n=730) had remained on their 1L TKI by 3, 6, 12 and 24 mos, respectively. In this non-controlled study, proportions of pts achieving CCyR were similar for pts tested by 12 and by 24 mos. For both periods, the proportion of pts achieving CCyR was highest for pts on 1L DAS, lower for 1L NIL, and lowest for 1L IM. Proportions of pts achieving MMR were higher for pts tested by 24 mos than by 12 mos. For both periods, the proportion of pts achieving MMR was highest for pts on 1L NIL, lower for 1L DAS, and lowest for 1L IM. Proportions were lower when calculated among pts followed through the period but not necessarily tested (intention-to-treat). Multivariate logistic regression analysis identified factors associated with MMR or CCyR by 12 and 24 mos after 1L TKI initiation. Receiving a second-generation (2G) TKI (i.e. DAS or NIL) as 1L therapy was associated with CCyR by 12 mos (odds ratio [OR]=2.6; p Conclusions: Response monitoring observed in clinical practice is not aligned with ELN/NCCN guidelines, so outcomes for the full SIMPLICITY cohort may differ from presented data on monitored patients. The lack of correlation between a 2G TKI as 1L therapy and achievement of MMR is unexpected, but may result from switches to 2L TKI in IM suboptimal responders or from differences in testing patterns in the individual cohorts; the uncontrolled nature of this study may have also contributed. Early switching of TKI treatment (previously found to be driven by toxicity, not response, and often from IM to 2G TKI) was associated with achieving MMR or CCyR by 12 mos. Not switching TKI, potentially a marker of better tolerance and adherence, was associated with achieving MMR or CCyR by 12 mos and 24 mos. Download : Download high-res image (116KB) Download : Download full-size image Figure . Disclosures Cortes: Teva: Research Funding; ARIAD: Consultancy, Research Funding; Sun Pharma: Research Funding; ImmunoGen: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Goldberg: Bristol Myers Squibb: Research Funding, Speakers Bureau; Pfizer: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; Jazz: Speakers Bureau; Ariad: Speakers Bureau; Celgene: Speakers Bureau; COTA: Employment, Equity Ownership. Hehlmann: Novartis: Research Funding; BMS: Consultancy. Mauro: Bristol-Myers Squibb: Consultancy. Zyczynski: Bristol-Myers Squibb: Employment. Sen: ICON Clinical Research: Employment. Foreman: ICON Clinical Research: Employment. Gajavelli: Bristol-Myers Squibb: Employment. Gambacorti-Passerini: BMS: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding.

Second-line tyrosine kinase inhibitors (TKIs) versus immunotherapy (IO) for advanced hepatocellular carcinoma (HCC): Real-world efficacy and safety analysis in patients with varying liver dysfunction.

271 Background: Within the last 4 years, the FDA approved five drugs as second-line therapies for advanced HCC. At our cancer center, the majority of our patients are Hispanic with varying liver dysfunction, and this real world population is not represented in registration trials of TKIs and IOs. Therefore, we analyzed survival and toxicities among second-line therapies for HCC at our Hispanic-majority NCI-designated cancer center. Methods: Retrospective analysis of patients with advanced HCC diagnosed at Mays Cancer Center from 1/2015-3/2019 who received second-line therapies, including IO (i.e. nivolumab), TKIs (i.e. cabozantinib, regorafenib), or hospice/best supportive care (BSC). Progression-free survival (PFS) was determined using Kaplan-Meier method, and hazard ratios estimated with Cox proportional hazards model. AEs according to Common Terminology Criteria for AEs v5.0 were analyzed with Fisher’s exact test. Results: Of the patients receiving first-line therapy, the median age was 60 years (n=65), and patients were 75% (n=49) Hispanics. 58 (89%) patients went onto receive second-line therapy. Child-Pugh (CP) score: A 17%, B 55%, C 28%. Median PFS was 3.1 months with TKI (n=6), 3.3 months with IO (n=27), and 1.3 months with BSC (n=25) (Table). There was improved survival with IO when compared to BSC (HR=3.26; 95% CI: 1.58-6.72; p=0.00136). There was no significant difference when comparing IO to TKI (HR=0.94; 95% CI: 0.31-2.86; p=0.92), but a trend to improved PFS with TKI when compared to BSC (HR=3.08; 95% CI: 0.96-9.84; p=0.06). TKI group had significantly more rash (p=0.01) and hand-foot syndrome (HFS) (p&lt;0.001) compared to IO and BSC. All other AEs demonstrated no significant difference between groups (Table). Conclusions: In our Hispanic-majority cohort, patients with varying liver dysfunction, including CP B &amp; C cirrhosis, were more likely to receive IO or BSC. Both second-line treatment groups (IO or TKI) had increased mPFS compared to BSC. Both IO and TKI groups were tolerable compared to BSC, with expected toxicity per class of drug. More prospective studies comparing second-line agents should be done in patients with varying liver dysfunction to understand survival, tolerability, and quality of life. [Table: see text]