Treatment completion and toxicity of trastuzumab or trastuzumab + lapatinib in older patients (pts): BIG 2-06; NCCTG N063D (Alliance).

11553 Background: Little is known about the toxicity of trastuzumab (T) or of trastuzumab + lapatinib (T + L), approved in the advanced setting, in older pts. We have performed a sub-analysis of the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) trial focused on treatment completion and toxicity of T and T+L in older pts (aged ≥65 years (yr)). Methods: The ALTTO trial (NCT00490139, NCCTG N063D) randomised 8381 pts with early HER2+ BC into 4 arms and we included the T and T+L arms in our analysis. Eligible pts for our study were those having received at least one dose of assigned treatment. Treatment completion was evaluated through the rate of temporary treatment interruptions (TTI), permanent treatment discontinuations (PTD) and lapatinib dose reductions (LDR). Toxicity was evaluated via a selected set of adverse events of interest (AEIs). Risk factors for TTI, PTD, LDR and AEIs were assessed, including comorbidities and polypharmacy at baseline (defined as use 5 or more co-medications) and AEIs during treatment. Results: A total of 430 pts≥65-year-old were identified for this sub-analysis, out of a total of 4190 pts with a median age of 68 yrs (range 65-80). Older pts were more likely to have comorbidities (70% vs 38%). Treatment completion was worse among older pts in the T+L arm but not in the T arm (Table). AEIs were more common in the T+L arm in all patients, with older patients having higher AEI rates (78.04% in older vs 63.38% in younger), particularly diarrhea (60.75% vs 38.0%). Identified risk factors (multivariate) for worse treatment completion in the T and T+ L arms included concomitant use of chemotherapy and the occurrence of grade 3 adverse events, among others. Conclusions: T + L has worse treatment completion and is more toxic in older patients, while T was well tolerated. Identifiable risk factors at baseline and during the course of treatment could be used to aid in regimen selection and management for both T and T + L in their respective indications. Support: UG1CA189823, Novartis;https://acknowledgments.alliancefound.org. [Table: see text]

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Outcomes based on age in the phase 3 METEOR trial of cabozantinib (cabo) vs everolimus (eve) in patients with advanced renal cell carcinoma (RCC).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.4578 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 4578-4578 ◽

Cited By ~ 1

Author(s):

Frede Donskov ◽

Robert J. Motzer ◽

Eric Voog ◽

Elizabeth J. Hovey ◽

Carsten Grüllich ◽

...

Keyword(s):

Adverse Events ◽

Older Patients ◽

Objective Response ◽

Age Groups ◽

Progression Free Survival ◽

Phase 3 ◽

Free Survival ◽

Previously Treated ◽

Grade 3 ◽

Dose Reductions

4578 Background: The incidence of RCC increases with age with the highest incidence at ~75 years of age (Znaor, Eur Urol 2015). The Phase 3 METEOR trial (NCT01865747) showed a significant improvement in progression-free survival (PFS; HR 0.58, 95% CI 0.45–0.74; P < 0.0001), overall survival (OS; HR 0.66, 95% CI 0.53–0.83, P = 0.0003), and objective response rate (ORR; 17% vs 3%; P < 0.0001) for cabo compared with eve in patients with advanced RCC previously treated with VEGFR TKIs (Choueiri, NEJM 2015, Lancet Oncol 2016). Here we present outcomes by 3 categories of age for the METEOR trial. Methods: 658 patients were randomized 1:1 to cabo (60 mg qd) or eve (10 mg qd). Stratification factors were MSKCC risk group and number of prior VEGFR TKIs. Endpoints included PFS, OS, and ORR. Subgroup analyses by age ( < 65, 65 to 74, and ≥75 years) are presented. Results: At baseline, 60% of patients were < 65 years old, 31% were 65 to 74 years old, and 10% were ≥75 years old. Subgroups by age generally had similar baseline characteristics in both arms. The HRs for PFS favored cabo for all age groups (HR 0.53, 95% CI 0.41–0.68 for < 65 years old; 0.53, 95% CI 0.37–0.77 for 65 to 74 years old; and 0.38, 95% CI 0.18–0.79 for ≥75 years old). ORR per independent radiology committee for cabo vs eve was 15% vs 5% for < 65 years old, 21% vs 2% for 65 to 74 years old, and 19% vs 0% for ≥75 years old. HRs for OS also favored cabo (HR 0.72, 95% CI 0.54–0.95 for < 65 years old; 0.66, 95% CI 0.44–0.99 for 65 to 74 years old; and 0.57, 95% CI 0.28–1.14 for ≥75 years old). Median OS for cabo vs eve was 21.4 mo vs 17.1 mo for < 65 years old, not reached vs 18.0 mo for 65 to 74 years old, and 18.4 mo vs 14.0 mo for ≥75 years old. Older patients more frequently had dose reductions (60% with cabo and 22% with eve for < 65 years old vs 85% with cabo and 36% with eve for ≥75 years old). Grade 3 or 4 adverse events were generally consistent with the safety profiles in the overall population although some events such as fatigue and hypertension occurred at a higher rate in older patients. Conclusions: Treatment with cabo improved PFS, ORR, and OS compared with eve in patients with advanced RCC irrespective of age. Adverse events in older patients were more frequently managed with dose reductions. Clinical trial information: NCT01865747.

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European Post-Approval Safety Study (PASS) of Relapsed/Refractory Multiple Myeloma (RRMM): Safety, Including SPM, in a Large Cohort of Patients Treated with Lenalidomide, Thalidomide, and Bortezomib

Blood ◽

10.1182/blood.v128.22.3331.3331 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3331-3331

Author(s):

Barbara Gamberi ◽

Miguel Hernandez ◽

Christian Berthou ◽

Eleni Tholouli ◽

Elena Zamagni ◽

...

Keyword(s):

Adverse Events ◽

Board Of Directors ◽

Research Funding ◽

Performance Status ◽

Treatment Discontinuation ◽

Second Primary ◽

Advisory Committees ◽

Grade 3 ◽

Noninterventional Study ◽

Dose Reductions

Abstract Background: EU PASS is an observational, noninterventional study designed to investigate the safety of lenalidomide (LEN) and other agents in the treatment of RRMM in a real-world setting. Aims:To assess the incidence of adverse events (AEs) of special interest, including neutropenia, thrombocytopenia, venous thromboembolism (VTE), peripheral neuropathy (PN), and second primary malignancies (SPMs) in RRMM patients (pts) treated with LEN and other antimyeloma therapies according to current clinical practice. Methods: Pts with RRMM who were commencing LEN treatment were enrolled at the investigator's discretion into a LEN cohort (LEN + dexamethasone, the approved combination for the treatment of RRMM); pts who received ≥ 1 prior therapy and were commencing a non-LEN-based therapy were enrolled into a background cohort (all other treatments, including novel agents). Thromboprophylaxis was per local standard practice. AEs were graded according to National Cancer Institute-Common Terminology Criteria for Adverse Events (version 3). SPMs were defined using Medical Dictionary for Regulatory Activities (MedDRA) terms under the category Neoplasms SOC. Following protocol amendment in 2011, assessments for SPMs were to be conducted up to 36 mos after treatment discontinuation. Results: As of June 2016, 3632 pts across 269 institutions in 17 European countries were included in the safety population. Of those, 59.2% received LEN (n = 2151), 32.7% received bortezomib (BORT; n = 1188), 3.8% received thalidomide (THAL; n = 137), and 4.3% received other therapies (n = 156). The majority of pts had discontinued from treatment (97.9%; n = 3556); of the 2.1% (n = 76) ongoing pts, 66 are treated with LEN, 6 with BORT, 0 with THAL, and 4 with other substances. Baseline characteristics were similar across the cohorts. Median age was 70 yrs (range, 25-95 yrs) and 54.0% were male. Of 2985 pts with available ECOG data, 2865 (96.0%) had good performance status (ECOG score 0-2), and the remaining 4.0% had an ECOG score of 3/4. The median number of prior therapies was 1 (range, 1-6) but was higher in the LEN cohort (2; range, 1-6) than in the BORT (1; range, 1-6) and THAL (1; range, 1-5) cohorts; the proportion of pts with only 1 prior treatment was also lower in the LEN cohort (44.3%), whereas BORT was 70.8% and THAL 56.2%. Overall, 50.7% of pts (n = 1842) had grade 3/4 AEs. Grade 3/4 neutropenia occurred in 17.1%, 3.5%, and 4.4% of pts in the LEN, BORT, and THAL cohorts, respectively, and grade 3/4 thrombocytopenia in 9.2%, 7.3%, and 3.6%. The incidence rate of SPM was 3.63 per 100 pt-yrs, with 3.18 per 100 pt-yrs in the LEN cohort, 5.23 per 100 pt-yrs in the BORT cohort, 2.73 per 100 pt-yrs in THAL, and 6.48 per 100 pt-yrs in others. AEs of interest of all grades are listed in Table 1. The median duration on study treatment was 6.6 mos (range, 0.1-81.6 mos) for LEN, 4.1 mos (range, 0-63.6 mos) for BORT, and 4.6 mos (range, 0.2-36.9 mos) for THAL. Treatment discontinuation rate due to AEs was similar in each cohort (22.1% in the LEN, 20.0% in the BORT, and 21.2% in the THAL cohorts). In the LEN cohort, dose reductions occurred in 38.1% of pts, with a median time to first dose reduction due to AEs of 12.4 weeks. Treatment-emergent adverse events leading to dose reductions were similar across cohorts, with 23.7% in the LEN cohort, 21.4% in the BORT cohort, and 17.5% in the THAL cohort. Conclusions: Results of this noninterventional study in RRMM show that AEs were similar across cohorts except for higher rates of neutropenia and lower rates of PN with LEN compared with THAL or BORT. Higher rates of neutropenia did not translate into increased febrile neutropenia. Infections, independent from neutrophil counts, occurred in all cohorts, but few pts developed serious infections such as pneumonia. VTEs as well as myocardial infarctions were low throughout all cohorts. The occurrence of SPMs was generally low and comparable between cohorts. LEN was generally well tolerated. Disclosures Tholouli: Johnson and Johnson: Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Celgene: Honoraria; MSD: Speakers Bureau; Giles: Speakers Bureau. Hájek:Janssen: Honoraria; Takeda: Consultancy; BMS: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding. Minnema:Celgene: Consultancy; BMS: Consultancy; Amgen: Consultancy; Jansen Cilag: Consultancy. Dimopoulos:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genesis: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Frost Andersen:Celgene: Research Funding. Waage:Amgen: Speakers Bureau; Celgene: Consultancy, Honoraria; Novartis, Amgen, Celgene: Membership on an entity's Board of Directors or advisory committees. Crotty:BMS, Takeda, Novartis, Janssen, Roche: Honoraria. Kueenburg:Celgene International Sarl: Consultancy, Honoraria. Di Micco:Celgene: Employment. Bacon:Celgene: Employment, Equity Ownership.

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Effect of lenalidomide (LEN) on biochemical responses and clinical benefit (CB) as a single agent in chemotherapy-naive castration-resistant prostate cancer (CRPC).

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.5_suppl.128 ◽

2012 ◽

Vol 30 (5_suppl) ◽

pp. 128-128 ◽

Cited By ~ 1

Author(s):

Chadi Nabhan ◽

Anand Patel ◽

Dana Villines ◽

Kathy Tolzien ◽

Susan K. Kelby ◽

...

Keyword(s):

Adverse Events ◽

Clinical Benefit ◽

Single Agent ◽

Complete Response ◽

Median Number ◽

Castration Resistant Prostate Cancer ◽

Serious Adverse Events ◽

Biochemical Responses ◽

Grade 3 ◽

Dose Reductions

128 Background: LEN has anti-angiogenesis and immunomodulatory properties making it ideal to investigate in CRPC. We report on a phase II study investigating LEN in chemotherapy-naïve CRPC patients (pts) Methods: Eligible pts received LEN at 25 mg daily on days 1 – 21 every 28-days until progression. Daily aspirin or coumadin were required. Responses were assessed every 2 cycles. Toxicity was assessed every cycle. Primary end point: The CB of LEN [Sum of complete response (CR), partial response (PR) and stable disease (SD)]. Secondary end points: Toxicity, time to radiographic and PSA progression (TTP and TTP-PSA), time to next treatment (TTNT), overall survival (OS), and LEN’s impact on quality of life (QOL). Results: 31 pts were enrolled; 27 response-evaluable (1 withdrew consent, 3 off per choice after adverse events). Median age is 74 (range 58-89) with 24 (77%) having Gleason ≥ 7 disease. Median PSA is 66 (2.1-918.6). Six pts (19%) had liver/lung involvement. Fourteen pts (51%) showed biochemical response with 4 (15%) having >50% PSA drop. TTP-PSA is 4 months (2-11). No radiographic responses seen but 17 pts had SD for a median of 4 months (2-16) (CB=55%). Median number of LEN cycles was 3 (2-15). With a median follow-up of 18 months (5-38), 17 patients (55%) remain alive; median OS of 18 months. Grade 3/4 hematologic toxicities were most common (neutropenia 41%, leukopenia 12%, anemia 9%, thrombocytopenia 9%). Other grade 3/4 toxicities: venothromboembolism, atrial fibrillation, and dehydration (6% each). Serious adverse events (SAEs) were witnessed in 10 pts (32%) with only 1 (3%, rash) definitely related to LEN. Others were not related or possibly related. Of 27 pts, 7 (26%) had a dose reduction and 2 (7%) required two dose reductions. Dose reductions occurred after cycle 3. QOL scales suggested no adverse impact. Median TTNT is 2 months (9 pts received chemotherapy, 10 pts went onto studies, 3 pts received hormonal therapies, 4 pts received radiation, 3 pts had no therapy yet, and 2 pts remain on LEN). Conclusions: LEN is active as monotherapy in CRPC. Biochemical responses are witnessed and clinical benefit is observed. Myelosuppression is the most common toxicity.

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Immune checkpoint inhibitor induced hepatitis: Risk factors, outcomes, and impact on survival.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e14525 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e14525-e14525

Author(s):

Abdul Miah ◽

Songzhu Zhao ◽

Sandip H. Patel ◽

Andrew Johns ◽

Madison Grogan ◽

...

Keyword(s):

Risk Factors ◽

Adverse Events ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Checkpoint Inhibitors ◽

Comprehensive Cancer Center ◽

Rank Test ◽

Cancer Center ◽

Grade 3

e14525 Background: Immune checkpoint inhibitors (ICIs) have improved the survival of patients with multiple cancer types, however ICI treatment is associated with a unique set of immune-related adverse events (irAEs) that can affect any organ. Few studies have evaluated the risk factors and outcomes of ICI induced hepatitis (ICIH). Methods: We utilized an institutional database of patients with advanced cancers treated with ICI between 2011 and 2017 at The OSU Comprehensive Cancer Center to identify patients with ICIH. Any patient who received at least one dose of ICI alone or in combination with other systemic therapies either as part of clinical trial or standard of care were included. Clinical data were extracted through chart abstraction. irAEs were graded using the Common Terminology Criteria for Adverse Events v5. Overall survival (OS) was calculated from the date of ICI initiation to death from any cause or the date of the last follow-up. OS with 95% confidence intervals were estimated using the Kaplan–Meier method. OS was also evaluated by occurrence of ICIH using the log-rank test. Results: We identified 1,096 patients treated with at least one dose of ICI. Most common cancers included lung (n=224, 20%) and melanoma (n=342, 31%). The most common ICIs were PD1/L1 (n=774, 71%) and CTLA-4 inhibitors (n=195, 18%). ICIH of any grade occurred in 64 (6%) patients. Overall, 46 (71%) were male and median age was 60 years. Severity of hepatitis was grade 1-2 in 30 patients (47%) (Table 1). The incidence of ≥grade 3 ICIH in the entire cohort was 3.1%. Median time to ICIH diagnosis was 63 days. ICIH occurred alone in 24 patients, and co-occurred with other irAEs in 40 patients. The most common co-occurring irAEs were pneumonitis (n=7); colitis (n=15), thyroid abnormality (n=14); and dermatitis (n=15). ICIH was more common in women (p=0.038), in patients treated with combination ICIs (p<0.001), and among patients receiving first line therapy (p=0.018). Patients who developed ICIH had significantly longer OS than patients who did not develop ICIH; there was no difference in OS between patients with ≥grade 3 ICIH vs grade 1-2 (Table). 33 out of 34 patients with ≥grade3 ICIH were treated with steroids; 3 received mycophenolate and one received infliximab. Of patients with ≥grade 3 ICIH, 11 resumed ICI therapy without recurrent ICIH. Conclusions: Female sex, combination immunotherapy, and line of therapy were associated with ICIH. Patients with ICIH had improved clinical outcomes compared to those that did not develop ICIH, even those with higher grade toxicity. Further study is needed to assist in developing risk stratification models and optimal treatment for ICIH. OS of patients with and without immune checkpoint inhibitor hepatitis.[Table: see text]

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Dermatologic adverse events of brentuximab vedotin: Characteristics, management, and their relationship with dose regimen.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.3049 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 3049-3049

Author(s):

Yuna Oh ◽

Alexander Bang ◽

Nicholas Kurtansky ◽

Niloufer Khan ◽

Melissa Pulitzer ◽

...

Keyword(s):

T Cell ◽

Adverse Events ◽

Dose Regimen ◽

Management Strategies ◽

Brentuximab Vedotin ◽

Single Cycle ◽

Treatment Interruptions ◽

Grade 3 ◽

Dermatologic Adverse Events ◽

Dose Dependent

3049 Background: Owing to its high efficacy and tolerability, brentuximab vedotin (BV) is increasingly being favored over other aggressive systemic therapies for the treatment of various CD30+ Hodgkin and non-Hodgkin lymphomas, including peripheral T-cell lymphoma and cutaneous T-cell lymphomas. Dermatologic adverse events (dAE) are one of the most common toxicities associated with BV but data regarding their characteristics including correlation to dose, time to occurrence, and management is scarce. We aim to describe the clinical and pathologic characteristics of dAEs associated with BV, their relationship with administered dose regimen, and available management strategies. Methods: An IRB-approved retrospective analysis was conducted for all patients who had received at least one cycle of BV from Memorial Sloan Kettering Cancer Center in 2009-2020. Logistic regression, χ2, student’s t-test were performed for univariate analyses. Kaplan-Meier survival and multivariate Cox proportional hazard model evaluated dAE occurrence stratified by 5 major dose regimens (single cycle, 1.2mg q1w, 1.2mg q2w, 1.2mg q3w, 1.8mg q3w). Results: Of 611 patients, 201 experienced dAE with median time-to-event of 24 days and 29% experiencing > 1 dAEs. Rash was the most common (62%; 142/230), followed by alopecia (20%) and xerosis (13%). For rash, 50% reported involvement of only the extremities and/or acral sites compared to 25% who had generalized rash. Of those reported (111), 68 patients had grade 1 dAE (61%), 38 grade 2 (34%), and 5 grade 3 (5%)-all grade 3 were rash (maculopapular/morbilliform). 14 cases (7%) resulted in treatment interruptions and 6 in discontinuations due to dAEs (3%). Pathology were often nonspecific consistent with a hypersensitivity reaction: spongiotic/psoriasiform dermatitis with perivascular lymphocytic infiltrates . Patients undergoing weekly regimen were at a statistically and clinically significantly higher risk of dAE during the first 100 days of BV treatment (p = 0.001). Between the two most frequently administered dose regimens (1.8mg vs. 1.2mg, q3w), the higher dose carried 105% higher risk for dAE (HR: 2.047, p = 0.053). Those who had received a single cycle of BV had the lowest risk compared to all other regimen (1/42, p = 0.001). Topical and/or systemic steroids were most frequently prescribed (43%) with 12% of patients requiring systemic steroids. Other treatments varied ranging from antihistamines to moisturizers. Conclusions: Understanding of the detailed characteristics, management strategies, dose-dependent effects associated with BV is critical to provide clinical guidance for primary providers and minimize treatment interruptions or discontinuations. The results overall suggest that the risk for dAEs is dose-dependent with those undergoing frequent dosing regimens having a greater risk, although most dAEs remain mild or low-grade.

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Incidence of Vascular Thrombotic Events in 183 Consecutive Patients Treated with Nilotinib: A Single Centre Experience

Blood ◽

10.1182/blood.v124.21.3147.3147 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3147-3147 ◽

Cited By ~ 1

Author(s):

James Gilbert ◽

Simona Deplano ◽

Richard Szydlo ◽

Renuka Palanicawandar ◽

Gareth Gerrard ◽

...

Keyword(s):

Risk Factors ◽

Cardiovascular Risk ◽

Side Effects ◽

Adverse Events ◽

Cardiovascular Risk Factors ◽

Board Of Directors ◽

Older Patients ◽

Research Funding ◽

Kinase Inhibitors ◽

Advisory Committees

Abstract Introduction The spectrum of adverse events occurring in nilotinib is broadly similar to that of other tyrosine kinase inhibitors but recent reports suggest an increase in the incidence of vascular thrombotic events (VTE) compared to imatinib. Many patients treated with ponatinib, where the association of VTE with treatment is now widely accepted, have previously received nilotinib and it remains unclear as to whether the adverse events are a result of the cumulative use of the two drugs. It is important to clearly delineate the risk of VTE with nilotinib in order to estimate risk and provide better information for patients. Methods We conducted a chart review to identify adverse events in 183 consecutive patients who received nilotinib in our institution from February 2006 until June 2014. Patients were to be considered at risk of side effects in they had received at least 24 hours of treatment. Data were collected from out-patient consultations in which side effects and their severity were self-reported and recorded in the medical case notes. The cohort contained 93 women and 90 men and had a median age of 56 years (range 21-93). 8% of patients received nilotinib as first line therapy: 46% and 39% respectively were treated after failure of imatinib only or imatinib and dasatinib . The remainder were treated for relapse post allogeneic transplant. Of those who were treated after one or two prior tyrosine kinase inhibitors (TKI), 57% and 43% were intolerant or resistant respectively. Results The median duration of treatment with nilotinib was 714 days (range 10 -2816 days). Information was available for pre-existing cardiovascular risk factors in 93% of patients and were present in 59%. We recorded 20 occurrences of VTE in 10% of patients with 9 (5%), 7 (4%) and 4 (2%) episodes of myocardial ischaemia, peripheral arterial occlusive disease and cerebrovascular disease respectively. Only one patient without pre-existing cardiovascular risk factors experienced a VTE, The median age of patients with VTE was 67 years (range 35-79) compared to 55 years (range 21-93) in those without VTE. In contrast to previously reported results VTE were more common (18%) in patients who had received two prior TKI compared to 8% in those who had been treated with a single TKI and 7% who received nilotinib upfront. 75% of VTE occurred in patients who have been treated with nilotinib for more than 2 years but this may in part be because of continuation of treatment at a time of lack of awareness of the association of nilotinib with VTE. The remaining adverse events reported on nilotinib were in accordance with published data. Side effects occurring in >10% of patients are given in the table. Conclusions The incidence of VTE in patients treated with nilotinib in our institution was 10%. VTE was more frequent in older patients, in those with pre-existing cardiovascular risk factors and in those who received prolonged therapy with nilotinib. Without a suitable control group matched for age and cardiovascular risk factors it is difficult to provide an accurate estimate of any potential increased risk of treatment with nilotinib. Nevertheless caution must be exercised in older patients with pre-existing risks for VTE and appropriate counselling and monitoring provided. Table 1Adverse eventIncidence (%)Rash and/or pruritus43Fatigue31Elevated transaminases21Myalgia18Abdominal pain17Headaches17Arthralgia16Nausea14Thrombocytopenia12Neutropenia12Anaemia7 Disclosures Gerrard: Novartis: Research Funding. Foroni:Novartis: Research Funding. Apperley:Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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SAT0157 NINTEDANIB DOSE ADJUSTMENTS AND ADVERSE EVENTS IN PATIENTS WITH PROGRESSIVE AUTOIMMUNE DISEASE-RELATED INTERSTITIAL LUNG DISEASES IN THE INBUILD TRIAL

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.2322 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1019.1-1019

Author(s):

E. Volkmann ◽

I. Castellví ◽

S. Johnson ◽

E. Matteson ◽

J. Distler ◽

...

Keyword(s):

Placebo Group ◽

Autoimmune Disease ◽

Adverse Events ◽

Dose Reduction ◽

Treatment Interruption ◽

Treatment Discontinuation ◽

Research Support ◽

Treatment Interruptions ◽

Trial Drug ◽

Dose Reductions

Background:In the INBUILD trial in patients with progressive fibrosing ILDs, the adverse event (AE) profile of nintedanib was characterised predominantly by gastrointestinal AEs. Dose adjustments were used to manage AEs.Objectives:Assess AEs and dose adjustments in patients with autoimmune disease-related ILDs in the INBUILD trial.Methods:Patients with progressive fibrosing ILDs other than idiopathic pulmonary fibrosis were randomised to nintedanib 150 mg bid or placebo. Dose reductions to 100 mg bid and treatment interruptions were permitted to manage AEs. AEs over 52 weeks of treatment (or 28 days after last trial drug intake for patients who discontinued drug before week 52) were assessed in patients who received ≥1 dose of trial drug.Results:Of 663 patients in the INBUILD trial, 170 (82 nintedanib, 88 placebo) had autoimmune disease-related ILDs (89 RA-ILD, 39 SSc-ILD, 19 MCTD-ILD, 23 other autoimmune ILDs). In the nintedanib and placebo groups of patients with autoimmune disease-related ILDs, respectively, over 52 weeks, the proportions of patients with ≥1 dose reduction were 28.0% and 3.4%, with ≥1 treatment interruption were 31.7% and 10.2%, and with ≥1 dose reduction and/or treatment interruption were 40.2% and 12.5% (Table). Dose intensity (amount of drug administered divided by amount that would have been received had 150 mg bid been administered over 52 weeks or until permanent treatment discontinuation) was >90% in 80.5% of patients in the nintedanib group and 95.5% in the placebo group. AEs led to permanent treatment discontinuation in 17.1% and 10.2% of patients treated with nintedanib and placebo, respectively. Diarrhoea was the most common AE, reported in 63.4% and 27.3% of patients in the nintedanib and placebo groups, respectively. Diarrhoea AEs led to dose reduction, treatment interruption and permanent treatment discontinuation in 7.3%, 9.8% and 4.9% of patients in the nintedanib group, compared with 0%, 1.1% and 1.1% of patients in the placebo group, respectively. Of the nintedanib-treated patients who experienced ≥1 diarrhoea AE, 80.8% experienced 1 or 2 events and 76.9% experienced events that were mild at worst (Common Terminology Criteria for Adverse Events [CTCAE] grade 1).Conclusion:In the INBUILD trial, management of AEs via dose adjustments enabled most patients with autoimmune disease-related ILDs to remain on treatment for 52 weeks. Diarrhoea was the AE that most commonly led to dose adjustment.TableNintedanib(n=82)Placebo (n=88)Patients with ≥1 dose reduction or treatment interruption33 (40.2)11 (12.5)Patients with ≥1 dose reduction23 (28.0)3 (3.4)Total number of dose reductions253Patients with ≥1 dose re-escalation after dose reduction5 (6.1)2 (2.3)Patients with ≥1 treatment interruption26 (31.7)9 (10.2)Total number of treatment interruptions3211Total duration of treatment interruptions, days, mean (SD)20.1 (15.1)19.3 (20.7)Data are n (%) of patients unless otherwise indicated.Disclosure of Interests:Elizabeth Volkmann Grant/research support from: Forbius, Corbus Pharmaceuticals, Consultant of: Boehringer Ingelheim, Forbius, Speakers bureau: Boehringer Ingelheim, Ivan Castellví Consultant of: Boehringer Ingelheim, Actelion, Kern Pharma, Speakers bureau: Boehringer Ingelheim, Actelion, Bristol-Myers Squibb, Roche, Sindhu Johnson Grant/research support from: Boehringer Ingelheim, Corbus Pharmaceuticals, GlaxoSmithKline, Roche, Merck, Bayer, Consultant of: Boehringer Ingelheim, Ikaria, Eric Matteson Grant/research support from: Pfizer, Consultant of: Boehringer Ingelheim, Gilead, TympoBio, Arena Pharmaceuticals, Speakers bureau: Simply Speaking, Jörg Distler Grant/research support from: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Paid instructor for: Boehringer Ingelheim, Speakers bureau: Boehringer Ingelheim, James Seibold Shareholder of: BriaCell, Pacific Therapeutics, Consultant of: Atlantic, Blade Therapeutics, Eicos Sciences, Eiger Biopharmaceuticals, Indalo Therapeutics, Mitsubishi Tanabe Pharma, Bayer, Xenikos, Boehringer Ingelheim, Camurus, Corbus Pharmaceuticals, EMD Serono, Speakers bureau: Boehringer Ingelheim, Ulrich Costabel Consultant of: Boehringer Ingelheim, Roche, Fibrogen, Global Blood Therapeutics, Speakers bureau: Boehringer Ingelheim, Roche, AstraZeneca, Alexandra James Employee of: Employee of Boehringer Ingelheim, Carl Coeck Employee of: Employee of Boehringer Ingelheim, Manuel Quaresma Employee of: Employee of Boehringer Ingelheim, Vincent Cottin Grant/research support from: Boehringer Ingelheim, Roche, Consultant of: Boehringer Ingelheim, Roche, Actelion, Bayer, Gilead Sciences, Novartis, Promedior, Celgene, Galapagos, Galecto. He was a member of the INBUILD trial Steering Committee., Speakers bureau: Actelion, Boehringer Ingelheim, Novartis, Roche, Sanofi

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Ponatinib As Frontline Therapy for Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

Blood ◽

10.1182/blood.v124.21.4535.4535 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4535-4535 ◽

Cited By ~ 2

Author(s):

Preetesh Jain ◽

Hagop M. Kantarjian ◽

Elias Jabbour ◽

Gautam Borthakur ◽

Naveen Pemmaraju ◽

...

Keyword(s):

Adverse Events ◽

Research Funding ◽

Clonal Evolution ◽

Arterial Disease ◽

Molecular Response ◽

Coronary Syndrome ◽

Treatment Interruptions ◽

Frontline Therapy ◽

Grade 3 ◽

Gastrointestinal Ischemia

Abstract Background: Ponatinib is a third generation tyrosine kinase inhibitor (TKI) that has demonstrated efficacy in patients (pts) with CML who have failed multiple therapies and those with a T315I mutation or other BCR-ABL mutations. In this study, we have assessed the efficacy and safety of ponatinib as a frontline therapy in pts with CML-CP. Methods: Fifty one pts with CML-CP were treated with ponatinib as initial therapy for CML in a single-arm, single-institution clinical trial. The starting dose of ponatinib was 45 mg orally daily in 43 pts and, after an amendment, 30 mg in 8 pts. Other eligibility criteria included age ≥18 yrs, ECOG PS 0-2, normal organ function, and absence of significant cardiac history or prior pancreatitis. Pts with clonal evolution at time of diagnosis were eligible without other evidence of accelerated phase. Dose reductions to 30mg/d, 15 mg/d, or 15 mg every other day were indicated for adverse events. Pts were followed with cytogenetic analysis and PCR every 3 months for the first 12 months, then every 6 months. Cytogenetic and molecular (by International Scale) response criteria were standard. Results: From May 2012 to June 2014, 51 pts were treated. The median age was 48 yrs (range, 21-75), 1 patient had clonal evolution, and 3 started therapy while in CHR. Sokal risk score was low in 69%, intermediate in 22% and high in 10%. The median follow-up was 15.6 months (range 5.6-23.7 months). Complete hematologic response (CHR) was achieved in 95% of pts, complete cytogenetic response (CCyR) in 95%, major molecular response (MMR) in 80%, molecular response 4.5-log (MR4.5) in 55% and undetectable BCR-ABL in 38%. At 3 months, 90% of 50 evaluable pts achieved CCyR, and at 6 months 93% of 45 evaluable pts had CCyR. The median transcript levels at 3 months was 0.096 and at 6 months 0.005. Rates of MMR at 3 and 6 months were 50% and 80%, and rates of undetectable BCR-ABL1 were 0% and 22%, respectively. None of the pts progressed, including no transformations to accelerated or blast phase and all pts were alive. Forty three (85%) pts required treatment interruptions. The median duration of treatment interruptions was 9 days (range, 1-48). The median dose for all pts was 30 mg/d. As of June 2014, all pts were taken off study – 38 per FDA recommendation for concerns of risk of thrombotic events and 13 due to adverse events. Of these 13 pts – 3 had vasoocclusive disease grade 3 (peripheral arterial disease, femoral artery thrombosis, gastrointestinal ischemia), 2 with acute coronary syndrome (grade 3), 2 had cerebrovascular events grade 3 (1 transient ischemic attack and 1 Moya Moya disease), 2 multiple toxicities, 1 grade 3 hypertension, 1 with resistance and grade 2 arthralgia, 1 grade 3 skin xerosis, 1 grade 4 myelosuppression. Cardiovascular events were observed in 24 (47%) pts, of which 11 had >1 cardiovascular event. Hypertension in 14 pts (7 were grade 3), chest pain in 8 (one pericarditis grade 2), acute coronary syndrome in 2 (grade 3), vasoocclusive disease in 3 (one suspected gastrointestinal ischemia; all grade 3), stroke in 3 (one TIA and one carotid arterial disease both grade 3), Raynaud’s phenomenon in 2 (grade 1-2), one each had toe cramps with tingling, palpitations, prolonged QTc. Non-cardiovascular adverse events included - skin rash in 35 (2 pts with grade 3/4), dry skin in 22 (all grade 1/2), lipase elevation in 32 (23 with grade 3/4), symptomatic grade 3 pancreatitis in 10 pts, constipation in 26 pts (all grade 1/2), and memory loss in 6 pts (all grade 1/2). Grade 3-4 myelosuppression occurred in 14 pts. Conclusion: Ponatinib therapy leads to fast and deep cytogenetic and molecular responses in pts with CML-CP. Cardiovascular toxicities, skin toxicity and lipase elevation were observed in several patients. Dose adjustment, regular monitoring and counselling of the pts for thromboembolic events can be used to manage pts on ponatinib. However, considering the risk of vascular thrombotic events and the availability of alternative options for these patients, the study has been terminated at the recommendation of the FDA. Disclosures Borthakur: Tetralogic Pharmaceuticals: Research Funding. Ravandi:Cellerant Therapeutics: Research Funding. O'Brien:Amgen, Celgene, GSK: Consultancy; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; MorphoSys, Acerta, TG Therapeutics: Research Funding.

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Immune checkpoint inhibitor-related thrombocytopenia: Incidence, risk factors, and effect on overall survival.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e14549 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e14549-e14549

Author(s):

Tyler Haddad ◽

Songzhu Zhao ◽

Mingjia Li ◽

Sandip H. Patel ◽

Andrew Johns ◽

...

Keyword(s):

Risk Factors ◽

Overall Survival ◽

Adverse Events ◽

Immune Checkpoint ◽

Clinical Decision Making ◽

Comprehensive Cancer Center ◽

Cancer Center ◽

Cancer Type ◽

Grade 3 ◽

Line Of Therapy

e14549 Background: Immune checkpoint inhibitors (ICI) are a standard of care therapy for patients with many different cancers. ICI are generally well tolerated but are associated with unique immune-related adverse events (irAEs). Immune-related thrombocytopenia (irTCP) is an understudied and poorly understood toxicity and risk factors for irTCP are unknown. Although other irAE have been associated with clinical benefit, little data is available regarding either risk of irTCP or the effect of irTCP on clinical outcomes of patients treated with ICI. Methods: We conducted a retrospective review of sequential patients with any solid or hematologic cancer treated with ICI between 2011 and 2017 at The Ohio State University Comprehensive Cancer Center. All patients who received ICI alone or in combination with other systemic therapy in any line of treatment were included; those with thrombocytopenia ≥ grade 3 at baseline were excluded. Thrombocytopenia grading was performed utilizing the Common Terminology Criteria for Adverse Events version 5.0. Attribution to ICI was defined as timing after ICI initiation, lack of alternative causes, and improvement with either holding treatment or use of immune suppressive therapy. Overall survival (OS) was calculated from the date of initiation of ICI to death from any cause or date of the last follow-up examination. Cox proportional hazard models were used to examine the associations between platelet categories with OS. Median OS was estimated using Kaplan-Meier method with 95% CI. Results: We identified 1,038 patients treated with ICI therapy after excluding patients with baseline thrombocytopenia. The median age was 61.4; 613 (59.1%) were male and 613 (59.1%) had history of smoking. The most common cancer types were melanoma (n = 337, 32.5%), lung (n = 213, 20.5%), and renal cell carcinoma (n = 114, 11%). The most common ICI were PD1/L1 (n = 729, 70.2%) and CTLA4 (n = 191, 18.4%). Overall, 89 (8.6%) patients developed grade ≥3 thrombocytopenia; twenty were attributed to ICI (1.93% overall). Patients who developed ≥3 irTCP had worse overall survival compared to those whose thrombocytopenia was unrelated to ICI (5.45 vs 11.3 months; HR. 2.077, 95% CI 1.231, 3.503; log-rank p = 0.005). Patients with ≥3 irTCP also had shorter survival compared to those without thrombocytopenia of any etiology (5.45 vs 13.3 months; HR 2.247, 95% CI: 1.414, 3.571; p < 0.001). irTCP was more common among those treated with PD1/L1 (p = 0.03) but was not associated with cancer type, smoking status, age, gender, race, or line of therapy. Conclusions: Type of immunotherapy is related to irTCP, whereas cancer type and line of therapy are not. Unlike other irAEs, we found that irTCP was associated with shorter overall survival. These findings provide important insight into a poorly understood and rare toxicity. irTCP should be evaluated in more extensive studies to better inform clinical decision making.

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Comparison of checkpoint inhibitor treatment-related cutaneous adverse events in racial and ethnic minority and Caucasian cohorts at Memorial Sloan Kettering Cancer Center.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.2632 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 2632-2632

Author(s):

Amaris Geisler ◽

Dulce M. Barrios ◽

Gregory Phillips ◽

Rosa Nouvini ◽

Mario E. Lacouture ◽

...

Keyword(s):

African American ◽

Native American ◽

Adverse Events ◽

Ethnic Minority ◽

Maculopapular Rash ◽

Cancer Center ◽

Treatment Interruptions ◽

Caucasian Cohort ◽

Grade 3 ◽

Racial And Ethnic Minority

2632 Background: Immune-related cutaneous adverse events (irCAEs) are the most common and often the first toxicity of immune checkpoint inhibitors (CPIs). In the general population, irCAEs occur on average within 3.6 weeks of treatment initiation and most commonly manifest as maculopapular rash, lichenoid rash, and pruritus. Less is known about these irCAEs in racial and ethnic minority patients. The purpose of this study is to compare the irCAEs of cohorts of Caucasian and racial and ethnic minority patients at Memorial Sloan Kettering Cancer Center. Methods: Herein, we conducted a retrospective chart review of racial and ethnic minority patients treated with CPIs between 2012-2019 at Memorial Sloan Kettering Cancer Center. irCAEs were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. These were compared to a Caucasian cohort matched by demographics and cancer therapy regimen. Results: One hundred ten racial and ethnic minority patients presented to dermatology for irCAEs. Our population consisted of 59 (53.6%) females and 51 (46.4%) males with a mean age of 59 (range 20-85). Of the patients who were seen by dermatology, 63/110 were Asian (57.3%) followed by 34/110 African American (30.9%), and 1 Native American. Twelve patients were of Hispanic ethnicity (10.9%), which included those of both African American and Caucasian race. The 110 patients that were evaluated by dermatology had 221 cutaneous adverse events. Rash (96, 43.4%), pruritus (40, 18.1%), and xerosis (23, 10.4%) were most frequently diagnosed (average time from treatment start to presentation was 125 days). Dermatology identified 87 (39.3%) grade 1, 103 (46.6%) grade 2, 30 (13.5%) grade 3, and 1 (0.4%) grade 4 events. There were 17 (15.5%) treatment interruptions, including 7 patients who required permanent discontinuation. In the Caucasian cohort, mean time to onset was 228 days (range 1-1500). Dermatology identified 48 (43.6%) grade 1, 44 (40.0%) grade 2, 18 (16.4%) grade 3, and 0 (0.0%) grade 4 events, with maculopapular rash (55, 50.0%) and pruritus (25, 22.7%) most frequently diagnosed. Conclusions: Our findings suggest that irCAEs occur frequently in cancer patients from racial and ethnic minority groups, with similar grade and morphology as Caucasian patients. When irCAEs develop in this population, the diagnosis occurred later than what has previously been reported, possibly due to these patients seeing MSK oncologists with an established dermatology consultation system and insight into how to manage these patients on their own. Prospective evaluation of underrepresented minorities receiving CPI therapy is warranted in order to identify risk factors and therapeutic strategies for these untoward events, so that optimal cancer care may be delivered.

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