Pharmacogenetics as predictor of sunitinib and mTOR inhibitors toxicity in patients with metastatic renal cell carcinoma (mRCC).

4570 Background: Single nucleotide polymorphisms (SNPs) in major pharmacokinetics (PK) and pharmacodynamics (PD) pathways of targeted agents may affect the incidence of drug toxicities. Methods: Germline DNA was extracted fromwhole blood or normal kidney parenchyma frommRCC pts of European ancestry in two cohorts: those treated with VEGF-targeted therapy (sunitinib) (n=159) or with an mTOR inhibitor (everolimus or temsirolimus) (n=62). Ten SNPs in 6 candidate genes: CYP3A4 (rs2242480, rs4646437, rs2246709), CYP3A5 (rs15524), ABCB1 (rs2032582, rs1045642), VEGFR2 (rs2305948), NR1I3 (rs2307424, rs2307418), FLT3 (rs1933437) were genotyped using Sequenom iPlex Gold platform. Logistic regression model tested the association of genotype variants with adverse events of 1) grade 3/4 (G3/4) toxicity and G3/4 hypertension (for sunitinib cohort) and 2) grade 3/4 toxicity and all grade pneumonitis (for mTOR inhibitors cohort), adjusted for clinical factors associated with toxicity outcomes. Results: In the sunitinib cohort, median treatment duration was 7.7 months (IQR=3-15.5), 83 (52%) pts had grade 3/4 toxicities and 22 (14%) had grade 3/4 hypertension. Rare variant (AG) of CYP3A4 rs464637 was associated with the reduced risk of grade 3/4 toxicities (4 events/17 cases) vs. wild-type (GG, 73 events/134 cases), (Odds Ratio (OR) = 0.27, 95%CI: 0.08-0.88, p=0.03). No association between SNPs and hypertension was observed. In the mTOR inhibitor cohort, median treatment duration was 3.4 months (IQR=1.4-6), 21(34%) pts had G3/4 toxicities and 27 (43%) had all grade pneumonitis. No association between SNPs and G3/4 toxicities was observed. Rare homozygote (GG) of FLT3 SNP rs1933437 was associated with increased risk of all grade pneumonitis (7 events/ 9 cases) vs. wild-type (AA, 4 events/12 cases), however, given the very small variant group size, further investigation is required to verify the association. Conclusions: The minor allele of SNP rs464637 in the gene CYP3A4 may influence sunitinib toxicity. Further validation is needed to determine if the marker could be used for in targeted therapy dosing strategies and direct patient care. (IQR=Interquartile Range).

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Outcomes of second-targeted therapy for mRCC: A retrospective chart review of community practices in the United States.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.6_suppl.424 ◽

2013 ◽

Vol 31 (6_suppl) ◽

pp. 424-424

Author(s):

Eric Jonasch ◽

James E. Signorovitch ◽

Peggy L. Lin ◽

Zhimei Liu ◽

Kenneth W. Culver ◽

...

Keyword(s):

Targeted Therapy ◽

Targeted Therapies ◽

Treatment Duration ◽

Dose Adjustment ◽

Chart Review ◽

Retrospective Chart Review ◽

Common Reason ◽

Median Treatment ◽

Median Treatment Duration ◽

Imaging Test

424 Background: Sequential use of targeted therapies has become standard practice for the treatment of metastatic renal cell carcinoma (mRCC). This study describes treatment outcomes of the 2nd-targeted therapy among patients with mRCC treated in the community setting. Methods: A retrospective chart review and survey was conducted during May through June 2012 among community-based oncologists or hematologists. Charts were reviewed for adult mRCC patients initiated on 2nd -targeted therapy on or after January 1, 2010. Abstracted data included patient demographics, disease characteristics, treatment duration, dose adjustment, progression, mortality, and imaging test patterns. Kaplan-Meier analysis was used to estimate treatment duration, overall survival (OS) and progression-free survival (PFS) during 2nd-targeted therapy. Patients were censored at the most recent contact. Results: Charts were reviewed for 433 mRCC patients. Mean age was 63 years at initial mRCC diagnosis and 64% were male. The most commonly used 2nd targeted therapies were everolimus (36% of patients), temsirolimus (17%), pazopanib (15%), and sunitinib (14%). The median duration of 2nd -targeted therapy was 10.5 months (95% CI: 8.8-11.5). The majority of patients (73%) had no dose adjustment on 2nd-targeted therapy; the most common reason for adjustment was drug toxicity (70%). Among the 44% of patients who discontinued 2nd-targeted therapy, disease progression was the most common reason for discontinuation. The proportion of patients who received imaging test within 3, 6, and 12 months after 2nd-line treatment initiation was 57%, 92%, and 99%, respectively. Routine monitoring (83%) was the most common reason for imaging tests. Median durations of OS and PFS after initiation of the 2nd-targeted therapy were 30.4 months (95% CI: 23.5-not reached) and 10.7 months (95% CI: 8.4-12.2), respectively. Conclusions: In this large, retrospective chart review study, median treatment duration of 2nd -targeted therapy was 10.5 months, median OS was 30.4 months, and median PFS was 10.7 months. Median treatment duration in community practice was longer than in clinical trials for targeted therapies in mRCC.

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Activity of single-agent bevacizumab (B) in patients with metastatic renal cell carcinoma (RCC) previously treated with VEGF- and mTOR-based therapies.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.5_suppl.435 ◽

2012 ◽

Vol 30 (5_suppl) ◽

pp. 435-435

Author(s):

Andrew J. Armstrong ◽

James D. Turnbull ◽

Julien Cobert ◽

Tracy Jaffe ◽

Michael Roger Harrison ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Metastatic Renal Cell Carcinoma ◽

Renal Cell ◽

Mtor Inhibitor ◽

Single Agent ◽

Progression Free Survival ◽

Mtor Inhibitors ◽

Mtor Inhibition ◽

Grade 3

435 Background: Given a lack of clinical information on therapeutic efficacy of agents following progression after vascular endothelial growth factor (VEGF) tyrosine kinase inhibition (TKI) and mammalian target of rapamycin (mTOR) inhibition in metastatic renal cell carcinoma (mRCC), we investigated the activity of single agent bevacizumab (B) in this setting. Methods: We conducted a retrospective analysis of single agent B-treated patients with mRCC in the second/third line setting, and identified 21 subjects who met inclusion criteria. The primary endpoint was progression-free survival (PFS). Baseline characteristics, survival, response efficacy outcomes, and toxicities were assessed and summarized. Results: 21 patients (15 women/6 men) were treated with B at a dose of 5 mg/kg/week, dosed q2-3 weeks. Median age was 63, 80% were white, 14% black; 80% had clear cell histology. Median time from diagnosis to B therapy was 3 years (range 1-18); 100% had prior VEGF TKI therapy; 43% had prior mTOR inhibitor; 43% had prior IFN and 19% prior IL-2; median number of prior therapies was 3 (range 1-7); 100% were considered Motzer intermediate risk. Median PFS on B for all subjects was 4.4 mo (95% CI 2.8-9.6) and median OS was 19.4 mo (95% CI 9.9-NR) from start of B therapy. ORR was 2 CR/PR (9.5%), 11 SD (52%), 5 PD, 3 NE. For subjects treated with prior VEGF and mTOR inhibitors, median PFS and OS were 4.4/13.2 mo. Toxicities were as expected and severe adverse events included grade 3-4 fatigue (6), grade 3-4 dehydration (5), and grade 4 failure to thrive (2), grade 4 constipation (2), and grade 3 muscle weakness (2). Conclusions: Single agent B therapy has acceptable toxicity and moderate disease stabilizing activity in selected patients with mRCC who have failed prior VEGF TKI and mTOR inhibitor therapy, and suggests a benefit to continued ongoing VEGF inhibition. Further prospective study of B alone, in combination with mTOR inhibition, or with alternative targeted agents is warranted.

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A first-in-human phase I/II study of HL-085, a MEK Inhibitor, in Chinese patients with NRASm advanced melanoma.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.10047 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 10047-10047

Author(s):

Xuan Wang ◽

Lu Si ◽

Lili Mao ◽

Chuanliang Cui ◽

Zhihong Chi ◽

...

Keyword(s):

Phase I ◽

Treatment Duration ◽

Malignant Tumors ◽

Mek Inhibitor ◽

Advanced Melanoma ◽

Chinese Patients ◽

Median Treatment ◽

Median Treatment Duration ◽

Anti Cancer ◽

Cancer Activity

10047 Background: MEK inhibitors have confirmed effects on malignant tumors, especially for those induced by RAS/RAF dysfunction. There is no effective drug in clinic for NRASm advanced melanoma. HL-085 is a selective MEK inhibitor, showing good safety and efficacy in preclinical studies. This study is a phase I/II study to evaluate the safety, tolerability, pharmacokinetic and preliminary anti-cancer activity of HL-085 in patients(pts) with NRASm advanced Melanoma. Methods: The phase I/II study is conducted using a “3+3” regimen for dose escalation. The pts are treated with HL-085 at a starting dose of 0.5mg BID to 18mg BID. Adverse events (AEs) are reported per NCI CTCAE version 5.0. Preliminary anti-cancer activity is evaluated by ORR, DCR, PFS and DoR. Results: Total 33 pts were enrolled in the study. The histologic types were acral (51.4%), mucosal (27.2%) and other (21.2%). The NRAS mutation types were Q61 (72.7%), G12 (18.2%) with half for G12D, and G13 (9.1% ). Most AEs were G1 or G2, and the most common drug-related AEs were rash, increased creatine phosphokinase, peripheral edema, increased alanine aminotransferase and aspartate aminotransferase. No dose-limited toxicity was observed. PK analysis was shown linear PK profile with no obvious accumulation. Among 12 evaluable pts over 9 mg, 4 pts were at the stage of M1c with 1 liver metastasis. Average targeted tumor size was 74.6mm with the largest 184 mm. 10 pts achieved tumor shrinkage [ 60% with Q61, 20% with G12D, 10% each with G12S and G13R]. 4 pts ( 2 acral, 1 mucosal and 1 other, each pt has mutaiton type of Q61R,Q61L, Q61K and G12S respectively ) had confirmed partial response(PR) [median treatment duration 26.6 weeks (wks) with longest 47.6 wks]). 6 pts achieved stable disease (SD) (median treatment duration 15.72 wks with longest 24 wks), and 66.7% were over 14 wks . The median PFS was 17.4 wks, and confirmed best ORR was 33.3% with DCR 83.3% . Conclusions: Our data demonstrated that HL-085 is well tolerated, with manageable side-effects and promising anti-cancer activity in pts with NRASm advanced melanoma. Clinical trial information: NCT 03973151.

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Management of Patients with Relapsed/Refractory Multiple Myeloma (RRMM) Treated with Proteasome Inhibitor Based Therapy at First Relapse in Routine Clinical Practice in Germany

Blood ◽

10.1182/blood-2018-99-110937 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1953-1953 ◽

Cited By ~ 1

Author(s):

H. Tilman Steinmetz ◽

Moushmi Singh ◽

Andrea Lebioda ◽

Aurelien Mantonnier ◽

Leah Fink ◽

...

Keyword(s):

Multiple Myeloma ◽

Clinical Practice ◽

Treatment Duration ◽

Employment Equity ◽

Available N ◽

Median Treatment ◽

Median Treatment Duration ◽

Refractory Multiple Myeloma ◽

Equity Ownership ◽

Patient Profiles

Abstract Background: Proteasome inhibitors (PI) represent an important therapeutic advance in the treatment of patients with relapsed/refractory multiple myeloma (RRMM). In 2017, three distinct PIs (bortezomib [BTZ], carfilzomib [CFZ] and ixazomib [IXA]) were available in Germany but real-world data describing their usage was scarce. Aim: To describe characteristics and treatment experience of PI-treated patients with RRMM in Germany. Methods: A national retrospective medical chart review included consecutive patients treated with at least one dose of PI-based regimen in participating hospitals/centers across Germany between January and June 2017. The following data were extracted until April 2018 or death of patient, whichever occurred first: patient demographics, disease characteristics and treatment history at diagnosis and at initiation of PI-based therapy. Physician assessed treatment response were also collected. Results: Physicians from 44 participating centers extracted 302 patient charts, including 219 patients in 2nd line (2L) and 83 in 3rd line treatment (3L), as shown in Figure 1. Results for 2L patients are described below (Table 1, Figure 2): BTZ-treated patients represented 42% of patients (n=92) with a PI-based therapy in 2L. BTZ was often combined with dexamethasone (dex) alone (77%). Median age was 74 years and 56.5% had an ECOG status ≥2 at 2L initiation. Most patients (86%) did not receive a prior transplant. Median treatment duration was 6 months among 40 patients who completed 2L; based on 38 narratives, 2L was ended as planned (47.4%). Where response was available (n=83), 25% of patients achieved a complete response/very good partial response [CR/VGPR]. Median time to next treatment (TTnT) was 7.5 months for 12 patients who moved to 3L. Patient profiles differed in terms of prior treatment exposure: 22% of patients had been treated with a BTZ-based therapy in both 1L and 2L and 62% switched therapies from 1L lenalidomide (len) to BTZ. None of the patients receiving len in 1L were transplanted. A CR/VGPR was achieved by 65% of prior BTZ-treated patients (13/20) and 30% of patients with prior len therapy (17/57). CFZ-treated patients: 48% (n=106) of patients received CFZ-based therapy in 2L. Of those, 56% (n=59) received CFZ in combination with len/dex (KRd) and 44% (n=47) with dex alone (Kd). Median age was 68 years, 60.4% had an ECOG status of 0-1 at 2L initiation and 49% had received a transplant. In 1L, 82% had received a BTZ-based regimen. Where response was mentioned (n=89), a CR/VGPR was reached in 53% of CFZ-treated patients. Median treatment duration was 6.5 months (24/106). Based on 21 narratives, the main reason for discontinuing CFZ in 2L was disease progression (47.6%). Median TTnT was 9.5 months for 10 patients who moved to 3L. The patient profiles by KRd or Kd combination were as follows: at KRd initiation, median age was 65 years, 10.2% of patients had an ECOG status ≥2 and 72.9% were transplanted. At Kd initiation, median age was 71 years, 76.6% of patients had an ECOG ≥2 and 19.1% were transplanted. IXA-treated patients (n=21) represented only 10% of PI-treated patients in 2L. Median age was 66 years, 71.4% had an ECOG status of 0-1 at 2L initiation, 33% were transplanted, and 72% had received a BTZ combination in 1L. Information on response was premature as it was only available for 13 patients with no CR reached (VGPR 77%). Median treatment duration was 4 months (n=9) and median TTnT was 10 months for 4 patients who moved into 3L. Limitation: The main limitation of the study was the sample size of IXA-treated patients due to open inclusion criteria to select patient charts. This analysis was not powered to compare between PIs. Hence, results are descriptive of the clinical experience with PI-based therapy to date and reflect current treatment practices in Germany in 2017. Conclusion: In Germany, distinct patient characteristics are observed in clinical practice by selected PI-based therapy. Patients treated with novel PI agents in 2L are generally younger and more transplanted than bortezomib-treated patients; these appear to be important considerations when tailoring therapy in RRMM. In addition, the choice between triplet or doublet therapy for CFZ-based combinations seems to reflect prior transplant status and patients' overall functional performance. Evidence suggests that use of novel PI agents such as CFZ can translate into deeper response in 2L. Disclosures Steinmetz: Amgen, Celgene, Novartis, Vifor: Research Funding; Amgen; BMS, Celgene, Hexal-Sandoz, Medice, Novartis; Janssen-Cilag; Pharmacosmos; Pfizer, Vifor; Ariad: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion, Amgen, Bayer, Celgene, Janssen-Cilag, Novartis: Other: Travel grants. Singh:Amgen: Employment, Equity Ownership. Lebioda:Amgen: Employment, Equity Ownership. Mantonnier:Kantar Health: Employment, Other: Received funding to conduct this research. Fink:Kantar Health: Employment, Other: Received funding to conduct this research. Rieth:Amgen: Employment, Equity Ownership. Suzan:Amgen: Employment, Equity Ownership. Gonzalez-McQuire:Amgen: Employment, Equity Ownership.

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Safety and efficacy of BAY1436032 in IDH1-mutant AML: phase I study results

Leukemia ◽

10.1038/s41375-020-0996-5 ◽

2020 ◽

Vol 34 (11) ◽

pp. 2903-2913 ◽

Cited By ~ 1

Author(s):

Michael Heuser ◽

Neil Palmisiano ◽

Ioannis Mantzaris ◽

Alice Mims ◽

Courtney DiNardo ◽

...

Keyword(s):

Treatment Duration ◽

Overall Response Rate ◽

Response Rate ◽

Maximum Tolerated Dose ◽

Dose Escalation Study ◽

Median Treatment ◽

Median Treatment Duration ◽

Overall Response ◽

Investigational Agent ◽

Study Results

Abstract The mutant IDH1 (mIDH1) inhibitor BAY1436032 demonstrated robust activity in preclinical AML models, supporting clinical evaluation. In the current dose-escalation study, BAY1436032 was orally administered to 27 mIDH1 AML subjects across 4 doses ranging from 300 to 1500 mg twice-daily. BAY1436032 exhibited a relatively short half-life and apparent non-linear pharmacokinetics after continuous dosing. Most subjects experienced only partial target inhibition as indicated by plasma R-2HG levels. BAY1436032 was safe and a maximum tolerated dose was not identified. The median treatment duration for all subjects was 3.0 months (0.49–8.5). The overall response rate was 15% (4/27; 1 CRp, 1 PR, 2 MLFS), with responding subjects experiencing a median treatment duration of 6.0 months (3.9–8.5) and robust R-2HG decreases. Thirty percent (8/27) achieved SD, with a median treatment duration of 5.5 months (3.1–7.0). Degree of R-2HG inhibition and clinical benefit did not correlate with dose. Although BAY1436032 was safe and modestly effective as monotherapy, the low overall response rate and incomplete target inhibition achieved at even the highest dose tested do not support further clinical development of this investigational agent in AML.

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Evaluation of the role of UGT1A1 genotype testing in colorectal cancer patients administered irinotecan and the occurence of grade 3 and 4 neutropenia.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.4_suppl.412 ◽

2012 ◽

Vol 30 (4_suppl) ◽

pp. 412-412 ◽

Cited By ~ 1

Author(s):

Sushma M. Patel ◽

Jim Chan ◽

Rita L. Hui ◽

Michele M. Spence

Keyword(s):

Colorectal Cancer ◽

Cohort Analysis ◽

Median Number ◽

Rank Test ◽

P Value ◽

Wild Type ◽

Kaiser Permanente ◽

Adjusted Risk ◽

Increased Risk ◽

Grade 3

412 Background: Irinotecan is metabolized primarily in the liver by the carboxylesterase enzyme to the SN-38 active metabolite and is then inactivated through conjugation by the UGT1A1 enzyme, a polymorphic enzyme. Individuals genotyped with the homozygous allele have an increased risk for grade 3 and 4 neutropenia. Methods: A retrospective cohort analysis was conducted in the Kaiser Permanente California regions. The study period was November 1, 2005 to July 1, 2010 and included patients that were 18 years of age or older, newly initiated on irinotecan for colorectal cancer and had no previous irinotecan therapy within six months of the initiation dose. Patients were excluded if they were enrolled in clinical trials, on granulocyte-colony stimulating factor prophylaxis, and genotype tested for UGT1A1 and subsequently not treated with irinotecan. Patients tested with the UGT1A1 assay were grouped according to their genotype results: wild-type, heterozygous, or homozygous*28. The incidence of grade 3 and 4 neutropenia were compared among patients tested for UGT1A1 variant alleles by their genotype results. Results: A total of 305 (28%) patients were tested with the UGT1A1 assay with a mean age of 62 (+/- 12) years, and 52% of the population female. There were 161 (53%) wild-type, 123 (40%) heterozygous, and 21 (7%) homozygous patients. The median irinotecan dose was 150 mg/m2 (124-180 mg/m2) and median number of irinotecan cycles were 6 (3-12). The wild-type, heterozygous, homozygous*28 population had a 21% (33/161), 24% (29/123), and 48% (10/21) rate of grade 3 and 4 neutropenia. When the homozygous*28 group was compared to the heterozygous and wild-type genotype the adjusted Cox Proportional Hazard was 3.05 (95% CI, 1.55-5.99), p = 0.001. The Kaplan-Meier Log Rank Test yielded a p-value of 0.002. Conclusions: The adjusted risk for homozygous genotyped patients was three times higher compared to the wild-type and heterozygous group for grade 3 and 4 neutropenia. Additional investigational studies examining the benefits of UGT1A1 genotyping as a prognostic test and further effect of dosage adjustments in UGT1A1*28 homozygous initiated on irinotecan therapy are needed.

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Real-World Treatment Patterns and Transfusion Burden Among US Patients with Newly Diagnosed Myelodysplastic Syndromes (MDS)

Blood ◽

10.1182/blood-2019-123425 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3499-3499

Author(s):

Sudipto Mukherjee ◽

S. Lane Slabaugh ◽

Ronda Copher ◽

Jonathan Johnson ◽

Paul Buzinec ◽

...

Keyword(s):

Board Of Directors ◽

Treatment Duration ◽

Research Funding ◽

Index Date ◽

Treatment Patterns ◽

Newly Diagnosed ◽

Advisory Committees ◽

Median Treatment ◽

Medical Claims ◽

Median Treatment Duration

Introduction: Symptomatic anemia transfusion support represents a significant problem for patients with MDS. The principal strategy in managing these patients remains supportive care with erythropoiesis-stimulating agents (ESAs) and red blood cell (RBC) transfusions. However, there is paucity of real-world data regarding patterns of use of ESA and other therapies, and its impact on transfusion needs in these patients early in their clinical course. To address this question, we performed a retrospective claims-based study to characterize treatment patterns and transfusion burden in patients with MDS. Methods: In this retrospective claims analysis of a large national health insurance plan, all patients aged ≥ 18 years with newly diagnosed MDS (≥ 2 medical claims with an International Classification of Diseases, 9th or 10th Revision [ICD-9 or ICD-10] diagnosis codes ≥ 30 days apart) identified between January 2012 and May 2018 were included. Index date was defined as date of first diagnosis. Continuous health plan enrollment for ≥ 6 months pre- and 3 months post-index date was required. RBC transfusion status was evaluated during the 16 weeks prior to first diagnosis as well as 16 weeks prior to and immediately following line of therapy (LOT) 1 and LOT2. Transfusion burden categories were adapted and modified from the proposed International Working Group 2018 revised criteria (Platzbecker U, et al., Blood. 2019;133(10):1096-1107). Categories included transfusion independence (TI), defined as patients receiving no transfusions during the observation period; low (LTB), moderate (MTB), and high transfusion burden (HTB) were defined by patient's having 1-3, 4-7, and ≥ 8 unique dates for a transfusion during the observation periods, respectively. Therapies in each LOT were captured using pharmacy and medical claims data. The end of a LOT was defined after ≥ 60-day gap in therapy, a claim for any new or additional MDS therapy, or patient death; LOT durations are described for non-censored patients. Results: Among the 3,587 patients identified (mean age = 74.9 years, 44.3% female), transfusion burden during 16 weeks prior to index was: 78.8% TI, 19.2% LTB, 1.9% MTB, and 0.2% HTB. Among the 1,935 patients who received LOT1, transfusion burden in the 16 weeks preceding LOT1 was: 57.0% TI, 36.3% LTB, 5.6% MTB, and 1.1% HTB. The top 5 regimens in LOT1 were ESA monotherapy (61.9%), hypomethylating agent (HMA) monotherapy (19.2%), white blood cell growth factor (WBCGF) monotherapy (3.5%), immunomodulators (3.3%), and HMA + ESA (2.7%) (Figure). Of 824 patients who received LOT2, transfusion burden prior to LOT2 was: 49.4% TI, 28.6% LTB, 16.5% MTB, and 5.5% HTB. The top 5 regimens in LOT2 were ESA monotherapy (44.2%), HMA monotherapy (12.1%), HMA + ESA (9.2%), WBCGF + ESA (6.9%), and WBCGF monotherapy (6.4%) (Figure). In LOT1, the median treatment duration for ESA monotherapy was 2.8 months (mean = 5.2 months, standard deviation [SD] = 6.8) whereas in LOT2, the median treatment duration was 2.0 months (mean = 3.7 months, SD = 5.0). Amongst patients receiving ESA monotherapy as LOT2, 90.4% had prior ESA monotherapy as LOT1. In patients treated with HMA monotherapy in LOT1 that also experienced a LOT2, 39.1% moved on to a variety of LOT2 regimens (Table), while in 15.5% ESAs were combined with HMA (Table). Conclusions: Our results show that at the time of diagnosis, 20% of MDS patients were transfusion dependent, but up to 50% require treatment. The high rate of ESA use is likely due to anemia-related symptoms. In those treated with ESA monotherapy, approximately 50% have a LOT1 duration that is < 3 months, and interestingly, the majority of patients restart a second LOT with an ESA as the most common regimen. Additional analyses are necessary to determine whether this indicates a switch in ESA agent, escalation in dose of prior ESA, treatment cycling due to elevated hemoglobin, or other reasons. Considering the short median treatment duration and worsening of transfusion dependency beyond first line, there remains a high unmet need for MDS therapy that more effectively slows the progression of transfusion dependence. Disclosures Mukherjee: Bristol-Myers Squibb: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Projects in Knowledge: Honoraria; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Partnership for Health Analytic Research, LLC (PHAR, LLC): Consultancy; McGraw Hill Hematology Oncology Board Review: Other: Editor. Slabaugh:Celgene Corporation: Employment, Equity Ownership. Copher:Celgene Corporation: Employment. Johnson:Optum: Employment; Celgene Corporation: Consultancy. Buzinec:Optum: Employment. Mearns:Celgene Corporation: Employment.

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Landmark analysis of immunotherapy duration and disease free survival in advanced melanoma patients with a complete response.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.10054 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 10054-10054

Author(s):

Grayce N. Selig ◽

Alexander Chan Chi Huang ◽

Giorgos C. Karakousis ◽

Wei Xu ◽

Cathy Zheng ◽

...

Keyword(s):

Treatment Duration ◽

Locally Advanced ◽

Disease Free Survival ◽

Complete Response ◽

Free Survival ◽

Median Treatment ◽

Median Treatment Duration ◽

Significant Difference ◽

Care Costs ◽

Disease Free

10054 Background: Checkpoint blockade improves survival in patients with melanoma, with durable complete responses (CR) after stopping therapy. Based on data from KEYNOTE-001, immunotherapy is often continued for 24 months in patients with confirmed CR. Outcomes with treatment of less than 24 months hav not been adequately evaluated and reported. If equally efficacious, shorter courses would potentially reduce health care costs and toxicity. Methods: 45 patients with locally advanced stage III and IV melanoma who received immunotherapy (pembrolizumab, nivolumab or ipilimumab/nivolumab) as 1st line or subsequent therapy, achieved a CR, and stopped therapy were identified under an IRB approved protocol at Penn. Disease Free Survival (DFS) was defined as time from declaration of CR until recurrence or date of analysis (1/15/20). Landmark DFS from time of CR was analyzed based on duration of therapy (less than or greater than 7 months, based on early trial requirements to treat patients with confirmed CR for at least 6 months). Rationale for stopping (toxicity or CR) was also analyzed. Results: Of 45 patients with CR, 27 (60%) were treated less then 7 months (median 4.8, range 1 day to 6.7 months) and 18 (40%) were treated for greater than 7 months (median 12.4, range 7.5 to 24.2 months). Patients who were treated for less than 7 months had a median DFS from time of CR of 30.4 months (95% CI 23.7 to 37.2, range 2.9 to 65.7 months). Patients treated for greater than 7 months had a median DFS of 28.0 months (95% CI 18.9 to 37, range 8.5 to 73.7 months). Patients who stopped due to toxicity (N = 17, 40%) had a median treatment duration of 3.7 months. Their median DFS from time of CR was 30.4 months (95% CI 20.7 to 40.1, range of 2.9 to 65.7 months). Patients who stopped due to CR (N = 28, 60%) had a median treatment duration of 8.5 months. Their median DFS was 27.6 months (95% CI 21.2 to 34 range 7.2 to 73.7 months). Two of 27 (7.4%) patients treated for less then 7 months and 3 out of 18 (16%) patients treated greater than 7 months recurred after stopping. One out of 17 (5.8%) recurred after stopping for toxicity vs. 4/28 (14.3%) who stopped after CR. Conclusions: Patients who stop therapy at less than 7 months have CRs that are equally durable as those treated longer than 7 months, without reduction in landmark DFS. Patients who stopped therapy due to toxicity and then achieved a CR had no difference in DFS compared to patients treated until CR. There was no significant difference in recurrence after achieving a complete response in patients treated for a longer vs shorter treatment course.

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