Utilization and Early Discontinuation of First-Line Ibrutinib for Patients with Chronic Lymphocytic Leukemia Treated in the Community Oncology Setting in the United States

Introduction: Ibrutinib, an orally and continuously administered Bruton tyrosine kinase inhibitor, allows for targeted, non-chemotherapy based treatment for chronic lymphocytic leukemia (CLL). While the initial US marketing approval for ibrutinib in CLL was for relapsed disease (February 2014), several trials have since shown favorable efficacy in the first-line setting. Ibrutinib was well tolerated in these pivotal studies, with discontinuation occurring in less than 9% at 12 months (O'Brien et al., Am J Hemato. 2019). Most early ibrutinib discontinuations in the first-line setting are due to adverse events (Tedeschi et al., EHA 2019), and optimal strategies to manage ibrutinib-related toxicities are not well defined. We hypothesized that ibrutinib is increasingly utilized for first-line treatment of CLL during routine management in the US, but that ibrutinib discontinuation rates for the real-world population are greater than those reported in clinical trials. Further, we expected to find greater odds of discontinuation in older adults and those with poor performance status, two groups underrepresented in clinical trials. Methods: We conducted a retrospective cohort study of CLL patients treated at community oncology practices using the nationwide Flatiron Health database. The Flatiron Health database is a longitudinal, demographically and geographically diverse database derived from de-identified electronic health record data from over 280 cancer clinics in the US. All patients initiated CLL therapy in the first-line setting between March 1, 2014 and February 28, 2019. We first assessed trends in the use of first-line ibrutinib (i.e., ibrutinib with/without an anti-CD20 antibody). We then focused on patients who received ibrutinib and had at least 180 days of available follow up or had died within this period. We used multivariable logistic regression to assess the association of patient characteristics with early discontinuation (defined as stopping within 180 days of initiation). Covariates included in our model were patient age, sex, race, insurance type, ECOG performance status, year of treatment, time from CLL diagnosis to ibrutinib initiation, chromosome 17p status, and geographical region. Results: We identified 5,634 individuals initiating first-line treatment for CLL, of whom 1,639 (29.1%) received an ibrutinib-based regimen. Use of ibrutinib in the first-line setting increased over time (Cochrane-Armitage test for trend, p <.001; Figure 1), making up approximately 40% of first-line CLL initiations by late 2018. Of the 1,497 individuals with adequate follow up, early discontinuation of ibrutinib occurred in 16.2%. Early discontinuation of ibrutinib was more common in individuals aged ≥80 years (26.2% vs. 9.4% for individuals 60-70 years old), those requiring treatment within 1 year of their CLL diagnosis (22.1% vs. 14.8% for those with CLL diagnosis ≥5 years prior to ibrutinib initiation), and those with ECOG performance status of 2 or greater (33.8% vs. 10.2% for ECOG = 0). On multivariable logistic regression, older age (≥80 years vs. 60-70 years, adjusted odds ratio (aOR) = 2.94, 95% confidence interval (CI) 1.79 - 4.76, p <.001) and worse performance status (ECOG ≥2 vs 0, aOR = 3.45, 95% CI 2.16-5.53, p <.001) remained independently associated with increased odds of early ibrutinib discontinuation. Conclusion: While ibrutinib was increasingly utilized in the first-line setting for CLL within our large representative US community patient cohort, early discontinuation was more common than reported in pivotal trials. Given the complexity of the rapidly changing CLL treatment landscape, clinical decision support tools and other modern cancer care delivery approaches should be explored to improve administration of novel CLL therapies in the real-world setting. Disclosures Huntington: Genentech: Consultancy; Bayer: Consultancy, Honoraria; AbbVie: Consultancy; Celgene: Consultancy, Research Funding; DTRM Biopharm: Research Funding; Pharmacyclics: Honoraria. Barr:Merck: Consultancy; Janssen: Consultancy; AbbVie: Consultancy; Pharmacyclics LLC, an AbbVie company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy; Celgene: Consultancy; Genentech: Consultancy; Verastem: Consultancy; Gilead: Consultancy; Astra Zeneca: Consultancy, Research Funding. Jacobs:Genentech: Speakers Bureau; AstraZeneca: Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Research Funding, Speakers Bureau; TG Therapeutics: Honoraria, Research Funding; AbbVie: Consultancy, Speakers Bureau; JUNO: Consultancy; Gilead: Consultancy. Davidoff:PhRMA: Research Funding; Celgene: Research Funding. Gross:Johnson and Johnson: Research Funding; 21st Century Cancer: Research Funding; Pfizer: Research Funding.

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A Single-Institution Retrospective Cohort Study of Patients Treated with R-EPOCH for Richter's Transformation of Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v126.23.2951.2951 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2951-2951 ◽

Cited By ~ 3

Author(s):

Kerry A. Rogers ◽

Galena Salem ◽

Deborah M. Stephens ◽

Leslie A. Andritsos ◽

Farrukh T. Awan ◽

...

Keyword(s):

B Cell ◽

Research Funding ◽

Performance Status ◽

B Cell Lymphoma ◽

Neutropenic Fever ◽

Lymphocytic Leukemia ◽

Aggressive Lymphoma ◽

First Line ◽

Ecog Performance Status

Abstract Background: Richter's transformation (RT), the occurrence of an aggressive lymphoma in patients with prior chronic lymphocytic leukemia (CLL), occurs in up to 10% of CLL patients. Anthracycline-based chemoimmunotherapy remains standard, but outcomes are poor (median survival approximately 12 months). R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) has demonstrated superior efficacy to R-CHOP in HIV-associated diffuse large B-cell lymphoma, Burkitt's lymphoma, and primary mediastinal B-cell lymphoma. We conducted a single-institution retrospective cohort study to characterize efficacy and toxicity of R-EPOCH as first-line treatment for RT. Methods: The study included patients treated with R-EPOCH as first-line therapy for histologically confirmed RT at the Ohio State University between January 1st 2006 and May 31st 2014. Characteristics of the CLL and RT, ECOG performance status, and laboratory assessment of bone marrow and organ function were abstracted from medical records. Toxicity of R-EPOCH was assessed by reviewing the frequency of adverse events (AE). R-EPOCH treatment outcomes were assessed as documented by the treating physician and not secondarily verified. Progression free survival (PFS) and overall survival (OS) durations were calculated from date of Richter's biopsy until date of event (PFS: relapse/death; OS: death), censoring patients without event at last follow-up. PFS and OS estimates were obtained using the Kaplan-Meier method. Univariable proportional hazards models were used to model PFS and OS as a function of each clinical variable. Results: The study included 46 patients. Median age at RT diagnosis was 67 (range 38-83). Median number of months from CLL to RT diagnosis was 53 (range 0.4-198). A median of 3 (range 0-13) prior CLL treatments had been given with 10 (22%) patients receiving ibrutinib as the most recent. The majority of patients where CLL risk was evaluable demonstrated poor-risk disease: 24/43 (56%) complex karyotype, 20/41 (49%) del(17)(p13.1), 27/32 (84%) unmutated IGHV. The majority of evaluable patients had an ECOG performance status of 0 or 1 (18/28, 64%). Table 1 shows RT characteristics for these patients. Treatment with R-EPOCH was started a median of 5 days after RT diagnosis (range 0-110). The majority of patients did not complete 6 cycles: 16 (35%) completed 1 cycle, 10 (22%) 2 cycles, 5 (11%) 3 cycles, 4 (9%) 4 cycles, 2 (4%) 5 cycles, and 9 (19%) 6 cycles. Of 131 cycles given, 114 (87%) were fully evaluable for AE with results in table 2. Outcome of R-EPOCH treatment was known for 44 patients: 9 (20%) achieved complete response, 8 (18%) clinical response documented by the treating physician, 14 (32%) progressive disease, and 13 (30%) died without (known) lymphoma progression. With a median follow up of 39 (range 13-54) months, 9 (20%) patients were alive without lymphoma progression. All patients with lymphoma progression died. Median PFS was 3.5 months (95% CI: 2.0-7.6) and median OS was 5.9 months (95% CI: 3.2-10.3) (Figure 1). In univariable analysis, risk of death was higher for patients with complex CLL karyotype (HR 4.38, p=0.0002), del(17)(p13.1) (HR 3.04, p=0.003), higher number of CLL treatments (HR 1.16, p=0.004), higher bilirubin (HR 1.68, p=0.04), and higher serum creatinine (HR 1.65, p=0.05). Conclusions: Patients with RT treated with first-line R-EPOCH had poor PFS (median 3.5 months) and OS (median 5.9 months) with only 20% of patients alive at last follow up. Characteristics of underlying CLL influenced outcomes of R-EPOCH with worse PFS and OS in deletion 17p and complex karyotype patients. Better therapies for RT are urgently needed, especially in patients with poor risk CLL. Table 1. Characteristics of Aggressive Lymphoma n=46 Histology, no. (%)- Large Cell- Early large-cell/Prolymphocytic- Plasmablastic (EBV+)- High-grade B-cell 42 (91) 2 (4) 1 (2) 1 (2) Extranodal Disease- Yes- No 20 (43) 26 (57) Bulky Disease, no. (%)- Yes ≥5, <10 cm- Yes ≥10 cm- No- Unknown 16 (42) 8 (21) 14 (37) 8 Table 2. Adverse Events by Cycle Cycle 1 (n=40) Cycle 2 (n=29) Cycle 3 (n=15) Cycle 4 (n=12) Cycle 5 (n=11) Cycle 6 (n=7) Any AE* Infection Neutropenic Fever Hospitalization ICU Stay 29 (72%) 14 14 14 4 17 (59%) 7 4 7 0 7 (47%) 1 0 1 0 4 (33%) 1 0 1 0 2 (18%) 1 1 1 0 1 (14%) 0 0 1 0 *Hospitalization, infection, neutropenic fever, non-neutropenic fever, ICU stay, transfusion, mucositis, fatigue requiring treatment delay, and ileus. Disclosures Stephens: Immunomedics: Research Funding; Acerta Pharma BV: Research Funding. Byrd:Acerta Pharma BV: Research Funding. Maddocks:Janssen: Research Funding; Novartis: Research Funding; Pharmacyclics: Consultancy, Research Funding. Jones:AbbVie: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding.

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The prognostic impact of bone metastasis in urothelial carcinoma treated with first-line platinum-based chemotherapy.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.6_suppl.415 ◽

2021 ◽

Vol 39 (6_suppl) ◽

pp. 415-415

Author(s):

Husam Alqaisi ◽

Zachary William Neil Veitch ◽

Carlos Stecca ◽

Jeenan Kaiser ◽

Scott A. North ◽

...

Keyword(s):

Urothelial Carcinoma ◽

Performance Status ◽

Progression Free Survival ◽

Response To Treatment ◽

Prognostic Impact ◽

First Line ◽

Ecog Performance Status ◽

Cancer Centre ◽

Platinum Based Chemotherapy ◽

Line Setting

415 Background: Metastatic urothelial carcinoma (mUC) is an aggressive disease with a median overall survival (OS) of ≈ 15 months. In the first-line setting, key prognostic factors include ECOG performance status, white blood cell count, and response to treatment per the Galsky nomogram. Bone metastases (BM) in mUC are associated with morbidity and mortality but are grouped with visceral disease; hence, their impact on prognosis is not well established. We aimed to assess the survival impact of BM in mUC patients treated with first-line platinum-based chemotherapy (PBC). Methods: A retrospective collection of patient and tumor characteristics, with clinical response to treatment (complete response [CR], partial response [PR]; stable disease [SD] or progressive disease [PD]) for patients treated at Princess Margaret Cancer Centre, Tom Baker Cancer Centre, and Cross Cancer Institute from 2005-2018 was performed. Progression-free survival (PFS) and OS were estimated using the Kaplan-Meier method. Univariate (UVA) followed by multivariate analysis (MVA) of patient variables [Cox] using PFS and OS was performed. Results: Overall 376 mUC patients were included; 222 (59%) had soft-tissue metastases (STM) only, 70 (19%) had bone-only metastases, and 84 (22%) had both STM and BM. Overall, 35% had PR or CR, 19% had SD, and 39% had PD (7%: unknown response). The median PFS and OS for the whole cohort were 5.6 months (95%CI: 4.8-6.4) and 9.7 months (95% CI: 8.8-10.8) respectively. Select UVA by metastatic site showed inferior PFS for bone-only (p=0.03) and combination STM and BM (p=0.017). Only combination STM and BM were significant on UVA for OS (p=0.002). MVA showed that bone-only metastases (p=0.03) and ECOG 3-4 (p<0.0001) were associated with worse PFS (Table). Predictors of worse OS were the combination of STM and BM (p=0.02), ECOG 3-4 (p=0.001), and WBCs ≥ULN (p=0.02), (Table). Conclusions: BM are a significant predictor of worse outcomes for mUC patients treated with first-line PBC. Consideration as a treatment stratification factor for future studies is suggested. Strategies for the treatment of mUC patients with BM (ie: bone targeted agents) in the first-line setting should be addressed in future trials. [Table: see text]

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Multiple Myeloma (MM) in the Very Old: Disease Characteristics, Treatment Patterns and Outcomes in the Real World

Blood ◽

10.1182/blood-2020-143223 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 21-22

Author(s):

Smith Giri ◽

Susan Bal ◽

Kelly N. Godby ◽

Grant R Williams ◽

Luciano J. Costa ◽

...

Keyword(s):

Older Adults ◽

High Risk ◽

Research Funding ◽

Performance Status ◽

Surrogate Marker ◽

Progression Free Survival ◽

First Line ◽

Ecog Performance Status ◽

Systems Research ◽

Ecog Ps

Introduction: Older adults with MM continue to remain under-represented in clinical trials, leading to paucity of information regarding the clinical characteristics and treatment outcomes, particularly among those 80y or older at the time of diagnosis. The International Myeloma Working Group (IMWG) classifies any patient >80y as frail, irrespective of their fitness status. The value of geriatric assessment and frailty evaluation in this subgroup remain unclear. Methods: We used the Flatiron Health electronic record-derived de-identified database to source patients with incident MM diagnosed between January 1, 2011 and February 1, 2020. We compared clinical and demographic characteristics of patients ≥80y at the time of diagnosis with patients who were <80y of age. We abstracted baseline labs and cytogenetic data documented within 90 days from the start of first-line therapy. For those ≥80y, we captured the receipt of first line anti-myeloma therapy and examined early mortality (death within 6 months of diagnosis), derived progression-free survival (dPFS) and overall survival (OS) using Kaplan-Meier methods and Cox multivariate regression, with date of diagnosis as the index date. Finally, we compared dPFS and OS among potentially fit ≥80yo MM vs those between 75-79y, using ECOG performance status (PS) of zero as a surrogate marker of fitness status. Results: Of 8298 MM patients in this cohort, 1144 (13.5%) patients were ≥80y at diagnosis (median 81y, range 80-85y). Compared with the younger cohort, those ≥80y were more likely to be white, and have anemia, renal insufficiency, higher β2-microglobulin and higher stage at diagnosis. However, there was a lower prevalence of documented high-risk cytogenetic abnormalities, particularly high risk translocations (t4;14 and t14;16) even after adjusting for race/ethnicity (Mantel Haenszel OR=0.67; p 0.001). Common first line therapies included proteasome inhibitor (PI) + Immunomodulatory agent (Imid) based triplet (23%), Imid doublet (21%) and PI doublet (27%) (Table). Patients ≥80y received a median of 1 (IQR 1-2) lines of therapy, as opposed to those <80 (median 2, IQR 1-3). Overall, the outcome was significantly inferior among the ≥80y patients be those <80y (median dPFS 16 vs. 39 months, p<0.01; median OS: 26 vs 37 months, p<0.01; and 6-month mortality rate: 20.1% vs 6.2%, p<0.01). However, patients ≥80y and ECOG PS of 0 had similar 3y-dPFS (36.8 vs 33.1%; p=0.66) and 3y-OS (61.8 vs 65.2%; p=0.50) when compared to those between 75-79y with similar PS (ECOG PS of 0) (Figure). Conclusion: Patients 80y or above with newly diagnosed MM have distinct clinical and treatment characteristics as compared to their younger counterparts. Similar survival outcomes between older adults with good performance status vs their younger fit counterparts suggest the need for conducting a comprehensive frailty evaluation and individualized decision-making even in this cohort. Disclosures Giri: Carevive Systems: Honoraria; Pack Health: Research Funding; Carevive Systems: Research Funding. Costa:Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Genentech: Consultancy; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy; Sanofi: Consultancy, Honoraria.

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Increasing Karyotypic Complexity Predicts Outcomes in Patients with Chronic Lymphocytic Leukemia Treated with Ibrutinib

Blood ◽

10.1182/blood-2020-136714 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 2-3

Author(s):

Daniel Goldstein ◽

Kyle A. Beckwith ◽

Cecelia Miller ◽

Ying Huang ◽

Lynne V. Abruzzo ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Retrospective Analysis ◽

Research Funding ◽

Performance Status ◽

Single Agent ◽

Lymphocytic Leukemia ◽

Complex Karyotype ◽

Ecog Performance Status ◽

Cytogenetic Abnormalities ◽

Mutational Status

Introduction: Our group and others have previously shown that the presence of complex karyotype (>/= 3 cytogenetic abnormalities) is an important prognostic factor in relapsed/refractory (RR) chronic lymphocytic leukemia (CLL) patients treated with ibrutinib (Woyach JCO 2017, Thompson Cancer 2015, Maddocks JAMA Oncology 2015). It has been shown recently that increasing karyotypic complexity is a prognostic marker (Baliakis Blood 2019), but whether this is relevant for patients treated with novel therapies is unclear. Here, we aimed to determine whether the degree of karyotypic complexity beyond the dichotomy of complex versus not is a prognostic variable for patients with CLL treated with ibrutinib. Methods: We conducted a retrospective analysis of all patients with CLL treated with ibrutinib as a single agent or in combination with a monoclonal anti-CD20 antibody (MOAB) from 2010 through 2019 at The Ohio State University. We included patients with both treatment-naïve (TN) and RR disease. To determine karyotype, cells were stimulated with mitogen cocktail (PWM/PMA/CpG-ODN) and analyzed according to standard laboratory procedures. FISH using probes for D13S319, D12Z3, ATM, and TP53 were done according to manufacturer's recommendations. PCR was used to determine IGHV mutational status. Cytogenetic testing was included in the analysis if done <6 months before or within 60 days after ibrutinib initiation. All characteristics were measured at ibrutinib start. Multivariable Cox proportional hazards models were built to correlate karyotypic complexity (defined as a continuous variable with 1 unit increases) with progression free survival (PFS) and overall survival (OS), adjusted for age, RR status, ECOG performance status (PS), lactate dehydrogenase (LDH), white blood cell (WBC) count, hemoglobin (HgB), platelet (PLT) count, presence of del17p13 and IGHV mutational status. Multivariable models were fit in imputed datasets, and estimates were obtained from combining results from across 30 imputed datasets. Results: We analyzed 561 patients with a median age of 65 (range 26-91). 86% were treated with ibrutinib monotherapy, 22% were TN, and median number of prior therapies was 2 (range 0-13). 96% had an ECOG performance status (PS) of 0 or 1. Median LDH, WBC, HgB and PLT were 213 U/L, 23.2 K/uL, 11.2 g/dL, and 115 K/uL respectively. With available data, del13q14, trisomy 12, del11q22, and del17p13 was present in 50%, 22%, 30%, and 29% of patients respectively; 74% of patients were IGHV unmutated. 63 patients were excluded from cytogenetic analyses as the test was not done during the specified time window. Of the 458 evaluable, 50% had >3 cytogenetic abnormalities including 30% with >5 abnormalities. After a median follow up of 55.5 months, for the entire cohort estimated median PFS was 61.6 months (95% CI 56.1-69.5), and estimated median OS was 95.4 months (95% CI 86.3-not reached). On univariable analysis, older age, RR status, higher ECOG PS and LDH, lower HgB and PLT, presence of del17p13 and increasing karyotypic complexity were found to be statistically significant predictors of worse PFS and OS. To illustrate the relationship between increasing karyotypic complexity and clinical outcome, Kaplan-Meier plots are provided grouping pts with 0-2, 3-4, and 5 or higher aberrations (Figure 1). Accounting for statistically and clinically important factors on multivariate analysis (MVA, Table 1), increasing karyotypic complexity continued to be a statistically significant predictor of both PFS (p=0.01, HR 1.08 (95% CI 1.02-1.15)) and OS (p=0.001, HR 1.14 (95% CI 1.05-1.23)). Del17p13 did not retain statistical significance independently of karyotypic complexity on MVA. The interaction effect between prior treatment status and karyotypic complexity term was not significant for OS (p=0.89) and PFS (p=0.46), suggesting the prognostic effect of karyotypic complexity is similar across TN and RR cohorts. Conclusions: In this single center retrospective analysis, we found that increasing karyotypic complexity predicts inferior survival for patients with CLL treated with ibrutinib. This highlights that it is not only important to dichotomize presence of complex karyotype as >3 abnormalities, but to describe the number of karyotypic abnormalities in subsequent studies. Disclosures Bond: Seattle Genetics: Honoraria. Byrd:Acerta Pharma: Research Funding; Trillium: Research Funding; Pharmacyclics LLC, an AbbVie Company, Janssen, Novartis, Gilead, TG Therapeutics: Other; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, Novartis, Janssen: Speakers Bureau; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, BeiGene: Research Funding; Janssen: Consultancy; Leukemia and Lymphoma Society: Other; Novartis: Research Funding; Kartos Therapeutics: Research Funding; Vincera: Research Funding; Syndax: Research Funding. Rogers:AstraZeneca: Other: Travel; Abbvie, Acerta, AstraZeneca, Pharmacyclics: Consultancy; Abbvie, Genetech, Janssen: Research Funding. Woyach:Pharmacyclics: Consultancy, Research Funding; AbbVie: Research Funding; Janssen: Consultancy, Research Funding; Karyopharm: Research Funding; Morphosys: Research Funding; Loxo: Research Funding; Verastem: Research Funding.

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Understanding treatment patterns and outcomes in patients with metastatic NSCLC treated in a US community oncology network.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e20643 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e20643-e20643

Author(s):

Eric S. Nadler ◽

Janet L. Espirito ◽

Melissa Pavilack ◽

Marley Boyd ◽

Andrea Leninka Vergara-Silva ◽

...

Keyword(s):

Performance Status ◽

Ecog Performance Status ◽

Optimal Sequencing ◽

Kaplan Meier ◽

Community Oncology ◽

The Us ◽

Observational Cohort ◽

Never Smokers ◽

Retrospective Observational Cohort Study

e20643 Background: Multiple therapeutic options exist for metastatic non-small cell lung cancer (mNSCLC), including chemotherapy (CH), targeted therapy (T), and immunotherapy (IT). The first IT for mNSCLC was FDA approved in 2015 for use after progression on platinum-based CH and T in patients (pts) with EGFR or ALK mutations. The current study evaluates treatment (tx) patterns and outcomes in mNSCLC pts receiving first- (1L), 2nd- (2L), and 3rd-line (3L) therapy. Methods: This is a retrospective, observational cohort study of mNSCLC pts receiving initial tx from 1/2012–4/2016, with follow-up to 6/2016. Data were obtained from The US Oncology Network/McKesson Specialty Health electronic health records database. Demographics, clinical characteristics, and tx patterns were characterized. Overall survival (OS) was assessed using the Kaplan-Meier method. Results: 10,689 1L pts were identified during the study period. Median age was 68 y, and 54% were male. Most pts (59%) had an ECOG performance status of 1, 77% had nonsquamous histology, and 85% were former or current smokers. Initial tx was CH in 93% of pts. Among pts receiving initial T therapy, most were never smokers (48%) vs initial CH pts (12%; P< 0.0001). Median OS (mOS) for all pts at 1L was 12.3 mo (95% CI, 11.9–12.7), and mOS was significantly longer in pts who received T (24.3 vs 11.7 mo for T vs CH, p< 0.0001). Among pts who received 2L therapy in the study period (n = 4235), 66%, 17%, and 17% received CH, T, and IT respectively. Pemetrexed or docetaxel monotherapy was most commonly used for 2L CH, erlotinib was most used as 2L T, and nivolumab for 2L IT. mOS from start of 2L for CH, T, and IT was 9.2, 11.2, and 9.7 mo, respectively (log rank P= 0.01). In 3L pts (n = 1580), nivolumab was most frequently used (17%), and mOS from 3L for CH, T, and IT was 8.0, 7.4, and 11.3 mo, respectively ( P= 0.0187). Conclusions: These data demonstrate integration of novel therapies for mNSCLC in the community. Longer survival was observed in 2L and 3L patients treated with T and IT as compared with CH. This warrants additional randomized studies to investigate optimal sequencing of these agents.

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Real-world outcomes of first-line pembrolizumab plus pemetrexed-carboplatin for metastatic nonsquamous NSCLC at US oncology practices

Scientific Reports ◽

10.1038/s41598-021-88453-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Vamsidhar Velcheti ◽

Xiaohan Hu ◽

Bilal Piperdi ◽

Thomas Burke

Keyword(s):

Real World ◽

Performance Status ◽

Clinical Settings ◽

First Line ◽

Ecog Performance Status ◽

Kaplan Meier ◽

Outcome Information ◽

Genomic Aberrations ◽

Line Setting ◽

Nonsquamous Nsclc

AbstractEvidence from real-world clinical settings is lacking with regard to first-line immunotherapy plus chemotherapy for the treatment of non-small cell lung cancer (NSCLC). Our aim was to describe outcomes for patients treated with first-line pembrolizumab-combination therapy for metastatic nonsquamous NSCLC in US oncology practices. Using an anonymized, nationwide electronic health record-derived database, we identified patients who initiated pembrolizumab plus pemetrexed-carboplatin in the first-line setting (May 2017 to August 2018) after diagnosis of metastatic nonsquamous NSCLC that tested negative for EGFR and ALK genomic aberrations. Eligible patients had ECOG performance status of 0–1. An enhanced manual chart review was used to collect outcome information. Time-to-event analyses were performed using the Kaplan–Meier method. Of 283 eligible patients, 168 (59%) were male; median age was 66 years (range 33–84); and the proportions of patients with PD-L1 tumor proportion score (TPS) of ≥ 50%, 1–49%, < 1%, and unknown were 28%, 27%, 28%, and 17%, respectively. At data cutoff on August 31, 2019, median patient follow-up was 20.3 months (range 12–28 months), and median real-world times on treatment (rwToT) with pembrolizumab and pemetrexed were 5.6 (95% CI 4.5–6.4) and 2.8 months (95% CI 2.2–3.5), respectively. Median overall survival (OS) was 16.5 months (95% CI 13.2–20.6); estimated 12-month survival was 59.5% (95% CI 53.3–65.0); rwProgression-free survival was 6.4 months (95% CI 5.4–7.8); and rwTumor response rate (complete or partial response) was 56.5% (95% CI 50.5–62.4). Median OS was 20.6, 16.3, 13.2, and 13.7 months for patient cohorts with PD-L1 TPS ≥ 50%, 1–49%, < 1%, and unknown, respectively. These findings demonstrate the effectiveness of pembrolizumab plus pemetrexed-carboplatin by describing clinical outcomes among patients with metastatic nonsquamous NSCLC who were treated at US oncology practices.

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First-line nivolumab (NIVO) plus ipilimumab (IPI) plus two cycles of chemotherapy (chemo) versus chemo alone (4 cycles) in patients with advanced non-small cell lung cancer (NSCLC): Two-year update from CheckMate 9LA.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.9000 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 9000-9000

Author(s):

Martin Reck ◽

Tudor-Eliade Ciuleanu ◽

Manuel Cobo ◽

Michael Schenker ◽

Bogdan Zurawski ◽

...

Keyword(s):

Clinical Benefit ◽

Performance Status ◽

Objective Response ◽

Stage Iv ◽

Progression Free Survival ◽

Expression Level ◽

First Line ◽

Ecog Performance Status ◽

Grade 3

9000 Background: In the randomized phase 3 CheckMate 9LA trial (NCT03215706), first-line NIVO + IPI combined with 2 cycles of chemo significantly improved overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) vs chemo alone (4 cycles). Clinical benefit was observed regardless of programmed death ligand 1 (PD-L1) expression level and histology. Here we report data with 2 years’ minimum follow-up from this study. Methods: Adult patients (pts) with stage IV / recurrent NSCLC, ECOG performance status ≤ 1, and no known sensitizing EGFR/ALK alterations were stratified by PD-L1 (< 1% vs ≥ 1%), sex, and histology (squamous vs non-squamous) and were randomized 1:1 to NIVO 360 mg Q3W + IPI 1 mg/kg Q6W + chemo (2 cycles; n = 361) or chemo alone (4 cycles; n = 358). Pts with non-squamous NSCLC in the chemo-alone arm could receive pemetrexed maintenance. The primary endpoint was OS. Secondary endpoints included PFS and ORR by blinded independent central review, and efficacy by different PD-L1 levels. Safety was exploratory. Results: At a minimum follow-up of 24.4 months for OS (database lock: Feb 18, 2021), pts treated with NIVO + IPI + chemo continued to derive OS benefit vs chemo, with a median OS of 15.8 months vs 11.0 months, respectively (HR, 0.72 [95% CI, 0.61–0.86]); 2-year OS rates were 38% vs 26%. Median PFS with NIVO + IPI + chemo vs chemo was 6.7 months vs 5.3 months (HR, 0.67 [95% CI, 0.56–0.79]); 8% and 37% of pts who had disease progression received subsequent immunotherapy, respectively. ORR was 38% with NIVO + IPI + chemo vs 25% with chemo. Similar clinical benefit with NIVO + IPI + chemo vs chemo was observed in all randomized pts and across the majority of subgroups, including by PD-L1 expression level (Table) or histology. Any grade and grade 3–4 treatment-related adverse events were reported in 92% and 48% of pts in the NIVO + IPI + chemo arm vs 88% and 38% in the chemo arm, respectively. Conclusion: With 2 years’ minimum follow-up, first-line NIVO + IPI + chemo demonstrated durable survival and benefit versus chemo in pts with advanced NSCLC; no new safety signals were identified. Clinical trial information: NCT03215706. [Table: see text]

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Lenalidomide and Rituximab Maintenance Therapy after Front-Line Induction Chemoimmunotherapy in Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

Blood ◽

10.1182/blood-2019-124489 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5470-5470

Author(s):

Julie E Chang ◽

Vaishalee P. Kenkre ◽

Christopher D. Fletcher ◽

Aric C. Hall ◽

Natalie Scott Callander ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Maintenance Therapy ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Second Malignancies ◽

Front Line ◽

First Line ◽

11Q Deletion ◽

Line Chemotherapy

Introduction: Chronic lymphocytic leukemia (CLL) is incurable with standard therapy. With first-line chemotherapy, some patients (pts) may achieve durable remissions of many months/years. Lenalidomide (LEN) has improved progression-free survival (PFS) when given as maintenance (MNT) therapy after front-line chemotherapy (CALGB10404, CLLM1). The combination of LEN + rituximab (LR) has activity in relapsed CLL, hypothesizing benefit as MNT therapy after first-line chemotherapy. Methods: Adult pts ≥18 years with previously untreated CLL received induction bendamustine (B) 90 mg/m2 IV days 1 & 2 and rituximab (R) IV day 1 (375 mg/m2 cycle 1, then 500 mg/m2 cycles 2-6) for 6 treatment cycles (as few as 4 cycles allowed). MNT therapy with LR was initiated within 12 weeks after cycle 6, day 1 of BR. Criteria to start LR MNT included: neutrophils ≥1000/microliter (uL), platelets ≥75 K/uL, and creatinine clearance ≥40 mL/min. LEN was administered in 28-day cycles for 24 cycles, initially 5-10 mg daily continuous dosing, later modified to 5-10 mg on days 1-21 of each 28-day cycle in 6/2018 due to neutropenia and second malignancy risk. LEN was reduced to 5 mg every other day for toxicities at 5 mg/day. R 375 mg/m2 IV was given every odd cycle (total of 12 doses). Patients discontinuing LEN for any reason were allowed to continue R MNT per protocol. The primary endpoint is PFS with LR MNT therapy, calculated from the first day of MNT therapy until progressive disease (PD), death, or start of a new therapy. Secondary endpoints are response rate and overall survival. Results: Thirty-four pts have enrolled beginning 11/2013, with follow-up through 6/2019. Median age is 64 years, with 8 pts ≥70 years; 8 women and 26 men. CLL FISH panel is available on all pts: 14 with 13q (as sole abnormality), 9 with 11q deletion, 6 with trisomy 12, 4 with normal FISH panel and 1 with 17p deletion. Heavy chain mutation analysis is available on 11 pts: 8 unmutated, 2 mutated, 1 indeterminate. Thirty-one pts completed 4 (n=2) or 6 cycles of induction BR; 3 pts are receiving induction BR. Twenty-four pts have received MNT LR; 7 did not receive LR for reasons of PD during induction (n=2), infection (n=1), pt preference (n=2), renal insufficiency (n=1), and new carcinoma (n=1). MNT LR was completed in 7 pts; 9 pts are still receiving LR. Fourteen subjects have discontinued protocol therapy, 3 during induction due to PD (n=2) and infection (n=1), and 8 during MNT. Toxicities that led to discontinuation of LR were recurrent infections in 7 pts, including 2 events of PJP pneumonia; 4 pts had recurrent neutropenia with infections; 1 pt had neutropenia without infections. Response is assessable in 31 patients using the International Working Group Consensus Criteria. Best responses to treatment were: partial response 65% (22/34), complete response (CR)/unconfirmed CR 24% (8/34). The median number of MNT cycles received is 16. The dose intensity of LEN across total cycles received (n=278): 5 mg every other day (52.5%), 5 mg/day (43.9%), and 10 mg/day (3.6%). The most common reason for dose reduction or dose holding was neutropenia. Most common Gr 3/4 toxicities (reported as events Gr3/Gr4) during MNT therapy were: neutropenia (20/20), leukopenia (19/4), febrile neutropenia (3/1), and infections (11/-). The majority of Gr3 infections were pneumonia/respiratory (n=5). One event of disseminated herpes zoster occurred. Second malignancies during MNT included: basal cell CA (n=1), squamous cell carcinoma (n=5), and colon cancer (n=1). No unexpected second malignancies were observed in pts receiving LR. Two-year PFS (defined from day 1 of MNT therapy) is 90% (95% confidence interval [CI] 0.78-1), and the median follow-up for 24 patient who started maintenance therapy is 1.79 years (95% CI 1.53-2.7). There have been no deaths. Conclusion: The combination of LR is effective in sustaining remissions after a BR induction in previously untreated CLL, but with frequent neutropenia and infections even at low doses of LEN. Most patients discontinuing MNT did so due to neutropenia and/or infections. A shorter planned interval of MNT LR (i.e., 6-12 months) may confer similar benefit to extended dosing that is more tolerable. Pts at high risk for short remissions after front-line chemotherapy (e.g., unmutated heavy chain status, 11q deletion and/or failure to achieve minimal residual disease after induction) may be the populations for which LR MNT therapy is most appropriate. Disclosures Chang: Genentech: Research Funding; Adaptive Biotechnologies: Research Funding; Celgene: Research Funding. OffLabel Disclosure: Lenalidomide administered as maintenance therapy for first treatment of CLL/SLL.

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Update results from ALTER-C-001: Efficacy and safety of anlotinib plus XELOX regimen as first-line treatment followed by maintenance monotherapy of anlotinib for patients with mCRC-A single-arm, multicenter, phase Ⅱ clinical trial.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e15550 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e15550-e15550

Author(s):

Jin Yan ◽

Yunwei Han ◽

Li Zhang ◽

Yongdong Jin ◽

Hao Sun

Keyword(s):

Clinical Trial ◽

Adverse Events ◽

Performance Status ◽

Phase Iii ◽

Line Treatment ◽

First Line ◽

Open Label ◽

Ecog Performance Status ◽

Multicenter Phase ◽

First Line Treatment

e15550 Background: The combination of anti-VEGF or anti-EGFR targeted drugs with chemotherapy is the standard first-line therapy for metastatic colorectal cancer (mCRC), and the followed maintenance treatment is an optional approach to balance the efficacy and toxicity. However, studies regarding the maintenance strategies based on antiangiogenic TKIs are limited currently. Anlotinib, a novel oral multi-target TKI which can inhibit both tumor angiogenesis and tumor cell proliferation simultaneously, substantially prolonged the PFS with manageable toxicity for refractory mCRC in the phase III ALTER0703 clinical trial. Here we report an update on the effectiveness and safety of anlotinib plus XELOX as first-line treatment followed by anlotinib monotherapy for mCRC. Methods: In this open label, single-arm, multicenter phase II clinical trial, 53 mCRC patients without prior systemic treated, aged 18-75 and an ECOG performance status of 0 or 1 were planned to recruit. Eligible patients received capecitabine (1000 mg/m2, po, d1-14, q3w) and oxaliplatin (130 mg/m2, iv, d1, q3w) plus anlotinib (10mg, po, d1̃14, q3w) treatment for 6 cycles. After 6 cycles of inducing therapy, patients would receive anlotinib (12mg, po, d1̃14, q3w) as maintenance therapy until disease progression or intolerable adverse events (AEs). The primary endpoint was PFS; Secondary endpoints included ORR, DCR, DOR and safety. Results: By the data analysis cutoff date of January 22, 2021, a total of 18 patients were enrolled, of which 12 patients were available for efficacy assessment. In best overall response assessment, there were 50.0% PR (6/12), 33.3% SD (4/12) and 16.7% PD (2/12). The ORR was 50.0% (95% CI, 21.1-78.9%) and DCR was 83.3% (95% CI, 51.5-97.9%). The longest duration of treatment was 8.8 months and the response was still ongoing. The median PFS was not reached. The most common treatment related adverse events (TRAEs) of any grade (≥20%) were leukopenia, hypertension, neutropenia, diarrhea, fatigue, hypertriglyceridemia. Grade 3/4 TRAEs included hypertension (22.2%), hypertriglyceridemia (11.1%), lipase elevated (11.1%) and neutropenia (5.6%). No grade 5 AEs occurred. Conclusions: The update results suggested that anlotinib combined with XELOX as first line regimen followed by anlotinib monotherapy showed promising anti-tumor activity and manageable safety for patients with mCRC. And the conclusions needed to be confirmed in trials continued subsequently. Clinical trial information: ChiCTR1900028417.

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