1L Tyrosine Kinase Inhibitors Research Articles

Abstract 1191: Personalized neoantigen DNA vaccine GNOS-PV02 and pembrolizumab as second-line treatment for advanced hepatocellular carcinoma

Abstract Background: PD-1 inhibitors have modest efficacy as monotherapy in hepatocellular carcinoma (HCC). A personalized therapeutic cancer vaccine (PTCV) tailored against neoantigens identified in an individual’s tumor may enhance responses to PD-1 inhibitors through the induction of tumor-specific immunity. Here, we present results from a single-arm Phase Ib/2a trial evaluating a DNA plasmid (GNOS-PV02) encoding up to 40 neoantigens co-administered with plasmid-encoded IL-12 (pIL12) in combination with pembrolizumab (PEMBRO) in patients (pts) with advanced HCC.Methods: Pts were eligible for study therapy upon progression or intolerance with a 1L tyrosine kinase inhibitor (TKI). The PTCV [GNOS-PV02 (1mg) and pIL12 (0.34mg)] was administered intradermally via in vivo electroporation Q3w x 4 doses, and Q9w thereafter. PEMBRO was administered at 200mg IV Q3w. The primary endpoints were safety and immunogenicity. To evaluate the secondary endpoint of ORR per RECIST 1.1 by investigator review with a null hypothesis of an ORR of 16.9% (KN-240, Finn et al ASCO 2019), 36 pts were included to provide 80% power to reject the null hypothesis at the one-sided 0.10 level, assuming the true ORR rate of 33.1%. The data cut date was August 18, 2023.Results: Among the 36 enrolled pts who received at least one dose of treatment, there were no DLTs or treatment-related grade ≥3 events. The most common treatment-related adverse events were injection site reactions, observed in 41.6% of pts. ORR (mITT) per RECIST 1.1 was 30.6% (11/36; 9 confirmed and 2 unconfirmed) with 8.3% (3/36) of pts achieving a CR. This achieved statistical significance with a one-sided p-value = 0.031 (1-sided 90% CI 20.4%-100%) The mOS was 19.9 months. ctDNA changes correlated with radiographic responses and preceded them. A complete molecular response (100% ctDNA clearance) was detected in 7 pts including the 3 radiographic CRs, and 4 additional pts who continue to show durable tumor control (3PR, 1 SD). Immunological analyses confirmed the induction of neoantigen-specific T cell responses by IFNγ-ELISpot in 19/22 (86.4%) evaluable pts, and pts with a larger ELISpot response showed a trend towards longer OS. Multi-parametric cellular profiling and single-cell analysis revealed active, proliferative, and cytolytic vaccine-specific CD4+ and CD8+ effector T cells in the blood of immunized pts. In 14/14 (100%) of pts with paired pre- and on-treatment blood and tumor biopsies, we identified by TCRβ bulk sequencing expanded T cell clones in the peripheral blood that also trafficked into the tumor. Conclusions: Our results show that a PTCV plus PEMBRO is well tolerated and has clinical activity in pts with advanced HCC, and support the PTCV mechanism of action based on the induction of anti-tumor T cells in peripheral blood and tumor. A confirmatory phase 3 clinical study assessing OS is planned. Citation Format: Mark Yarchoan, Edward J. Gane, Thomas U. Marron, Renzo Perales-Linares, Jian Yan, Neil Cooch, Daniel Shu, Elana J. Fertig, Luciane T. Kagohara, Gabor Bartha, Josette Northcott, John Lyle, Sarah Rochestie, Joann Peters, Jason Connor, Elizabeth Jaffee, Alfredo Perales-Puchalt, David B. Weiner, Ildiko Csiki, Niranjan Y. Sardesai. Personalized neoantigen DNA vaccine GNOS-PV02 and pembrolizumab as second-line treatment for advanced hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1191.

Prospective Assessment of Co-Morbidities and Framingham Risk Score in Newly Diagnosed Chronic Myeloid Leukemia (CML) Patients and Its Impact on Clinical Outcomes Following Frontline TKI Therapy: Toronto CML Genomic Alliance in Greater Toronto Area & Ontario (TCGA-GTA)

Introduction Front-line (1L) tyrosine kinase inhibitor (TKI) drug selection is a pearl of clinical practice in CML. It requires consideration of multiple aspects including the goal of therapy, potency of the drug as well as comorbidity of the patient (pt). Contemporary CML practice emphasizes the importance of comorbidity for TKI selection. However, such data is scarce particularly the prevalence of comorbidity and its impact on 1L drug selection. We are developing a shared care model with community hematologists in Greater Toronto Area (TCGA-GTA). Newly diagnosed CML pts in the community will be referred to the study core center for prospective enrolment into the CML registry, informed consenting for genetic testing/future research, and evaluation of baseline comorbidity. Pt will return to referring hematologists for management of CML, including 1L TKI treatment as per standard of care, and is scheduled to visit the study center at 6 and 12 months, then annually for 10 years. It gives us a unique opportunity to evaluate the impact of comorbidity on 1L TKI drug selection. Patients and method Adult pts with newly diagnosed CML of any phase within 2 months of diagnosis are eligible for the study unless they are not able to visit study core center. Comorbidities and Framingham risk score (FRS) were assessed at the time of initial evaluation. Mutation profile testing is done by a bar-coded error-corrected sequencing platform for 40 genes developed at the Ontario Institute for Cancer Research. Cumulative incidence of molecular response with 2 log (MR2), 3 log (MR3), 4 log reduction or deeper (MR4), and treatment failure (TF) were calculated using cumulative incidence method considering competing risk. Event-free survival (EFS) was defined as time from start of TKI until TKI stop/switch, TF or death. Failure-free survival (FFS) was defined as time from start of TKI to TF [primary resistance, loss of complete cytogenetic response, new additional cytogenetic abnormalities (ACAs), and progression to accelerated or blasts phase (AP/BP)] or death. Results From November 2020 until June 31, 2023 (data cutoff), a total of 77 pts were enrolled in the study. The median follow-up time was 12 months. The frequency of 1L TKI selection was as follows: IMATINIB (IM) (n=23, 30%), DASATINIB (n=25, 32%), NILOTINIB (n=22, 29%), BOSUTINIB (n=1, 1%), ASCIMINIB (n=6, 8%). Majority of the pts were male (n=51, 66%). Ninety-three percent of pts were in chronic phase at diagnosis, while 4% and 3% were in AP and BP, respectively. Presence of ACAs was detected in 18 pts (23%), 10 of which were high risk, while 6% (n=5) were not evaluable. The baseline clinical and disease characteristics of pts on 1L IM vs other TKIs (2G-TKI) are summarised in Table 1. Of note, pts on IM were significantly older with higher FRS and comorbidities, including coronary artery disease, diabetes mellitus, and hypertension. The OS of all pts at 1 year was 98.5% (95% confidence interval 90%-99.8%). At 1 year, pts with intermediate to high risk FRS had lower FFS (73.2% vs 86.5%, p=0.037) while history of hyperlipidemia was associated with lower EFS (59.3% vs 81.5%, p=0.023) and 6 times more likely to stop or switch therapy due to intolerance or resistance (HR 5.9, p=0.002). Baseline comorbidities did not demonstrate signifincant impact on MR2 and MR3 at 1 year but pts with low FRS were more likely to achieve MR4 within 1 year (22.3% vs 0%, p=0.023). Age did not affect any of the clinical and molecular endpoints. Compared to 2G-TKI, IM had worse EFS (HR 3.93, p=0.003), FFS (HR 5.66, p=0.011), and MR2 (47.3% vs 84.4%, p=0.003) at 1 year. Further, IM pts experienced higher rate of any side effects compared to those on 2G-TKI (69.6% vs 31.5%, p=0.003). Conclusion The TCGA-GTA study provides valuable insights into the impact of comorbidity on selection of 1L TKI and its outcome in a real-world setting. Pts who are older and with higher FRS and comorbidities tend to receive 1L IM. However, pts on 1L 2G TKIs are more likely to reach treatment goals faster with lower probability of TF. The present study did not reach a clear conclusion whether the worse outcomes in the pts receiving IM are from IM treatment or concurrent risk factors such as age and comorbidities, thus further study with an expanded cohort and longer follow-up is required. Elderly pts or those with comorbidities would need alternative treatment with better efficacy and tolerability, such as Asciminib, that can overcome comorbidity issues in the future.

ASC2ESCALATE: A US Phase 2, Open-Label, Single-Arm, Dose-Escalation Study of Asciminib (ASC) Monotherapy in Patients (Pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) As Second-Line (2L) and First-Line (1L) Treatment

CONCLUSIONS Adenosine triphosphate (ATP)-competitive tyrosine kinase inhibitors (TKIs) have increased survival in CML, although resistance and intolerance remain challenges, which often necessitate switch to another TKI. Many pts discontinue 1L treatment due to resistance/intolerance and switch to 2L therapy, to which resistance is typically higher. A need exists for effective, safe treatment options for pts in 1L and 2L. ASC is thefirst approved BCR::ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket (STAMP), with activity against most BCR::ABL1 kinase domain mutations conferring resistance to ATP-competitive TKIs, potentially providing a new early-line treatment option. ASC was first approved in the United States for pts with CML-CP after ≥2 TKIs at 80 mg once daily (QD) or 40 mg twice daily (BID) and for pts with CML-CP with the T315I mutation at 200 mg BID. A large, phase 1, dose-escalation trial (NCT02081378) demonstrated efficacy and tolerability of ASC across a broad range of dosages. Also, with >2 years of follow-up, ASC demonstrated superior efficacy and better safety and tolerability compared with bosutinib in pts with CML-CP without the T315I mutation after ≥2 prior TKIs in the phase 3 ASCEMBL study (NCT03106779). We describe the phase 2 ASC2ESCALATE trial investigating efficacy and safety of ASC with dose escalation in pts with CML-CP receiving ASC as their 2L or 1L therapy. This is a phase 2, open-label, multicenter, single-arm, dose-escalation study with sites in the United States (NCT05384587) (Figure). Pts receiving ASC as their 2L TKI must be adults with non-T315I CML-CP who discontinued their first ATP-competitive TKI for warning response ( BCR::ABL1IS >1%-10% after 6 months or >0.1%-1% after 12 months of 1L treatment), resistance ( BCR::ABL1IS >10% after 6-12 months or >1% or loss of major molecular response [MMR] after >12 months of 1L treatment), or intolerance (with BCR::ABL1IS >0.1% at screening). In addition to pts receiving ASC as their 2L TKI, a separate cohort of newly diagnosed pts will be included, and these pts may receive up to 4 weeks of prior treatment with imatinib or an approved second-generation TKI (Table). All pts will start treatment with ASC 80 mg QD. Pts achieving BCR::ABL1IS ≤1% at 6 months will continue at the same dose; pts not achieving BCR::ABL1IS ≤1% at 6 months will have their dose escalated to 200 mg QD. In pts not achieving MMR at 12 months, dose escalation from 80 to 200 mg QD or from 200 mg QD to 200 mg BID will occur or the pt will be taken off the study. If pts have grade ≥3 or persistent grade 2 toxicity refractory to optimal management, no dose escalation will occur, and pts will remain on ASC at their most current dose. This dose-escalation strategy applies to both the 2L and 1L cohorts. The primary endpoint is MMR rate at 12 months in pts using ASC as their 2L TKI. As all primary and secondary endpoints for the 2L cohort will be measured for the 1L cohort as secondary endpoints, the MMR rate at 12 months in pts receiving ASC as their 1L TKI is a secondary endpoint. Additional secondary endpoints are the same for both 2L and 1L cohorts and include MMR rates at 3, 6, 18, and 24 months; MMR rates by all scheduled time points; MR 2 ( BCR::ABL1IS ≤1%), MR 4 ( BCR::ABL1IS ≤0.01%), and MR 4.5 ( BCR::ABL1IS ≤0.0032%) at and by scheduled time points; time to and duration of MMR; time to treatment failure; progression-free survival; overall survival; and safety/tolerability. Exploratory endpoints include assessment of BCR::ABL1 mutations. ASC2ESCALATE is the first clinical trial designed to assess pts with CML-CP using ASC as their 2L TKI and will provide critical information on efficacy and safety of dose escalation in pts for whom certain response milestones are not met in 2L and 1L. Dose escalation of ASC in 2L and 1L is another treatment strategy and results from ASC2ESCALATE will add to the growing body of evidence for using ASC to treat pts with CML-CP. Recruitment for pts using ASC as their 2L TKI began November 2022, and as of July 10, 2023, 5 pts have been enrolled in this cohort; Up to 92 and 90 pts are estimated to enroll in the 2L and 1L cohorts, respectively, across 90 sites.

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

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

Treatment Patterns and Modifications of Tyrosine Kinase Inhibitors (TKI) Therapy in Early Lines in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP): Real-World Analysis from a Large Commercial Claims Database in the United States (US)

Introduction: Although current TKI options are often successful in managing CML-CP in early lines of therapy, patients may experience issues related to tolerability or resistance to TKIs. Physicians often have to proceed with treatment modifications including discontinuation, switching, temporary interruptions, or dose modifications when the patient's current treatment is not working as expected. This retrospective cohort study assessed these TKI therapy management patterns in patients with CML in first-line (1L) or second-line (2L) treatment in the US. Methods: A large administrative claims database of commercially insured patients, the OptumInsight Clinformatics database (January 2007-June 2022), was used to select adult patients with CML who received 1L TKI therapy (imatinib, dasatinib, nilotinib, or bosutinib; 1L cohort) and those who received 2L TKI therapy (imatinib, dasatinib, nilotinib, bosutinib, or ponatinib; 2L cohort), with treatment initiation (index date) on or after 2012. Patients were required to have ≥6 months of continuous health plan enrollment pre-index, with no hematopoietic stem cell transplantation (HSCT) or CML-related chemotherapy treatments for accelerated phase (AP) or blast crisis (BC) pre-index. Treatment modifications assessed post-index included 1) treatment discontinuation, defined as the earliest of HSCT/treatment switch (defined below)/initiation of a CML-related chemotherapy for AP or BC, 2) treatment switch defined as initiation of another TKI/omacetaxine mepesuccinate, 3) temporary treatment interruption defined as gap of ≥ 14 days followed by resuming the index TKI, and 4) dose reduction (as compared to the initial dose) were assessed. Time to first event post-index were conducted using Kaplan Meier analyses for each of these treatment modifications, in 1L and 2L cohorts, separately. Results: A total of 2,043 patients were included in the 1L cohort with 47.8% of them receiving imatinib, 31.0% dasatinib, 19.2% nilotinib, and 2.0% bosutinib (median age: 64 years; 44.9% female; 69.7% White; 49.5% with Medicare advantage plan operated by commercial insurance [Part C]). Patients in the 1L cohort were observed for a mean (SD) period of 29.1 (27.3) months from index date to earliest of loss of follow-up/end of data. Overall, more than a quarter of patients (27.3%) experienced treatment discontinuation, with rates of discontinuation of 16.1% at 6 months, 25.0% at 12 months, and 33.5% at 24 months post-index ( Figure 1). Treatment switch was observed in 26.0% of the patients, with rates of 15.5% at 6 months and 24.4% at 12 months post-index. The proportion of patients with temporary treatment interruption was 18.6%, with rates of 20.6% at 6 months and 22.2% at 12 months post-index. Dose reduction (as compared to initial dose) occurred in 21.9% of patients, with rates of 18.8% at 6 months and 23.3% at 12 months post-index. A total of 586 patients were included in the 2L cohort with 23.0% of them receiving imatinib, 36.9% dasatinib, 26.6% nilotinib, 10.9% bosutinib and 2.6% ponatinib (median age: 65 years; 47.3% female; 72.5% White; 48.3% with Medicare advantage plan operated by commercial insurance [Part C]). Patients in the 2L cohort were observed for a mean (SD) period of 28.4 (25.4) months from index date to earliest of loss of follow-up/end of data. Almost a third of patients (32.8%) experienced treatment discontinuation, with rates of discontinuation of 22.1% at 6 months, 29.9% at 12 months, and 43.1% at 24 months post-index ( Figure 1). Treatment switch was observed in 30.5% of patients, with rates of 20.5% at 6 months and 28.3% at 12 months post-index. The proportion of patients with temporary treatment interruption was 21.3%, with rates of 24.8% at 6 months and 25.4% at 12 months post-index. Dose reduction as compared to initial dose occurred in 20.6% of patients, with rates of 17.5% at 6 months and 27.2% at 12 months post-index. Conclusions: Findings from this real-world study demonstrate that almost a quarter of patients with CML treated with current TKI treatment options in 1L or 2L experienced treatment discontinuation/switch in the first year from TKI initiation suggesting lack of optimal response/tolerability to currently available TKIs, with more pronounced rates in 2L. This suggests that unmet clinical needs still persist in this population, warranting optimal 1L and 2L treatment options with better tolerability profile for CML management.

Clinical outcomes of patients with bone-predominant metastatic renal cell carcinoma.

703 Background: Bone-predominant metastatic renal cell carcinoma (mRCC) is associated with aggressive biology and poor prognosis. The optimal management of these patients (pts) remains not well-established. While contemporary trials showed the superiority of immune checkpoint inhibitors (ICI) compared to vascular endothelial growth factor tyrosine kinase inhibitors (TKI), these pts were often excluded due to non-measurable disease. mRCC bone metastases show an enhanced angiogenesis gene signature suggesting the potential for greater responses to TKI. We test this hypothesis in a retrospective study comparing treatment outcomes for the first line (1L) TKI versus ICI in pts with bone-predominant mRCC. Methods: Pts with mRCC who received care at the Ohio State University Comprehensive Cancer Center from 1/1/2008 to 6/1/2021 were identified through retrospective chart review. Bone-predominant metastasis was defined as the number of bone metastases > extra-osseous metastases. Pts who had ≥1 cycle of treatment and follow-up scans were evaluated for treatment responses per RECIST 1.1 criteria. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. The comparisons were made between TKI and ICI cohorts, and the significance was determined by logrank test. Pt who received ICI-TKI in 1L were excluded from the survival analysis due to limited N. Results: A total of 335 pts with mRCC were identified, of which 45 (13.4%) had bone-predominant metastasis. Most of the pts (44/45) had clear cell histology. TKI was the 1L intervention for 21 (47%) while 20 (44%) pts received ICI, and 4 (9%) pts received TKI-ICI. TKI and ICI cohorts were similar for International Metastatic RCC Database Consortium (IMDC) Risk (Table). In the TKI cohort, 19 pts had evaluable responses with ORR of 15.7% and SD of 42%. The mPFS was 5.9 months (95% CI 2.8–9), and mOS was 30.4 months (95% CI 3.3–57.6). In the ICI cohort, 16 had evaluable responses with ORR of 6% and SD of 43.8%. The mPFS was 3.4 months (95% CI 0–8.2), and mOS was 19.3 months (95% CI 14.9–23.7). The hazard ratio was 0.58 for PFS and 0.54 for OS, favoring TKI over ICI, although statistical significance was not reached due to the small sample size (p=0.10 and 0.12, respectively). Conclusions: In this single-center retrospective study, pts with bone-predominant mRCC who received TKI compared to ICI as 1L therapy showed improved ORR, PFS, and OS. These results warrant further investigation in larger studies comparing TKI-containing regimen vs ICI doublet. [Table: see text]

Racial differences in treatment patterns and outcomes of first-line (1L) therapies for advanced renal cell carcinoma (aRCC) in the real-world (RW) setting.

4548 Background: In 1L therapy for aRCC, nivolumab plus ipilimumab (NIVO+IPI) and pembrolizumab plus axitinib (PEM+AXI) have demonstrated significantly improved clinical outcomes versus sunitinib in phase III trials. African American/Black (AA) patients are grossly underrepresented in all aRCC trials. Little is known about the impact of racial differences on the use of 1L therapies and clinical outcomes in the RW setting. Methods: This retrospective chart review included AA and White American (WA) patients diagnosed with International Metastatic Renal Cell Carcinoma Database Consortium (IMDC)/Memorial Sloan Kettering Cancer Center (MSKCC) intermediate/poor (I/P)-risk aRCC who initiated on 1L NIVO+IPI, PEM+AXI, or tyrosine kinase inhibitor (TKI) monotherapy with sunitinib, pazopanib, or cabozantinib. Patients’ demographic/clinical characteristics and outcomes were abstracted from medical charts by treating oncologists. Use of 1L therapy, treatment discontinuation, and clinical outcomes including disease response, landmark progression-free survival (PFS), landmark overall survival (OS), and treatment-related adverse event (TRAE) rates were assessed descriptively by race. Results: Of 473 patients, 95 (20.1%) were AA, and 378 (79.9%) were WA patients. Median follow-up was 10.9 months. A higher proportion of AA vs. WA patients had received 1L TKI monotherapy (21.1% vs. 16.1%). Treatment discontinuation rate was higher in AA vs. WA patients (49.5% vs. 43.4%). Treatment response was lower in AA than WA patients (overall response rate [ORR]: 58.8% vs. 74.8%; complete response [CR]: 8.2% vs. 11.4%). The TRAE rate was slightly lower in AA vs. WA patients (25.3% vs. 32.5%). Stratified clinical outcomes including landmark PFS and OS rates at 6 and 9 months are shown in the Table. Conclusions: In this RW I/P-risk aRCC cohort, fewer AA patients were treated with standard of care immune-oncology (IO)-based therapy vs. WA patients, which may contribute to differences in therapy discontinuation and survival outcomes. Also, even with short follow-up, clinically meaningful ORR differences are noted in AA and WA patients. [Table: see text]

A real-world (rw) evidence study quantifying the clinical value of multi-gene testing in early-stage lung adenocarcinoma (LUAD).

8525 Background: Resected early-stage NSCLC has high risk of recurrence, and tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICI), each requiring testing for precision biomarkers, have recently been approved in the adjuvant (adj) setting. We assessed the potential value of multi-gene testing in early NSCLC via enabling timely 1L therapy selection at recurrence and through avoidance of adj ICI in pts with driver alterations unlikely to benefit per current guidelines and the label for atezolizumab in first line (1L) NSCLC. Methods: Using the nationwide (̃280 US cancer clinics) de-identified EHR-derived rw Flatiron Health- Foundation Medicine clinico-genomic database, we selected 6,725 evaluable pts with LUAD who underwent tissue comprehensive genomic profiling (CGP) as part of routine cancer care (01/2011 – 06/2021). We focused on alterations in 4 drivers ( EGFR, ALK, ROS1, RET) and studied prevalence in early-stage specimens versus advanced (adv) specimens, as well as the rate of timely delivery of 1L therapy at recurrence for pts receiving CGP in early disease. We estimated the cost implications of adj ICI in pts with PD-L1+ LUAD and an ALK, ROS1, or RET fusion with a probabilistic decision tree. Results: CGP was performed on 1,490 specimens collected prior to adv disease (stage I 36%, II 27%, IIIA 37%) and ordered prior to adv diagnosis for 981 pts (15% of total, median 10 weeks after initial diagnosis). In specimens collected in early (n = 1,490) or adv (n = 5,130) stage LUAD, CGP identified drivers in EGFR (early/adv: 13%/16%), ALK (2.0%/4.2%), ROS1 (0.7%/1.1%), RET (1.0%/1.1%), and prevalence was similar when limiting to PD-L1+ cases. Studying 596 pts with recurrence and CGP on samples collected prior to recurrence, pts with CGP results obtained before (n = 196) vs after (n = 400) recurrence had less time between recurrence and start of any 1L therapy (median 3.1 vs 5.9 weeks, p < 0.001). In the subset with a targetable driver detected, 32/42 (76%) with CGP before recurrence initiated matched 1L TKI while 43/67 (64%) with CGP after recurrence received matched 1L TKI (p = 0.2). Through avoidance of ICI in PD-L1+ early LUAD with an ALK/ ROS1/ RET driver, we estimate universal CGP (compared to EGFR single-gene testing) could reduce per pt expected costs by $875 (an average incremental $4,050 treatment cost reduction compared to a $3,175 increase in diagnostic cost per pt). Conclusions: CGP of early-stage LUAD can identify EGFR, ALK, ROS1 and RET drivers and enable appropriate selection of precision therapies and timely use of effective 1L therapy at recurrence. Assuming adj ICI maintains the lack of activity in RET/ ROS1 as seen for ALK, CGP could represent a cost-effective approach for avoiding futile adj ICI and reducing the risk of subsequent TKI-associated toxicity. Additional analysis of driver+ pts receiving adj ICI is needed to help balance the risk/benefit for these high risk pts.

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

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

Association between post-treatment (tx) alpha-fetoprotein (AFP) reduction and outcomes in real-world (rw) U.S. patients (pts) with advanced HCC (aHCC).

341 Background: A decrease in post-tx AFP may be associated with improved outcomes in clinical trials. However, the impact of AFP reduction after initiation of a first-line (1L) tyrosine kinase inhibitor (TKI) therapy on outcomes is unclear among pts with aHCC treated in routine clinical practice. Methods: This analysis utilized data from the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database and included pts with aHCC with ≥2 visits between 1/1/2011-7/31/2019 who received 1L TKI. Pts with a baseline serum AFP value (closest to 1L initiation within -30 to +7 days) and a post-tx AFP value (closest to 8 weeks after 1L initiation within ±2 weeks) were included. Post-tx AFP reduction was defined as a ≥20% decrease from baseline AFP, and no reduction as a <20% decrease or any increase. Rw overall survival (rwOS) was defined as time from post-tx AFP measurement to death (censored at last EHR activity). Rw progression-free survival (rwPFS) was based on clinician documentation and defined as the first progression event or death after post-tx AFP measurement (censored at last clinic note date). Adjusted hazard ratios (aHR) for reduction vs no reduction (reference) were estimated using multivariable Cox proportional hazards models adjusted for potential confounders and baseline AFP. Effect modification was assessed by conducting tests for interactions with analyses stratified by HCC risk factors. Results: 441 pts were included in the study. 8% had documented history (hx) of hepatitis B (HBV), 52% hepatitis C (HCV), 47% obesity/diabetes (DM), 42% heavy alcohol use, and 11% no documented risk factor. Median baseline AFP was 210 ng/mL (IQR 237 - 2981) and 150 ng/mL (IQR 17 - 1311) among pts with reduction (N = 150) and no reduction (N = 291). There was a 35% decrease in hazard of death for pts with reduction vs no reduction (median rwOS 10.3 vs 6.7 months; Table). Similarly, a 35% decrease in hazard of rw progression or death was observed for pts with reduction vs no reduction (aHR=0.65; 95% CI: 0.52-0.81; median rwPFS 4.4 vs 2.4 months). Reduction (vs no) was associated with better rwOS among pts with hx of HCV, obesity/DM or alcohol use vs without the respective risk factor, however, no statistically significant interactions were observed (Table). Conclusions: Results show post-tx AFP reduction may be prognostic for rwPFS and rwOS in pts with aHCC treated with 1L TKI. Further research may clarify if prognostic value differs by HCC risk factor profile. [Table: see text]

Effectiveness of Second-Line (2L) Tyrosine Kinase Inhibitor (TKI) Therapy after Resistance or Intolerance to a Prior TKI in Patients with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Chronic Phase (Ph+ CML-CP)

Effectiveness of Second-Line (2L) Tyrosine Kinase Inhibitor (TKI) Therapy after Resistance or Intolerance to a Prior TKI in Patients with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Chronic Phase (Ph+ CML-CP)

A Real-World Assessment of Hepatic Dysfunction Among Chronic Phase Chronic Myeloid Leukemia (CP-CML) Patients Receiving First-Line (1L) Tyrosine Kinase Inhibitors (TKIs) in the United States

Introduction:Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the unregulated proliferation of myeloid cells in the bone marrow and their accumulation in the blood. The approval of imatinib (IM) and second-generation TKIs have substantially improved survival for patients with CML. Despite the effectiveness of these TKIs in controlling CML, continuous therapy is necessary for most patients, and may be associated with the development of unfavorable adverse events such as hepatotoxicity. Although patients with elevated liver function tests are excluded from key clinical trials, case reports and small single-center studies have described cases of TKI-associated hepatotoxicity among patients with CML. This study sought to describe the prevalence and incidence of hepatotoxicity in patients with newly diagnosed Philadelphia chromosome-positive chronic-phase (Ph+ CP) CML treated with 1L TKIs in community oncology practices. Methods:This retrospective, observational cohort study identified adult patients newly diagnosed with Ph+ CP CML and treated with 1L dasatinib (DAS), IM, or nilotinib (NIL) within the US Oncology Network (USON) between 1 January 2008 and 30 November 2018. Patients were required to have at least one comprehensive metabolic panel (CMP) within 90 days of treatment start, and ≥ 1 CMP during follow-up. Additionally, patients had to have at least two visits within the USON, no enrollment in any clinical trial during the study period, and no documentation of other primary cancer diagnoses. Descriptive statistics were generated for baseline patient characteristics and prevalence and incidence of hepatotoxicity, and were stratified by 1L TKI treatment initiation. Grades for hepatotoxicity were derived from laboratory data using the Common Terminology Criteria for Adverse Events version 5. Results:A total of 2743 patients with CP-CML were identified. Of those, 730 (26.6%), 1455 (53.0%), and 558 (20.3%) patients were treated with 1L DAS, IM, or NIL, respectively. With the exception of age and region, patient demographic characteristics were well balanced across cohorts. However, baseline hepatic functioning differed across TKIs (Table 1). Prevalence of any-grade liver enzyme elevation was observed in almost one-third (31.9%) of patients, including 246 (33.7%) patients treated with DAS, 416 (28.6%) patients treated with IM, and 213 (38.2%) patients treated with NIL. Among all patients with normal baseline hepatic function, 48.9% developed any-grade hepatotoxicity while on 1L therapy. Across TKI cohorts, significantly more patients treated with NIL developed any-grade hepatotoxicity (70.1%) compared to patients treated with DAS (45.5%) or IM (43.5%) (P< 0.0001). Among all patients receiving 1L treatment, 1.5% to 3.8% of patients experienced grade 3-4 hepatotoxicity. Significant differences in the proportion of patients that developed grade 3-4 hepatotoxicity were observed across treatments and were most common among patients treated with NIL (Table 2). Conclusions:Findings from this analysis suggest that hepatic dysfunction may be common at baseline among patients with CP-CML treated in real-world community oncology settings. Among patients with normal baseline hepatic function, more patients treated with NIL experienced any-grade hepatotoxicity. Patients treated with NIL were also more likely to develop grade 3-4 hepatotoxicity compared to patients treated with DAS or IM. These findings may provide insight into the effects of long-term TKI treatment on hepatic functioning and help to inform treatment choices for patients. Disclosures Kolibaba: AbbVie:Research Funding;Compass Oncology:Ended employment in the past 24 months;Janssen:Research Funding;TG Therapeutics:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;McKesson Life Sciences:Consultancy;Sumitomo Dainippon Pharma Oncology:Consultancy, Other: travel, accommodations, expenses, ;Gilead:Research Funding;Genentech:Research Funding;Cell Therapeutics:Research Funding;Celgene:Research Funding;Acerta:Research Funding;Atara Biotech:Membership on an entity's Board of Directors or advisory committees;Verastem:Honoraria;Seattle Genetics:Research Funding;Novartis:Research Funding;Pharmacyclics:Research Funding.Zhou:McKesson Corporation:Current Employment.Keating:Bristol Myers Squibb:Current Employment.Clark:McKesson Life Sciences:Current Employment, Current equity holder in publicly-traded company.Brokars:Bristol Myers Squibb:Current Employment.Kee:Bristol Myers Squibb:Current Employment.Copher:Bristol Myers Squibb:Current Employment.Stwalley:Bristol Myers Squibb:Current Employment, Current equity holder in publicly-traded company.Jabbour:Adaptive Biotechnologies:Other: Advisory role, Research Funding;Genentech:Other: Advisory role, Research Funding;BMS:Other: Advisory role, Research Funding;Amgen:Other: Advisory role, Research Funding;Pfizer:Other: Advisory role, Research Funding;Takeda:Other: Advisory role, Research Funding;AbbVie:Other: Advisory role, Research Funding.

Contemporary Practice Patterns of Tyrosine Kinase Inhibitor Use Among Older Patients with Chronic Myeloid Leukemia in the United States

Contemporary Practice Patterns of Tyrosine Kinase Inhibitor Use Among Older Patients with Chronic Myeloid Leukemia in the United States

CML-330: Incidence of Cardiovascular (CV)-Related Hospitalizations and Associated Costs Among US Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML) Treated with First-Line (1L) Tyrosine Kinase Inhibitors (TKI) in SIMPLICITY: An Observational Study

Context Evidence suggests that common CV risk factors (obesity, diabetes status, age, etc.), combined with TKI therapy, may contribute to CV events in patients with CP-CML. Furthermore, CV events occurring in patients with CP-CML are often associated with significant morbidity, mortality, and healthcare resource utilization. Objective To assess the incidence of CV-related hospitalizations, subsequent length of stay (LOS), and associated costs among patients with CP-CML in a real-world setting. Design Retrospective observational study. Setting SIMPLICITY is an ongoing observational study of patients with CP-CML in Europe and the U.S. who are treated with 1L TKIs. Patients from the U.S. cohort were included in this analysis. Interventions Dasatinib (DAS), imatinib (IM), nilotinib (NIL). Main outcome measures Incidence of CV-related hospitalizations and LO, adjusted per 1000 patient-years (PY) of follow-up. Mean total hospitalization costs for each CV event were analyzed; these results will be described in the poster. Results In all, 808 patients received 1L TKI therapy: IM (n=243), DAS (n=301), or NIL (n=264). Median follow-up was approximately 4 years (48.7–51.3 months). Age, treatment center type, duration of therapy, and baseline fatigue differed significantly among the groups (P Conclusions In this real-world study of CP-CML patients, assessment of CV-related hospitalizations and LOS showed that most hospitalizations occurred within 18 months of 1L TKI initiation. The incidence of CV-related hospitalizations and LOS were descriptively lowest among patients receiving dasatinib. CV-risk profile and comorbidities should be taken into account prior to 1L TKI therapy initiation. Funding BMS.

Clinical impact of early progression among patients (Pts) with metastatic renal cell carcinoma (mRCC) treated with tyrosine kinase inhibitors (TKIs) in first-line (1L) setting: IMPACT RCC real-world study.

e17079 Background: Previous research has indicated a high burden of illness among mRCC pts who progressed to second line (2L) systemic therapy, suggesting benefits to delaying 1L progression. This study examined the clinical impact of early vs delayed disease progression among mRCC pts treated with 1L TKI monotherapies followed by 2L therapy in the US Veterans Health Administration (VHA) database. Methods: Newly diagnosed mRCC pts treated with 1L TKIs followed by 2L therapy were identified between OCT2013-MAR2018 within the VHA database (1L start date = index date). Eligible pts were required to have continuous enrollment for ≥6 months post-2L therapy initiation unless the pt died. A Kaplan-Meier (KM)-derived median time to 2L therapy initiation was used as the cut-off to categorize pts into early (≤median) and delayed ( > median) progression cohorts. KM analysis and Cox proportional hazards models were used to compare and assess the impact of predictive factors on clinical outcomes including overall survival (OS), time to 2L discontinuation (index date to 2L discontinuation or death), and time to 3L treatment initiation (index date to 3L start or death) among pts in the early vs delayed progression cohorts. Results: Among 289 mRCC pts, the mean age was 67.4 years and the median time to 2L initiation was 6.1 months. Pt characteristics were similar between the early (n = 145) and delayed (n = 144) progression cohorts. During follow-up, the delayed progression cohort had better clinical outcomes than the early progression cohort did (Table below). Conclusions: Early progression is associated with worse clinical outcomes, confirming the need to delay disease progression among mRCC pts with effective 1L treatment strategies. Results indicate the need for use of more efficacious therapies, e.g. immuno-oncology-based combinations, in 1L that can delay disease progression and have potential to reduce disease burden. [Table: see text]

Treatment duration and response of advanced renal cell carcinoma (aRCC) patients (pts) who have completed first-line (1L) treatment (tx): Results from a cross-sectional real-world study.

643 Background: In 2019, there was an estimated 73,820 new cases of kidney cancers in the US. The tx landscape for aRCC is changing rapidly. Recently approved txs for 1L aRCC include new targeted agents and immuno-oncology (IO) therapies. We examine outcomes for pts who completed 1L tx. Methods: Real-world data were drawn from the RCC Disease Specific Programme; a cross-sectional survey administered to US oncologists, nephrologists and urologists. Physicians completed pt record forms (PRFs) for up to the next 8 consulting aRCC pts receiving drug tx, from February - September 2019, plus additional optional PRFs for pts receiving/who had received either 1L tx of nivolumab/ipilimumab combination or cabozantinib, where these pts were available. Results: Physicians (n=82) provided data on 687 pts; 230 had progressed from 1L tx and were on 2L tx at time of data collection. Of those receiving 2L tx, 61% male; mean age was 66.4 years (SD=11.0); 43% stage IV at diagnosis. At 1L, 72% (n=165) had received tyrosine kinase inhibitor (TKI) monotherapy; 16% (n=37) IO+IO, 3% (n=7) TKI+IO and 9% (n=20) other regimens. Mean 1L duration was 10.3 months (SD=9.4) and mean time to 2L initiation was 13.7 months (SD=21.1). 1L treatment responses were: 6% complete response, 21% partial response, 16% stable disease, and the remainder relapsed/progressed (44%) or unknown response (13%). Most common 2L regimens were TKI (37%) or IO (34%) monotherapy. 47% of 1L TKI monotherapy pts received 2L IO monotherapy. 86% of 1L IO+IO pts received 2L TKI monotherapy. Conclusions: Some pts with aRCC progress to 2L; many experience poor clinical outcomes with 1L txs, highlighting high unmet need in 1L for more efficacious txs. Optimal tx strategy (and sequencing) continues to evolve. Approval of IO+TKI therapies, approved during the fieldwork period, has broadened the therapeutic landscape for 1L aRCC. Whilst the proportion of 1L pts receiving IO+TKI therapies is still low, the adoption of these in 1L is likely to transform the management of aRCC. Further research is needed to determine the optimum tx sequence in these pts with high unmet need.

Cardiovascular (CV)-Related Hospitalizations and Associated Costs Among US Patients in Simplicity: An Observational Study of Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML) in Routine Clinical Practice

Cardiovascular (CV)-Related Hospitalizations and Associated Costs Among US Patients in Simplicity: An Observational Study of Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML) in Routine Clinical Practice

Cytogenetic and Molecular Response with First- and Second-Generation Tyrosine Kinase Inhibitor (TKI) Therapy in Simplicity: An Observational Study of Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML)

Introduction: SIMPLICITY (NCT01244750) is an ongoing observational study of patients (pts) with CP-CML receiving first-line (1L) imatinib (IM), dasatinib (DAS), or nilotinib (NIL) in routine clinical practice in Europe and the United States (US). The study aimed to assess the effectiveness and safety of TKIs for pts with CP-CML outside the clinical trial setting. Here, we analyze the clinical outcomes (complete cytogenetic response [CCyR] and major molecular response [MMR]) associated with the CML risk level in SIMPLICITY pts with CP-CML receiving first-generation (1G: IM) or second-generation (2G: DAS/NIL) TKI therapy. Methods: Clinical outcomes after 1L TKI initiation were assessed by CyR (karyotype analysis or fluorescence in situ hybridization) and polymerase chain reaction MR tests. Proportions of pts achieving CCyR and MMR are presented for those with at least one recorded response test during 1L TKI therapy. Outcomes were stratified by CML risk level (Hasford scoring; low [≤780] and intermediate/high risk [≥781]), and the differences between 1L 1G and 2G TKI cohorts analyzed. Statistical comparisons for continuous variables were made using t-tests and the Mann-Whitney U test, and chi-square test for categorical variables. Multivariate logistic regression models, adjusted for age, gender, region, risk level (low vs intermediate/high), and baseline (BL) comorbidities, were used to determine if generation of TKI therapy (1G/2G) was associated with clinical response (CCyR or MMR) after start of 1L TKI. Performance and timing of CyR and MR tests were at the discretion of oncologists, limiting the analysis of outcomes and comparisons of CCyR and MMR rates. Results: There were 1,241 pts (IM: n=416; DAS: n=417; NIL: n=408) at database lock (October 2018); only 391 (31.5%) pts with CP-CML receiving 1L TKI were identified to have the elements needed for a Hasford risk assessment documented at diagnosis (IM: n=140; DAS: n=119; NIL: n=132). CML risk assessment (Hasford score) was significantly more common in Europe (68.7% vs 11.7% in the US, p<0.0001). No significant difference in risk score was observed across the different 1L TKI groups (p=0.7012). Of the 130 (33.2%) pts with recorded CyR test results, no significant differences in BL demographics were observed except for median age at start of 1L TKI and BL cardiovascular and gastrointestinal (GI) comorbidities (Table 1). A higher percentage of pts on 2G TKIs achieved CCyR compared with 1G TKI in both low (88.1% vs 79.2%) and intermediate/high (73.0% vs 44.4%) CML risk categories, with statistical significance reached in the intermediate/high-risk group (p=0.0209). Multivariate logistic regression analysis (Figure 1) showed that pts were approximately 3 times more likely to achieve CCyR if receiving 2G TKIs (odds ratio [95% confidence interval]: 2.93 [1.21, 7.13] vs 1G, p=0.0177). Other predictors of CCyR were low baseline CML risk (5.75 [2.00, 16.50] vs intermediate/high CML risk, p=0.0011) and treatment at European centers (2.72 [1.03, 7.18] vs US centers, p=0.0431). MR test results were recorded in 358 (91.6%) pts; median number of MR tests was significantly higher in Europe (8 vs 5 in the US, p<0.0001). No significant differences in pt demographics were observed except for age at start of 1L TKI and BL GI comorbidities (Table 1). A higher percentage of pts on 2G TKIs achieved MMR compared with 1G TKI in the low (82.0%vs 74.6%) and intermediate/high (87.0% vs 72.4%) CML risk groups, with significance reached in the latter cohort (p=0.0185). Multivariate logistic regression analysis showed that TKI generation was the sole predictor of MMR achievement; pts were approximately twice as likely to achieve MMR with 2G TKIs as with 1G TKI (OR: 2.13 [1.23, 3.70], p=0.0070) (Figure 1). Conclusions: Despite treatment guidelines recommending 2G TKI therapy for pts with higher CML risk, our analysis of SIMPLICITY pts showed no differences in 2G versus 1G TKI use in low and intermediate/high risk groups. Here, the use of 2G TKIs, compared with 1G TKI, was a significant predictor for achieving either CCyR or MMR, thereby validating the clinical response benefits of 2G TKIs regardless of BL CML risk. These findings emphasize the importance of adhering to treatment guidelines when making decisions on the generation of TKI, first (IM) or second (DAS/NIL), to be used in the 1L treatment of pts with CP-CML, particularly in higher risk pts. Disclosures Cortes: Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Biopath Holdings: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; BiolineRx: Consultancy. Chen:Bristol-Myers Squibb: Employment. Davis:Bristol-Myers Squibb: Employment, Equity Ownership. Goldberg:Cancer Outcomes Tracking and Analysis (COTA) Inc.: Equity Ownership; COTA: Equity Ownership; Bristol-Myers Squibb: Consultancy. Mauro:Bristol-Myers Squibb: Consultancy; Novartis Oncology: Consultancy, Research Funding; Takeda: Consultancy; Pfizer: Consultancy.

P1.16-36 Treatment Patterns Among Patients with EGFRm NSCLC Treated in the US Community Oncology Setting

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy is associated with improved outcomes in patients with EGFR mutation-positive (EGFRm) non-small cell lung cancer (NSCLC). Despite initial responses, most patients develop resistance. Little is known about treatment following first-line (1L) TKIs. This study aimed to understand real world treatment patterns, T790M testing rates, and disposition of EGFRm patients following availability of newer TKIs. Adult patients with EGFRm stage IV NSCLC treated between Dec 1, 2015 and Aug 31, 2017, were retrospectively identified from the US Oncology Network’s iKnowMedSM (iKM) electronic health record. Patient characteristics, treatment patterns, and T790M testing data were obtained via programmatic database abstraction and supplemented with chart review. 308 patients were identified during the study period. Median age at diagnosis was 69 years, 67% were female, 63% Caucasian, 49% never smokers and 59% with ECOG performance status 0–1. Nearly all patients (n=302; 98%) received treatment with a TKI, 80% (n=246) with a TKI as 1L therapy. The most frequently used TKIs as 1L monotherapy were erlotinib (n=204; 66%), afatinib (n=27; 9%), and gefitinib (n=3; 1%). Combination chemotherapy with or without a TKI was used in 24% of patients. Among all patients treated with a 1L TKI, 19% (n=47) were tested for the T790M mutation after 1L TKI, and 34% (n=16) were positive. The most common 2L therapies in patients who received a 1L TKI (n=44 patients) were pemetrexed-based chemotherapy (n=20; 45%), afatinib (n=7; 16%), and osimertinib (n=7; 16%). Among all patients who received a 1L TKI, 15% (n=41) had died, 18% (n=51) were still alive and on TKI therapy, 12% (n=29) went on to receive subsequent therapy, and 53% (n=149) stopped their TKI and received no subsequent therapy at the end of the follow-up period. The majority of patients with EGFRm advanced NSCLC received 1L TKI therapy, most often with erlotinib. Following 1L TKI, less than 20% of patients were tested for T790M, and most did not receive any subsequent therapy following TKI. As understanding of resistance mechanisms in mutation-driven lung cancer is rapidly evolving, and as ongoing studies evaluate optimal treatments, it is imperative to integrate this information into clinical practice.

Nivolumab + chemotherapy vs chemotherapy in EGFR-mutated NSCLC after 1L or 2L EGFR-TKIs (CheckMate 722)

Abstract Background Although osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI) is approved for first-line (1L) treatment of EGFR-mutated metastatic non-small cell lung cancer (NSCLC) and second-line (2L) treatment of pts who acquired the EGFR T790M mutation during 1L therapy with other TKIs, treatment options after progression on TKIs are limited; platinum-doublet chemotherapy (PT-DC) remains the standard therapy, including for pts with no T790M mutation. Nivolumab (NIVO), a fully human IgG4 programmed death-1 immune checkpoint inhibitor antibody, is approved worldwide for the treatment of advanced NSCLC on or after prior chemotherapy. CheckMate 722 (NCT02864251) will compare the efficacy and safety of NIVO + PT-DC vs PT-DC alone in pts with EGFR-mutated metastatic or recurrent NSCLC progressed on 1L or 2L EGFR TKI therapy. Methods This open-label phase 3 trial is enrolling ∼500 adults with confirmed stage IV or recurrent EGFR-mutated NSCLC progressed on prior EGFR TKI therapy. Patients are eligible if they progressed on 1L first- or second-generation TKIs with no T790M mutation or 1L or 2L osimertinib regardless of T790M status. Pts with CNS metastases that are adequately controlled and/or treated during screening are eligible. Pts are randomized 1:1 to NIVO (360 mg Q3W) + PT-DC (pemetrexed 500 mg/m2 Q3W + cisplatin 75 mg/m2 or carboplatin AUC 5 or 6 Q3W), or PT-DC alone; pts without disease progression after 4 cycles will receive NIVO + pemetrexed or pemetrexed, respectively, until disease progression or unacceptable toxicity. Randomization is stratified by programmed death ligand-1 status (≥ 1% or Results The estimated primary completion date is September 2019.