1st-line Tyrosine Kinase Inhibitor Research Articles

MET exon 14 skipping in NSCLC: An unMET Indian need.

e13537 Background: The approval of capmatinib and tepotinib, selective MET tyrosine kinase inhibitors (TKI), has further shifted the therapeutic paradigm of advanced NSCLC. MET exon 14 skipping (MET ex14) alteration is a complex mechanism, reported in ~3-4% cases of NSCLC. Controlled trials have reported remarkable outcomes of selective MET TKIs, however real world outcomes from this part of the world are currently lacking. Methods: This is a non-interventional study reporting real world outcomes of NSCLC with MET ex14 from two apex cancer centers of India. 49 eligible patients were recovered from the electronic medical record archives. All cases with MET ex14 were included irrespective of clinicopathologic characteristics and therapy offered. Statistical analysis was performed using R studio. Results: Clinical characteristics are shown (Table). Treatment patterns were heterogeneous across therapy lines and included chemotherapy, MET TKIs and immune checkpoint inhibitors. 42/49 patients opted for treatment; rest dropped out owing to economic restraints. 1st line TKI was offered to 14 patients, and chemotherapy to 28 patients. 1st line PFS of TKI treated was 11.9 months (95%CI:5.8-17.8) vs. 5.9months (95%CI: 3.9-16.8) (p<0.002*) for the chemotherapy treated cases (HR for TKI: 0.3295 (95%CI: 0.1630 to 0.6663). Presence of TP53 co-mutation and male gender and were factors affecting 1st line PFS (p<0.06) on multivariate analysis. 2nd line treatment was opted by 13/14 patients in TKI treated group of which 5 received sequential TKI, and 8 received chemotherapy and 22/28 in chemotherapy treated group (TKI: 14, chemotherapy: 8). PFS for 2nd line TKI was 7.7 months (95%CI: 2.8-14.8) vs 4.6 months (95%CI:2.1-9.8) for chemotherapy {HR for TKI: 0.3641 (95%CI: 0.1378 to 0.9616)} (p<0.04*). The dropout rate from 1st to 2nd line was 36% and 44% in subsequent line. 28 (57%) received MET TKI at any given point in disease course. Median OS for patients treated with 1st line TKI was not reached at study end (95%CI: 9.2-NR) and was 20.7 months (95%CI:18.1-36.1) for chemotherapy (p=0.3). One year and 2 year survival rates for 1st line TKI and Chemotherapy were 86%vs 73% and 47% vs 45%, respectively. Conclusions: This is the largest cohort from India reporting real world uptake of TKI therapy in MET ex14 altered NSCLC. There is a blaring disparity with respect to accessibility of drugs, as well as prevailing socioeconomic restraints. This study clearly depicts an unmet need for more global clinical trials for rare genomic alterations as well as patient access programs in this part of the world. [Table: see text]

What is a bad ALK? A scoping review of molecular markers of poor prognosis.

e20530 Background: Patients with non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase ( ALK) rearrangements derive a significant and durable clinical benefit from tyrosine kinase inhibitors (TKI). However, a portion of patients have progressive disease as their best response and progress to death much earlier than expected which is termed primary resistance. This scoping review aims to summarize the known molecular mechanisms that underlie this lethal ALK phenotype. Methods: We performed a systematic scoping review from scientific databases such as Ovid Medline, Ovid Embase, and Cochrane Central Register of Controlled Trials. Data was extracted from the database inception to March 13, 2023. Studies included molecular markers of poor prognosis, with a focus on TP53, variant 3 re-arrangements, and reports of poor clinical response to TKIs (defined as progression-free survival less than 3 months on 1st line TKI or overall survival less than 2 years from exposure to 1st line TKI). 2nd generation and 3rd generation ALK TKI clinical trial data were also included. Results: A total of 4360 studies were screened and 136 studies were included. Numerous studies implicated the negative prognostic role of variant 3 likely mediated through the acquisition of on-target resistance mutations compared to other variants. TP53 mutations were also associated with a worse prognosis and implicated with greater chromosomal instability and mutational burden. Furthermore, reports of both variant 3 and TP53 mutations together were associated with even worse survival suggesting both molecular mechanisms combined can confer primary resistance phenotype. Other mediators of primary resistance included aberrations in cell cycle regulators such as CDKN2A/B loss, mutations in cell signalling pathways such as the PI3K/ AKT/mTOR pathway, deficiencies in DNA repair mechanisms, and uncommon fusion partners. Consistent with these prior studies, comprehensive genomic analysis from clinical trial data of 2nd generation and 3rd generation TKIs was unable to identify a singular genomic signature that underlies this lethal phenotype. However, a general trend from the literature suggested that the combination of multiple aberrations is likely necessary to confer a primary resistance phenotype, though the relative contribution of each somatic mutation likely will vary. Conclusions: This scoping review highlights that in NSCLC, the lethal ALK phenotype is likely composed of a heterogeneous population of various combinations of poor prognostic factors including variant 3, mutations in cell cycle regulators and other aberrations in cell signalling pathways. There remains an unmet need for a genomic assay to integrate all these various molecular markers to predict the lethal ALK phenotype.

Treatment patterns and outcomes in ALK or ROS1 altered NSCLC: An ATOMIC Registry Study.

9077 Background: New tyrosine kinase inhibitors (TKIs) targeting ALK and ROS1 alterations in non-small cell lung cancer (NSCLC) have emerged over the last decade. Given the rarity of these genetic changes in NSCLC, data on long term outcomes with sequential therapies are limited. Methods: We conducted a multicenter retrospective cohort study of patients with metastatic NSCLC and ALK or ROS1 alterations across 12 Academic Thoracic Oncology Medical Investigators Consortium (ATOMIC) sites between 1/29/2007 and 3/31/2021. Data were abstracted from the electronic medical record. Median time to treatment discontinuation (TTD) of 1st TKI, overall survival (OS), and time to brain metastases were estimated using Kaplan-Meier methodology from start date of 1st TKI. Results: 566 patients with ALK (n = 464) or ROS1 (n = 102) were included. The majority (ALK: 426/464, 92%; ROS1: 88/102, 86%) received a TKI at some point during therapy (1st line TKI n = 262 ALK, 48 ROS1). Crizotinib was the most common 1st TKI (ALK: 57%; ROS1: 88%). Following crizotinib, alectinib (64%) and lorlatinib (41%) were the most common subsequent TKIs for ALK and ROS1, respectively. Alectinib (38%) and entrectinib (10.2%) were the 2nd most common initial TKIs used in ALK and ROS1, respectively. Additional treatment patterns presented in table. With a median follow up time of 31.1 (ALK, 95% CI, 27.6-35.0) and 32.6 (ROS1, 95% CI, 25.7-39.6) months, median OS from start of 1st TKI was 53.3 (ALK, 95% CI, 40.0-68.9) and 42.0 (ROS1, 95% CI, 31.8-NA) months. Out of the 321 patients with brain imaging prior to 1st line therapy, 40% (105/262, ALK) and 39% (23/59, ROS1) had CNS disease. Median time to development of brain metastases from start of 1st TKI in those without previous CNS disease (ALK: 278; ROS1: 58) was 30.0 (ALK, 95% CI, 25.3-39.1) and 27.0 (ROS1, 95% CI, 18.2-NA) months. Median TTD of 1st TKI was 11.2 (ALK) and 10.8 (ROS1) months. Conclusions: This is the largest retrospective cohort of NSCLC patients with ALK or ROS1 rearrangements treated in the real world setting. CNS metastases are common and subset analyses by agent and by year of diagnosis will be presented. Median time to CNS metastasis of > 2 years supports revision of the NCCN guidelines to include regular surveillance brain MRIs in this population. [Table: see text]

Monitoring of the presence of EGFR-mutated DNA during EGFR-targeted therapy may assist in the prediction of treatment outcome

The aim of our trial was to evaluate the prognostic significance of qualitative ctDNA analysis on different stages of EGFR mutated non-small cell lung cancer (NSCLC) treatment.We included 99 patients amendable for the first line treatment with either gefitinib/erlotinib (n = 87), afatinib (n = 10) or osimertinib (n = 2). Sequential qualitative analysis of ctDNA with cobas® EGFR Mutation Test v2 were performed before first dose, after 2 and 4 months of treatment, and on progression.Our analysis showed clinically significant heterogeneity of EGFR-mutated NSCLC treated with 1st line tyrosine kinase inhibitors (TKIs) in terms of progression-free and overall survival. When treated with conventional approach, i.e. monotherapy with TKIs, the patients falls into three subgroups based on ctDNA analysis before and after 2 months of treatment. Patients without detectable ctDNA at baseline (N = 32) possess the best prognosis on duration of treatment (PFS: 24.07 [16.8–31.3] and OS: 56.2 [21.8–90.7] months). Those who achieve clearance after two months of TKI (N = 42) have indistinguishably good PFS (19.0 [13.7 – 24.2]). Individuals who retain ctDNA after 2 months (N = 25) have the worst prognosis (PFS: 10.3 [7.0 – 13.5], p = 0.000). 9/25 patients did not develop ctDNA clearance at 4 months with no statistical difference in PFS from those without clearance at 2 months.Prognostic heterogeneity of EGFR-mutated NSCLC should be taken into consideration in planning further clinical trials and optimizing the outcome of patients.

Treatment Responses in Patients with Chronic Myeloid Leukemia on Tyrosine Kinase Inhibitors (TKI) Therapy

Background: Chronic myeloid leukemia (CML) is a cancer of white blood cells results by the BCR-ABL translocation. Part of BCR gene from chromosome 22 is fused with ABL gene on chromosome 9. Aim: To observe percentage of patients achieving Cytogenetics response (CR), and Deep molecular response (DMR) in CML patients taking TKI (Imatinib and Nilotinib). Study Design: Retrospective Cohort study. Methodology: This study was conducted in 2018-2019 in about 198 CML patients to evaluate TKI therapy response and observation was based upon their Quantitative PCR test which gave percentage of BCR-ABL gene translocation in IU. Patients which were diagnosed with CML in 2016 and was regular in their treatment for about 2 years were included in the study. No intervention was given as in vivo study. Statistical analysis: Data analyzed by SPSS 25.0v. Results: Results showed that out of 198 CML patients, started on 1st line TKI (imatinib) 95 males (48%) and 103 females (52%) showed cytogenetic response at start of therapy and after 2 years of therapy 157 (79.3%) patient showed DMR. Conclusion: This study concluded that regular 2-year treatment of chronic CML patients with TKIs produced significant response in patients. Keywords: BCR-ABL Translocation, Cytogenetic Response, Major Molecular Response, Complete Molecular Response and Deep Molecular Response.

Molecular Responses after Switching from a Standard-Dose Twice-Daily Nilotinib Regimen to a Reduced-Dose Once-Daily Schedule in Patients with Chronic Myeloid Leukemia: A Real Life Observational Study (NILO-RED)

IntroductionStandard dosing regimen for the BCR-ABL1 tyrosine kinase inhibitor (TKI) nilotinib in chronic myeloid leukemia (CML) is 300mg twice daily (BID) in the frontline setting and 400mg BID in the 2nd line setting or beyond. Patients (pts) are instructed to fast within 2 hours before and 1 hour after medication intake due to significant high-fat food effects on drug bioavailability. On-label dose adjustments to a lower-dose once-daily (QD) regimen are recommended solely in case of significant toxicity.Study goalThe primary aim of our observational two-center study was to ask whether nilotinib-treated adult CML pts were able to maintain major molecular responses (MMR) within 1 year after conversion to a more convenient nilotinib QD regimen at reduced doses, regardless of reasons for tapering nilotinib. Pts with minor transcripts or a history of blast crisis or allogeneic stem cell transplantation were excluded.PatientsEighty one pts in chronic phase were identified and included and results from the first 67 pts with a follow-up of at least 12 months after the switch to the once-daily dose-reduced nilotinib regimen are presented. Median age at study entry was 52 years (range: 19-82). There were 25 males (37.3%) and the Sokal score was low, intermediate, high or unknown in 43.3%, 37.3%, 13.4% and 6% of pts, respectively. All pts had major-type BCR-ABL1 transcripts. Nilotinib was started as 1st line TKI at 300mg BID in 68.6% of pts and as 2nd or subsequent line TKI at 400 or 300 mg BID in 31.4% of pts due to intolerance, warning, resistance or absence of a deep molecular response on prior therapy. Median duration of nilotinib prior switching to a reduced QD dosing was 29 months (range: 1-94) and median duration of MMR was 25 months (range: 3-212). Primary reason for the switch to a reduced QD nilotinib dosing was non-serious adverse events in 37.3% of pts and improvement in pts convenience in 62.7% of pts. Nilotinib was reduced down to 450mg QD, 400mg QD or 300mg QD in 86.6%, 10.4% and 3% of pts, respectively. A 2nd dose reduction from 450mg to 300mg QD was performed in 30 pts after a median time of 18 months (range: 4-37). The median duration of low-dose nilotinib QD was 24 months (5-54). No severe tolerance issues were encountered and no ischemic cardiovascular events occurred. Eleven pts stopped nilotinib due to treatment-free remission attempt (n=10) or persistent adverse event (n=1). All pts were alive at last follow-up.Evolution of molecular responsesAt baseline, the number of pts in MMR, MR4 and ≥MR4.5 was 9 (13.4%), 17 (25.4%) and 41 (61.2%), respectively and 32 pts (47.8%) had undetectable BCR-ABL1 transcripts. Median BCR-ABL1/ABL1 % IS was 0.006% (range: 0.0007-0.063) and median ABL1 copy number in pts with undetectable transcripts was 87259 (range: 36018-921339). Only 2 pts treated with 1st line nilotinib lost MMR 4 and 6 months after QD dose reduction of nilotinib with BCR-ABL1/ABL1 % IS at 0.13 and 0.11%, respectively. Both pts spontaneously regained MMR 4 months later without any treatment modification. Kaplan-Meier analysis of survival without unconfirmed MMR loss was 97% (95% CI: 92.9-100) at 12 months and analysis by molecular response category showed that none of the pts who were at least in MR4 at baseline lost MMR (Figure 1). At last follow-up on low-dose QD nilotinib, the number of pts in MMR, MR4 and ≥MR4.5 was 4 (6.3%), 11 (16.4%) and 52 (77.6%), respectively and 37 pts had undetectable transcripts (55.2%). Median BCR-ABL1/ABL1 % IS was 0.0035% (range: 0.00025-0.058) and median ABL1 copy number in pts with undetectable transcripts was 96000 (range: 23285-472000).Ten pts in long-lasting deep molecular response stopped nilotinib without further treatment after a median duration of TKI and of nilotinib of 60 months (range: 50-149) and 56 months (range: 42-87), respectively. Their follow-up after nilotinib discontinuation was 18 months (range: 5-33). Only 1 of them lost MMR and restarted therapy 5 months later while the others remained treatment-free.ConclusionSwitching to a nilotinib QD regimen at reduced doses as maintenance therapy after achievement of a MMR on standard-dose nilotinib BID schedule is feasible and safe in chronic phase CML pts regardless of prior treatment history and does not compromise the anti-leukemic efficacy of nilotinib. Our results may pave the way for clinical trials aiming at systematic avoidance of overtreatment and improvement of pts convenience in treatment with nilotinib. [Display omitted] DisclosuresRea:Pfizer: Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Incyte: Honoraria. Cayuela:BMS: Honoraria; Novartis: Honoraria. Etienne:BMS: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Consultancy, Research Funding.

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

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

Upfront admixing antibodies and EGFR inhibitors preempts sequential treatments in lung cancer models.

Some antibacterial therapies entail sequential treatments with different antibiotics, but whether this approach is optimal for anti‐cancer tyrosine kinase inhibitors (TKIs) remains open. EGFR mutations identify lung cancer patients who can derive benefit from TKIs, but most patients develop resistance to the first‐, second‐, and third‐generation drugs. To explore alternatives to such whack‐a‐mole strategies, we simulated in patient‐derived xenograft models the situation of patients receiving first‐line TKIs. Monotherapies comprising approved first‐line TKIs were compared to combinations with antibodies specific to EGFR and HER2. We observed uniform and strong superiority of all drug combinations over the respective monotherapies. Prolonged treatments, high TKI dose, and specificity were essential for drug–drug cooperation. Blocking pathways essential for mitosis (e.g., FOXM1), along with downregulation of resistance‐conferring receptors (e.g., AXL), might underlie drug cooperation. Thus, upfront treatments using combinations of TKIs and antibodies can prevent emergence of resistance and hence might replace the widely applied sequential treatments utilizing next‐generation TKIs.

Real-world (RW) outcomes for advanced non-small cell lung cancer (aNSCLC) patients (pts) with EGFR exon 19 deletions (x19del) stratified by deletion size.

9591 Background: EGFR x19dels are well-established targetable drivers in NSCLC. Historically x19dels have been treated as a single group, but it’s unclear whether responses vary for distinct subtypes. We compared demographic, clinical and genomic characteristics as well as outcomes to EGFR tyrosine kinase inhibitors (TKIs) for aNSCLC pts with x19dels of varying lengths using a RW Clinico-Genomic Database (CGDB). Methods: Eligible pts had a diagnosis of aNSCLC, received care within the Flatiron Health network between 1/2011-9/2019, and had comprehensive genomic profiling (CGP) by Foundation Medicine. Clinical characteristics, treatment history and RW progression were obtained via technology-enabled abstraction as previously described (Singal G, JAMA 2019). x19del length was evaluated for association with overall survival (OS) and RW progression-free survival (rwPFS) with Kaplan-Meier analysis and unadjusted/adjusted (practice type, gender, age at TKI start, EGFR TKI type, race) hazard ratios (HR/aHR) from Cox proportional hazards models adjusted for survival bias. Results: Among 6,577 aNSCLC pts, EGFR x19dels were detected in 336 cases (5%). E746_A750del was the most frequent (214; 64%) and generally 5 amino acid (aa) deletions (x19del-5) were the most common (241; 72%). Other deletions (x19del-other) of 6 (61; 18%), 3 (20; 6%), 4 (11; 3%) or 8 aa (3; 1%) were also observed. Among pts treated with 1st-line EGFR TKI monotherapy after CGP, the x19del-5 (n = 70) cohort was more frequently female compared to x19del-other (n = 27) (90% vs 59%, p = 0.001). No statistically significant differences in the frequency of co-occurring alterations were observed, specifically for genes associated with response to EGFR TKI response such as CTNNB1 (14% vs 19%) and PIK3CA (10% vs 15%). 1st line EGFR TKIs used were similar for x19del-5 vs x19del-other (43% vs 41% osimertinib, 30% vs 37% erlotinib, 24% vs 22% afatinib, 3% vs 0% gefitinib). x19del-5 pts had similar median rwPFS (10.6 vs 10.6 months, HR: 0.73 [0.41-1.28], aHR:0.78 [0.38-1.59]) and median OS (29.2 vs 24.9 months, HR: 0.64 [0.32- 1.29], aHR: 0.75 [0.32-1.75]) compared to x19del-other. Conclusions: In a RW CGDB of 336 aNSCLC pts with EGFR x19dels, 5 aa x19dels were most common (71%) and 29% of cases had 3, 4, 6 or 8 aa x19dels . For pts included in the treatment cohort, no significant differences in rwPFS or OS were observed. These results suggest that x19del length does not significantly impact clinical outcomes to 1st-line EGFR TKIs.

A phase II multicenter study of stereotactic radiotherapy (SRT) for oligoprogression in metastatic renal cell cancer (mRCC) patients receiving tyrosine kinase inhibitor (TKI) therapy.

5065 Background: SRT is increasingly considered to delay the need to change systemic therapy in metastatic cancer patients who develop oligoprogression. This prospective phase II study evaluated the use of SRT in the setting of mRCC patients who developed oligoprogression while on 1st or 2nd line TKI therapy. Methods: IMDC favourable or intermediate risk mRCC patients (pts) who had previous stability or response on ≥ 3 months of TKI therapy were eligible if they developed radiographic progression of ≤ 5 metastases. The oligoprogressive tumours were treated with SRT while other metastases which were stable or responding to TKI therapy were left alone. TKI therapy was temporarily stopped during SRT, and the same TKI drug then resumed. Endpoints included local control of the irradiated lesions, progression free survival (PFS), overall survival (OS), and cumulative incidence of changing systemic therapy after study entry. Results: 37 pts (median age 63, IMDC favourable 12, intermediate 25) with 57 oligoprogressive tumours were enrolled. 35 pts were on sunitinib and 2 on pazopanib. Median duration of TKI therapy prior to study entry was 18.6 months. 4 pts had IL-2 therapy prior to a 2nd line TKI. 21 pts had a solitary oligoprogressive tumour, while 17 pts had 2-3 oligoprogressive tumours treated with SRT. Median biological effective dose (BED10) was 72 Gy, corresponding to an SRT dose of 40 Gy in 5 fractions. Irradiated tumour sites were the following: 21 lung/pleural, 15 bone, 7 lymph node, 4 adrenal, 4 liver, 3 brain, 2 spleen, and 1 pancreas. At a median followup of 11.6 (1.8-53.5) months the median PFS from study entry was 9.6 months (95%CI 7.4-20.5) with the vast majority of progression occurring outside of the irradiated areas. The 2-year local control of the irradiated tumours was 96%. The 2-year OS from study entry was 77%. The cumulative incidence of changing systemic therapy was 47% at 1 year and 75% at 2 years, with a median time to a change in systemic therapy of 12.6 months. There were no grade 3-5 SRT related toxicities. Conclusions: To our knowledge, this is the first prospective evaluation of the use of SRT for oligoprogressive metastatic cancer. Local control of irradiated oligoprogressive mRCC tumours was high. After delivering SRT, mRCC patients did not need a change in their systemic therapy for a median of 1 year, effectively increasing the PFS of their TKI therapy. This novel approach should be studied in patients with oligoprogression on immunotherapy. Clinical trial information: NCT02019576 .

EGFR exon 20 insertion mutations in Chinese advanced non-small cell lung cancer patients: Molecular heterogeneity and treatment outcome from nationwide real-world study

ObjectivesTo describe the treatment patterns and outcomes of Chinese non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations in real-world as EGFR ex20ins consist of a diverse group of mutations with limited information on the clinical outcome of these patients treated with chemotherapy or EGFR tyrosine kinase inhibitors (TKIs). Materials and methodsReal-world treatment outcomes of Chinese NSCLC patients harboring EGFR ex20ins were retrospectively analyzed based on medical records at different institutions and detailed web-based patient questionnaires. ResultsBetween March 17, 2018 and December 20, 2018, 165 advanced EGFR ex20ins NSCLC patients treated in 99 hospitals from 26 different regions in China were analyzed. Thirty-nine different molecular variants of EGFR ex20ins were identified with V769_D770insASV being the most common (23.0 %). Central nervous system (CNS) metastasis occurred in 23.0 % of patients at the time of baseline diagnosis. Median progression-free survival (PFS) was significantly longer in patients who received first-line platinum-based chemotherapy (6.4 m; 95 % CI: 5.7–7.1) than all-generation EGFR TKIs (2.9 m; 95 %CI: 1.5–4.3; P < 0.001) or 1st-generation EGFR TKIs (2.0 m; 95 %CI: 0.2–3.8; P < 0.001). Median PFS was numerically longer in patients who received second-line chemotherapy (4.0 m; 95 %CI: 3.2–4.8) than those received second-line EGFR TKIs (2.0 m; 95 %CI: 1.1–2.9; P = 0.342). Patients with CNS metastasis had numerically shorter median PFS than those without CNS metastasis when treated with 1st-line chemotherapy (3.6 m; 95 %CI: 0–8.0 vs. 6.5 m; 95 %CI: 4.9–8.1; P = 0.645) or 1st-line EGFR TKIs (2.0 m; 95 %CI: 0.8–3.2 vs. 2.9 m; 95 %CI: 2.1–3.7; P = 0.058). ConclusionChemotherapy is superior to current approved EGFR TKIs as 1st- or 2nd-line treatment of EGFR ex20ins mutations. CNS metastasis conferred numerically shorter PFS with chemotherapy or EGFR TKIs treatment. Targeted agent against EGFR ex20ins with CNS activity is urgently needed.

Treatment outcomes of chronic-phase chronic myeloid leukemia with resistance and/or intolerance to a 1st-line tyrosine kinase inhibitor in Japan: the results of the New TARGET study 2nd-line.

We herein report the results of the New TARGET study 2nd-line, which collected data on patients with chronic-phase (CP) chronic myeloid leukemia (CML) who received a 2nd-line tyrosine kinase inhibitor (TKI) because of resistance and/or to a 1st-line TKI. A total of 98 patients were enrolled intolerance between April 2010 and March 2013, and 82 patients were analyzed. The median age was 54years (range 22-88years). Seventy-six patients (93%) received imatinib as the 1st-line TKI. Forty-five (55%) and 37 (45%) patients began nilotinib and dasatinib treatments at entry, respectively. First-line TKI treatment achieved complete hematological response in 79 patients (96%) and complete cytogenetic response (CCyR) in 49 patients (60%), respectively. Nine patients (11%) had BCR-ABL1 kinase domain point mutations at enrollment. The estimated 3-year progression-free-survival rate after enrollment was 98.7% (95% CI 91.1-99.8%). Overall, the probabilities of achieving CCyR and a major molecular response were 89.3% (95% CI 81.4-94.8%) and 87.2% (95% CI 78.1-93.8%), respectively. There were no new safety issues. This study demonstrated that CML-CP patients in Japan who are resistant and/or intolerant to a 1st-line TKI can achieve an extremely good outcome by 2nd-line TKI treatment.

Sequencing Systemic Therapy Pathways for Advanced Hepatocellular Carcinoma: A Cost Effectiveness Analysis

Introduction: Hepatocellular carcinoma (HCC) is the most common form of liver cancer worldwide and carries a poor prognosis. Historically, sorafenib was the only available systemic treatment for advanced HCC. However, in recent years, 6 new treatments have been approved by the US Food and Drug Administration (FDA): regorafenib, lenvatinib, cabozantinib, pembrolizumab, ramucirumab, and nivolumab. Data are lacking regarding the most appropriate sequencing pathway for these agents. Our objective was to conduct a comprehensive cost effectiveness analysis (CEA) of different 1st- and 2nd-line treatment pathways for HCC reflecting all new drug approvals, and then use our data to provide guidance for clinicians on which pathway is the most cost-effective. Materials and Methods: Markov models were used to evaluate the cost effectiveness of 8 different 1st- and 2nd-line treatment sequences. The model allowed for 9 possible states. Cost effectiveness ratios (CER) and incremental CER (ICER) were calculated to compare costs between different pathways and against a willingness-to-pay (WTP) threshold. Efficacy and toxicity data were extracted from the landmark trials for each agent. All agents except ramucirumab were included. The cost of each agent was based on the wholesale acquisition cost (WAC) in USD as of June 2019. Monte-Carlo methods were used to simulate the experience of 1,000,000 patients per treatment sequence for a 12-month period. Results: The pathway with the lowest CER was sorafenib, followed by pembrolizumab (USD 227,741.03/quality-adjusted life year [QALY]). ICER analysis supported implementing 2nd-line pembrolizumab-based pathways at a higher WTP threshold of 300,000/quality-adjusted life year. Sensitivity analysis did not substantially change these results. Conclusions: The most cost-effective strategy was 1st-line tyrosine kinase inhibitor therapy followed by 2nd-line immunotherapy. All pathways exceeded a commonly accepted WTP of USD 100–150,000/QALY. Our preliminary results warrant further studies to best inform real-world practices.

477O - Tepotinib plus gefitinib in patients with MET-amplified EGFR-mutant NSCLC: Long-term outcomes of the INSIGHT study

BackgroundIn patients with EGFR-mutant NSCLC, MET amplification (METamp) is a resistance mechanism to EGFR tyrosine kinase inhibitors (TKI). In the randomized phase Ib/II INSIGHT study (NCT01982955) that halted full enrolment due to low recruitment, tepotinib (TEP), a potent, selective MET TKI, plus gefitinib (GEF) improved progression-free survival (PFS) and objective response rate (ORR) vs chemotherapy (CTx) in patients with EGFR-mutant NSCLC and resistance to 1st-line EGFR TKIs due to METamp (≥6-month follow-up). We now present long-term survival outcomes (≥18-month follow-up) for this predefined analysis. MethodsPatients were randomized to TEP 500 mg + GEF 250 mg orally once daily (until progressive disease, intolerable toxicity or other withdrawal) or platinum + pemetrexed IV (≤6 x 21-day cycles). METamp was defined as GCN ≥5 and/or MET/CEP7 ratio ≥2. Primary endpoint was investigator-assessed (INV) PFS. Secondary endpoints included overall survival (OS), ORR, PFS by independent review (IRC), safety. ResultsFrom 04/24/15 to 06/12/17, 55 patients enrolled in the INSIGHT study and 19 were METamp (TEP+GEF 12; CTx 7); this predefined subgroup is analysed here. Median GCN was 8.8 (range 4.8–29.5); 18 patients had GCN ≥5, 13 had MET/CEP7 ratio ≥2. At data cutoff (12/12/18), median treatment duration (weeks [range]) for TEP+GEF was 49 (4.6–110.9; 3 patients still ongoing for ≥24 months), pemetrexed was 18.0 (5.9–60.4), cisplatin 12.0 (6.6–25.1) or carboplatin 12.8 (5.9–19.7), all CTx patients discontinued. TEP+GEF compared with CTx improved PFS (INV mPFS 21.2 vs 4.2 months, HR [90% CI] 0.13 [0.04, 0.43]; IRC mPFS 19.3 vs 5.5 months; 0.18 [0.06, 0.61]) and OS (mOS 37.3 vs 13.1 months, 0.08 [0.01, 0.51]), as well as ORR (INV 66.7 v 42.9%; OR 2.67 [0.37, 19.56]; IRC 75.0 vs 42.9%; OR 4.00 [0.51, 31.38]). Grade ≥3 treatment-related AEs in METamp patients (≥15% in either arm, TEP+GEF vs CTx) were amylase or lipase increased (both 33.3% vs 0%), anemia, neutrophil or WBC count decreased (all 0 vs 28.6%). ConclusionsTEP+GEF improved survival of patients with EGFR TKI-resistant NSCLC due to METamp. TEP + osmertinib is currently being investigated in patients with METamp, EGFR-mutant NSCLC with acquired EGFR TKI resistance (NCT03940703). Clinical trial identificationNCT01982955. Editorial acknowledgementMedical writing assistance was provided by Lisa Jolly, Bioscript, Macclesfield, UK, and funded by Merck KGaA, Darmstadt, Germany. Legal entity responsible for the studyMerck KGaA, Darmstadt, Germany. FundingMerck KGaA, Darmstadt, Germany. DisclosureK. Park: Advisory / Consultancy: AstraZeneca, Boehringer Ingelheim, Clovis; Elli Lilly; Hanmi; ONO; Roche; Novartis. R.A. Soo: Honoraria (self): BMS, Celgene, Ignyta, Lilly, Merck, Novartis, Pfizer, Roche, Taiho, Takeda, Yuhan; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Boehringer Ingelheim. R. Bruns: Full / Part-time employment: Merck KGaA. J. Straub: Full / Part-time employment: Merck KGaA. A. Johne: Full / Part-time employment: Merck KGaA. J. Scheele: Full / Part-time employment: Merck KGaA. J.C-H. Yang: Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech/Chugai, MSD, Merck Serono, Pfizer, Novartis, Celgene, Merrimack, Yuhan Pharmaceuticals, BMS, Ono pharmaceutical, Daiichi Sankyo and AstraZeneca, Takeda Oncology, Blueprint Medicines, Hansoh Pharmaceu. Y-L. Wu: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim ; Advisory / Consultancy: Merck; Honoraria (self): Eli Lilly, Pierre Fabre, Pfizer, Sanofi. All other authors have declared no conflicts of interest.

1560P - Disease monitoring of EGFR mutation-positive NSCLC patients via circulating tumour DNA

Background15–40% of NSCLC patients harbor EGFR sensitizing mutations. Tyrosine kinase inhibitors (TKI) provide significant clinical benefit in this population, yet all patients will develop resistance. Liquid biopsy has been demonstrated to reliably identify somatic tumor associated EGFR mutations. Quantitative assessment of mutated EGFR driven tumors could potentially be used to monitor disease progression and assess therapeutic response. Methods129 patients (68 F/61 M) with tissue biopsy-proofed EGFR sensitizing mutation-positive lung adenocarcinoma who were treated with EGFR-TKI and had one before TKI treatment and at least three post TKI treatment/follow-up blood samples were included in the study. 71% (92/129) patients were non-smokers. Plasma samples were tested with the cobas® EGFR Mutation Test v2, and the Semi-Quantitative Index (SQI) values for each mutation were reported by the software for the target mutation. The SQI is able to reflect a trend in the plasma EGFR mutation load. Molecular progression (MP) is defined as two consecutive non-zero SQI values or detection of T790M. ResultsThe most common EGFR mutations detected in the tissue were L858R (53%) and Exon 19 deletion (Ex19Del) (40%). One patient had both Ex19Del and T790M mutations. Plasma cfDNA analyses detected EGFR mutations in 74% (95/129) of the baseline samples. 64 of the 95 patients had MP. On average, MP was 42 days prior to clinical progression (CP) based on RECIST1.1. The PPV and NPV of using MP to predict CP were 84% and 68%, respectively. Analysis of the serial plasmas collected from patients who progressed while on 1st line TKI showed reappearance of the original EGFR sensitizing mutations with increasing SQI levels before emergence of a T790M mutation. T790M mutation was detected in 21% (27/129) of the patients on TKI treatment. ConclusionsThis study clearly demonstrated that monitoring EGFR mutation levels or changes in blood could be a meaningful approach to predict clinical progression for lung adenocarcinoma patients treated with EGFR-TKI. It warrants further studies to demonstrate the potential clinical utility of serial blood EGFR testing in NSCLC management. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Abstract CT193: Tepotinib + gefitinib vs chemotherapy in MET-amplified EGFR-mutant non-small cell lung cancer (NSCLC): Predefined subgroup analysis of a Phase Ib/II study

Abstract Background MET amplification (amp) is a resistance mechanism to EGFR tyrosine kinase inhibitors (TKIs). Tepotinib (TEP), an oral, selective MET TKI, has shown promising antitumor activity in combination with gefitinib (GEF) in patients with MET+ EGFR-mutant NSCLC and acquired resistance to 1st-line EGFR TKIs in a phase 1b/2 study (NCT01982955). In the phase 1b part of the study, 4/6 patients with METamp had an objective response with TEP+GEF (67%). Methods In the phase 2 part of the study, Asian patients with advanced MET+ (MET2+ or 3+ by immunohistochemistry and/or METamp by in-situ hybridization) EGFR-mutant T790M- NSCLC and acquired resistance to 1st-line EGFR TKIs were randomized to receive oral TEP 500 mg + GEF 250 mg once daily or platinum + pemetrexed chemotherapy (CTx). The primary endpoint was investigator-assessed PFS. Secondary endpoints included PFS by independent review committee (IRC), overall response rate (ORR), and safety. Data from a minimum follow-up of 6-months are presented (cut-off 26 Mar 2018) for the pre-planned analysis of patients with METamp, defined as gene copy number (GCN) ≥5 and/or MET/CEP7 ratio ≥2. Results Low recruitment halted enrolment into phase 2. From 24 Apr 2015 to 12 Jun 2017, 55/156 planned patients were enrolled; 19 had METamp (TEP+GEF, 12; CTx, 7) and are included in this analysis. Median age of METamp patients was 60.4 years (range 42-74), 6 were men, 13 were never smokers, 5 had ECOG PS 0 and 14 had PS 1. Median GCN was 8.8 (range 4.8-29.5); 18 patients had GCN ≥5, 13 had MET/CEP7 ratio ≥2. Median TEP+GEF treatment duration was 37 weeks (range 4.6-91.9) and 4 patients are still receiving treatment, ongoing for ≥18 months. Investigator-assessed PFS improved with TEP+GEF vs CTx (mPFS 21.2 vs 4.2 months; HR 0.17 [90% CI 0.05, 0.57]), as well as IRC-assessed PFS (19.8 vs 5.5 months; HR 0.25 [90% CI 0.07, 0.85]). ORR also improved with TEP+GEF (investigator: 66.7% vs 42.9%; OR 2.67 [90% CI 0.37, 19.56] and IRC: 75.0% vs 42.9%; OR 4.00 [90% CI 0.51, 31.38]). Disease control was achieved in 11 (91.7%) patients receiving TEP+GEF vs 5 (71.4%) patients receiving CTx. Related grade ≥3 treatment-emergent adverse events (TEAEs) were reported in 6 (50.0%) patients receiving TEP+GEF and 5 (71.4%) patients receiving CTx. The most common related TEAEs in the TEP+GEF arm were diarrhea (TEP+GEF 50.0% vs CTx 14.3%) and amylase increased (TEP+GEF 41.7% vs CTx 0%) and in the CTx arm were anemia (TEP+GEF 0% vs CTx 57.1%), white blood cell count decreased (TEP+GEF 8.3% vs CTx 57.1%), neutrophil count decreased (TEP+GEF 0% vs CTx 57.1%), and nausea (TEP+GEF 8.3% vs CTx 42.9%). Conclusions Promising antitumor activity with TEP+GEF was reported in patients with METamp, EGFR-mutant T790M- NSCLC and acquired resistance to 1st-line EGFR TKIs. No new safety signals were observed. METamp can be considered a biomarker for tepotinib that should be further explored. Citation Format: James Chih-Hsin Yang, Jianying Zhou, Dong-Wan Kim, Azura Rozila Ahmad, Ross Andrew Soo, Rolf Bruns, Josef Straub, Andreas Johne, Jürgen Scheele, Keunchil Park, Yi-Long Wu. Tepotinib + gefitinib vs chemotherapy in MET-amplified EGFR-mutant non-small cell lung cancer (NSCLC): Predefined subgroup analysis of a Phase Ib/II study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT193.

Eficacy and safety of first-line TKI in elderly with metastatic renal cancer.

588 Background: Data on 1st line treatment with tyrosine kinase inhibitors (TKI) in elderly patients(pts) with metastatic renal cell carcinoma (mRCC) is controversial, and there is rationale for inferior outcomes due to multiple comorbidities and polypharmacy. We aimed to compare the efficacy and safety between the elderly (E) and non-elderly (NE) in 1st line therapy, and to explore factors influencing survival and toxicity. Methods: We retrospectively reviewed all medical records of mRCC pts treated with 1st line TKI at our institution (2007 – 2018). Categorial variables were compared by Fisher’s exact test and continuous, Mann–Whitney. Survival was estimated by Kaplan-Maier method, prognostic factors adjusted by Cox regression model. Results: From 171 eligible pts, 64 (37.4%) had ≥ 65years old, with median age of 70.5 for E and 56 for NE. In both groups most were male, had clear cell histology, good/intermediate IMDC risk, prior nephrectomy and &gt; 1 metastatic (mets) site. Sites of mets were evenly distributed. E pts had more diabetes (35.9 vs16.8%, p.009) , hypertension (67.2 vs 46.7%, p.01), cardiovascular disease (15.6 vs 6.5%, p.06), moderate/severe renal dysfunction (62.5 vs 28.8%, p &lt; 0001), high Charlson Comorbidities Index (CCI≥3, 48.4% vs 20.8%, p &lt; .0001), polypharmacy (34.4 vs15.9%, p.008), worst ECOG (≥2, 28.2 vs 12.3%, p.01), and a trend to worst nutrition (weight loss 35.9 vs 22.5%, p.07). Sunitinib was used for 60.9 vs 79.4%, Pazopanib 35.9 vs 18.7%, Sorafenib 3.1 vs 1.9%, comparing E and NE pts. Median overall survival (OS) and progression free survival (PFS) was 23.7 vs 25.6m (p.8) and 9.3 vs 10.9m (p.7), respectively. After adjusting for prognostic factors, age continues not to influence OS (HR 1.17, IC95 0.77-1.78, p.45). Grade (G) 3/4 toxicity was seen in 59.4 vs 53.3%, dose reduction in 54.7 vs 53.3% and suspension due to toxicity 25 vs 13.3% for E and NE, respectively. In the E, none of the comorbidities, CCI or polypharmacy impaired OS or toxicity, but pts using sunitinibe had greater G3/4 toxicity than with pazopanib (71.8 vs 39.1%, p.02). Conclusions: Elderly had similar outcomes to NE pts, despite greater comorbidities and polypharmacy, hence efficacious therapies shouldn’t avoided. Pazopanib seems to be safer in this subgroup.

Influence of access on survival of renal cancer in a Brazilian center.

644 Background: The introduction of tyrosine kinase inhibitors (TKI) and recently immunotherapy has brought major survival benefits for metastatic renal cancer (mRCC) patients (pts). In Brazil, there is no approved 2nd line treatment for mRCC in the Public Health System (PHS). Our center is unique, because it provides care for both PHS and Private System (PrS) population, enabling us to make the comparison of overall survival (OS) of these pts. Methods: We retrospectively reviewed medical records of all mRCC pts treated with 1st line TKI at our service from 2007 to 2018. Categorial variables were compared by Fisher’s exact test and continuous by Mann–Whitney. Survival was estimated by Kaplan-Maier method, prognostic factors adjusted by Cox regression model. Results: 171 pts were eligible, 37 (21.6%) PHS and 134 (78.4%) PrS pts. Between the two groups, there was no differences in age, gender, number and sites of metastasis (mets). PHS pts had worst ECOG (≥2, in 35.1 vs 13.5%, p .007), a trend towards more poor IMDC risk (IMDC favorable 16.2 vs 26.6%, intermediate 51.4 vs 57%, poor 32.4 vs 16.4%, p.09), had less nephrectomies (73 vs 92.5%, p.008) and more non clear cell histology (32.4 vs 12.7%, p.01). Median lines of therapy were 1 for PHS vs 2 for PrS pts (p.03). Sunitinib was the 1st line agent for 91.9 vs 67.2%, and pazopanib 8.1 vs 29.9%, of the PHS and PrS pts, respectively. Median time from diagnosis of mets to treatment start was 2.29 vs 1.79 m (p.59). Median OS was 16.5 vs 26.5 m (p.0002) and progression free survival, 8.4 vs 11 m (p.01), for the PHS vs PrS. On multivariate analysis, after adjusting for factors that were present before the beginning of treatment and were statistically significant for OS in the univariate model, PHS pts still had higher risk of death (HR 1.85, IC 95 1.2-2.9, p.01), probably due to having received fewer lines of therapy (≥2 lines of therapy vs 1, HR 0.51, IC95 0.4-0.7, p .001). Conclusions: Brazilian PHS pts had significant worse OS compared to PrS pts, in part due to less access to drugs. Access to cancer drugs is a challenge worldwide, and in Brazil effort has to be done to change this reality.

Early tumor shrinkage as a predictive factor of metastatic renal cell carcinoma in molecular targeted therapy: A single institutional study.

The aim of the present study was to investigate the impact of metastatic sites and early tumor shrinkage (eTS) as prognostic predictive factors of metastatic renal cell carcinoma (mRCC) in molecular targeted therapy. A total of 209 advanced RCC cases treated with sorafenib, sunitinib, axitinib, pazopanib, temsirolimus and everolimus from our single institution were included in the present study. Several known prognostic predictive factors, including metastatic sites and the rate of eTS, were analyzed by Kaplan-Meier survival estimate analysis followed by Cox's proportional hazards model analysis. eTS was measured by three independent physicians. Four metastatic sites in the liver, bone, lymph nodes and brain as well as greater eTS were identified as potential independent predictors of overall survival (OS) in several cohorts: i) Metastatic RCC (n=194); ii) metastatic clear cell RCC (n=119); and iii) mRCC patients with eTS data (n=127). In sub-analyses of patients treated with each 1st line tyrosine kinase inhibitor, eTS was identified as a potentially potent predictor of OS in patients treated with axitinib. The liver, bone, lymph nodes, brain metastases and eTS were identified as independent predictive factors of OS by analyzing a limited Japanese cohort.

PCN373 - UNDERSTANDING PATIENT PERSPECTIVES OF RENAL CELL CARCINOMA USING SOCIAL MEDIA: A QUALITATIVE ANALYSIS

Treatment with tyrosine kinase inhibitors (TKI) is used frequently in 1st line metastatic renal cell carcinoma (RCC). Patient perspectives expressed on social media may help to better understand the lived experience of RCC and 1st line TKI treatment. Posts were extracted from a random selection of users on four publically available patient forums; one UK-based (Macmillan) and three US-based (Cancer Network, Cancer Compass, Daily Strength). Users were self-reported patients or caregivers of patients with stage IV RCC receiving 1st line TKI. Extracted posts were read into the RQDA qualitative package for R statistical software. Using thematic analysis, themes were identified inductively under either positive or negative impacts of treatment. A total of 2713 posts from 104 users were extracted and included in the analysis (UK site= 908 posts [29 users]; US sites= 1,805 posts [75 users]). Mentions corresponding to a negative impact of treatment were >3 times more common than to a positive impact (1246 mentions [96 users] vs. 382 [71]). Negative impacts were grouped under five themes (adverse events [AE], disease management, quality of life [QoL], disease status, and impact on family), and positive impacts under two themes (clinical benefit and QoL). The most commonly mentioned negative impact related to AE’s, and specifically involved pain/fatigue or gastrointestinal events (nausea/vomiting). There were almost twice as many negative mentions relating to QoL than positive (192 [53] vs. 109 [34]). These centred on emotional impacts (e.g., helplessness), work/productivity loss, and financial burden, although the extent to which negative impacts were specific to treatment vs. disease could not be determined. Little difference was observed in themes between UK- and US-based forums. The experience of RCC patients conveyed on social media suggests there is high unmet need associated with 1st line TKIs, with patients frequently expressing concerns related to AE’s and poor QoL.