Patterns Of Treatment Failure Research Articles

Real-World Analysis of Post-Progression Treatment Patterns and Outcomes for EGFR Mutation-Positive Patients Treated with First-Line Osimertinib.

Introduction: The use of osimertinib in the first-line (1L) setting is an effective treatment option for sensitizing EGFR-mutations (EGFRm+) and has significantly altered the standard of care practice for EGFRm+ disease in Canada. Unfortunately, acquired resistance to osimertinib is almost universal, and outcomes are disparate. Post-progression treatment patterns and the outcome of real-world Canadian EGFRm+ patients receiving 1L osimertinib were the focus of this retrospective review. Methods: The Glans-Look Lung Cancer Research database was used to identify and collect demographic, clinical, treatment, and outcome data on EGFRm+ patients who received 1L osimertinib in the Canadian province of Alberta between 2018 and 2022. Results: A total of 150 patients receiving 1L osimertinib were identified. In total, 86 developed progressive disease, with 56 (65%) continuing systemic therapy, 73% continuing osimertinib, and 27% switching to second-line (2L) systemic therapy. Patients were similar both in clinical characteristics at 1L osimertinib initiation and patterns of treatment failure at progression; those continuing 1L osimertinib post-progression had a longer time to progression (13.5 vs. 8.8 months, p = 0.05) and subsequent post-osimertinib initiation survival (34.7 vs. 22.8 months, p = 0.11). Conclusions: The continuation of osimertinib post-progression is an effective disease management strategy for select real-world EGFRm+ patients, providing continued clinical benefit, potentially due to different underlying disease pathogenesis.

Patterns of Treatment Failure in Primary Central Nervous System Lymphoma.

Progression of PCNSL remains a challenge with salvage therapies, including the risk of substantial morbidity and mortality. We report patterns of first tumor progression to inform opportunities for improvement. This is an institutional retrospective review from 2002 to 2021 of 95 consecutive patients with pathologically confirmed PCNSL, of whom 29 experienced progressive disease. Kaplan-Meier method, log-rank test, and Cox proportional hazard models are used to characterize associations of patient, tumor, and treatment variables with LC, PFS, and patterns of first failure. Most patients were below 65 years old (62%) with KPS >70 (64%) and negative CSF cytology (70%). In 70 patients with MRIs, the median tumor volume was 12.6 mL (range: 0.5 to 67.8 mL). After a median follow-up of 11 months, 1-year PFS was 48% and 1-year LC was 80%. Of the 29 patients with progression, 24% were distant only, 17% were distant and local, and 59% were local only. On MVA, LC was associated with age (HR: 1.08/y, P=0.02), KPS (HR: 0.10, P=0.02), completion of >6 cycles of HD-MTX (HR: 0.10, P<0.01), and use of intrathecal chemotherapy (HR: 0.03, P<0.01). On UVA, local only first failure trended to be increased with >14 mL tumors (OR: 5.06, P=0.08) with 1-year LC 83% (<14 mL) versus 64% (>14mL). There were no significant associations with LC and WBRT (P=0.37), Rituximab (P=0.12), or attempted gross total resection (P=0.72). Our findings reaffirm the importance of systemic and intrathecal therapies for local control in PCNSL. However, bulky tumors trend to fail locally, warranting further investigation about the role of local therapies or systemic therapy intensification.

Real-World Patterns and Economic Burden Associated With Treatment Failure With Advanced Therapies in Patients With Moderate-to-Severe Ulcerative Colitis

Abstract Background Some patients lose response during treatment for moderate-to-severe ulcerative colitis (UC). We aimed to characterize real-world treatment failure patterns and associated economic burdens during use of first-line advanced therapies for UC. Methods IBM MarketScan Commercial and Medicare Supplemental Databases were used to identify adults initiating ≥ 1 advanced therapy for UC (January 1, 2010–September 30, 2019). Treatment failure was defined as augmentation with non-advanced therapy, discontinuation, dose escalation/interval shortening, failure to taper corticosteroids, UC-related surgery, or UC-related urgent care ≤ 12 months after treatment initiation. The index date was the date of treatment failure (treatment failure cohort) or 12 months after treatment initiation (persistent cohort). Treatment failure rates were assessed using Kaplan–Meier analyses. All-cause and UC-related healthcare resource utilization (HCRU) and costs 12 months post-index were also assessed. Results Analysis of treatment failure patterns included data from 6745 patients; HCRU and cost analyses included data from 5302 patients (treatment failure cohort, n = 4295; persistent cohort, n = 1007). In the overall population, 75% experienced treatment failure within the first 12 months (median: 5.1 months). Augmentation with non-advanced therapy (39%) was the most common first treatment failure event. The treatment failure cohort had significantly (P &amp;lt; .001) higher mean costs than the persistent cohort (all-cause, $74 995 vs $56 169; UC-related, $57 096 vs $47 347) mainly attributed to inpatient admissions and outpatient visits. Dose escalation/interval shortening accounted for the highest total costs ($101 668) across treatment failure events. Conclusions Advanced therapies for moderate-to-severe UC are associated with high rates of treatment failure and significant economic burden. More efficacious and durable treatments are needed.

A population-based analysis of the impact of 1 vs. 2 doses of mitomycin on patterns of failure of anal cancer patients treated with concurrent chemoradiotherapy

PurposeWe report the impact of 1 vs. 2 doses of mitomycin-C (MMC) based chemoradiation (CRT) on patterns of treatment failure and long-term patient outcomes in anal squamous cell carcinoma (ASCC) and the predictors for locoregional failure (LRF) and distant metastasis (DM). MethodsIn this population-based study, we identified all patients with anal cancer in our province treated radically with radiation and concurrent 5-Fluorouracil (5FU) and 1 vs. 2 doses of MMC between the years 2000-2019. The primary outcomes analyzed were locoregional recurrence (LRR), disease free survival (DFS), ASCC cancer-specific survival (ASCC-CSS) and overall survival (OS). Results451 patients were identified. 272 (60%) patients received 1 cycle of MMC (MMC1) and 179 (40%) received 2 cycles (MMC2) as part of the CRT regimen. The median follow-up was 57 (36-252) and 97 (38-239) months for MMC1 and MMC2, respectively. Cox Regression analysis showed stage IIIb and IIIc were associated with worse locoregional recurrence free survival (RFS) (HR=2.851, p=<0.001) and distant RFS (HR=3.391, p=<0.001). Similarly, stage IIIb and IIIc patients had poorer DFS (HR 3.439, p=<0.001), ASCC-SS (HR 3.729, p=<0.001) and OS (2.230, p=<0.001). The use of MMC2 showed a positive impact on improved ASCC-SS (HR 0.569, p=0.029) and distant RFS (HR 0.555, p=0.040) in patients with stage IIIb and IIIc. ConclusionsOur analysis showed that 1 vs. 2 cycles of MMC along with 5FU and radiation is associated with comparable treatment outcomes in general. However, in patients with stage IIIb and IIIc cancer, 2 doses of MMC were associated with improved ASCC-SS and distant DFS.

Optimal sequence of LT for symptomatic BM in EGFR-mutant NSCLC: a comparative study of first-line EGFR-TKIs with/without upfront LT

BackgroundThe third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) can penetrate blood–brain barrier and are effective for brain metastases (BMs). There is no consensus on the optimal sequence of local therapy (LT) and EGFR-TKIs for symptomatic BM patients because patients suffering neurological symptoms were not enrolled in most clinical trials.MethodsNon-small cell lung cancer (NSCLC) patients with EGFR mutation (EGFRm) and symptomatic BM receiving first-line osimertinib and aumolertinib from two medical centers were collected. All participants were allocated into the third-generation EGFR-TKIs (TKIs) group and the upfront LT (uLT) plus third-generation EGFR-TKIs (TKIs + uLT) group. Demographic data, survival outcomes, treatment failure patterns, and adverse events were evaluated between the two groups. We also conducted subgroup analyses to explore the impact of BM number on survival outcomes.Results86 patients were enrolled, 44 in the TKIs group and 42 in the TKIs + uLT group. There were no significant differences in the short-term response between the groups. TKIs + uLT was associated with significantly longer overall survival (OS) (43 vs. 28 months; hazard ratio [HR], 0.36, 95% confidence interval [CI], 0.17–0.77; p = .011). No differences in progression-free survival (PFS), intracranial PFS (iPFS), failure patterns, or safety were observed. In subgroup analyses of oligo-BM patients, TKIs + uLT could prolong OS (43 vs. 31 months; HR 0.22; 95% CI 0.05–0.92; p = .015).ConclusionsEGFRm NSCLC patients with symptomatic BM might benefit from uLT, particularly oligo-BM patients. However, larger prospective cohort studies should be carried out to confirm the responses of the TKIs + uLT scheme.

A comparison of timing and patterns of treatment failure, and survival outcomes after progression between HPV+ and HPV- patients undergoing chemoradiation for oropharyngeal squamous cell carcinomas.

We aimed to analyze and compare the timing and patterns of treatment failure, and survival after progression between HPV-positive (HPV+) and HPV-negative (HPV-) patients undergoing chemoradiation for oropharyngeal squamous cell carcinomas (OPSCC). A retrospective review was performed of all patients undergoing primary chemoradiation for OPSCC between 2008 and 2021. Demographic and clinical data were collected. Kaplan-Meier estimates for overall survival (OS), and time to recurrence/metastases (TTR) were compared using the log-rank test, with Cox regression used for multivariable modeling comparing HPV+ and HPV- patients. HPV- patients developed recurrence or metastases at earlier time points than HPV+ patients (8.8 vs. 15.2 months, p < 0.05), due to earlier local/locoregional recurrence and distant metastases, but not isolated regional recurrences. HPV- distant metastases exclusively occurred in a single organ, most commonly the lungs or bone, while HPV+ metastases frequently had multi-organ involvement in a wide variety of locations (p < 0.05). Once progression (recurrence/metastases) was diagnosed, HPV+ patients experienced superior survival to HPV- patients on univariate and multivariate analysis, largely due to improved outcomes after treatment of local/locoregional recurrences (p < 0.05). There were no differences in survival after isolated regional recurrences or distant metastases. HPV+ OPSCC patients relapse later compared to HPV- patients in local/locoregional and distant sites. HPV+ patients with local/locoregional recurrence experience superior survival after recurrence, which does not hold true for isolated regional recurrences or distant metastases. These data can be useful to inform prognosis and guide treatment decisions in patients with recurrent OPSCC.

A Rare Cell State Underpins Diverse Mechanisms of Adaptive Resistance to CAR T-Cell Therapy in B-Cell Acute Lymphoblastic Leukemia

The most common pattern of treatment failure of B-cell acute lymphoblastic leukemia (B-ALL) following CD19-targeting chimeric antigen receptor T cell therapy (CAR T), is a measurable residual disease (MRD) negative response followed by relapse. Whilst in a fraction of patients relapse is associated with loss of function mutations &amp;/or deletions of the CD19 locus, a significant proportion of patients relapse with CD19+ disease. We hypothesised that this arises from a rare CAR T tolerant persister population that is able to survive the strong therapeutic pressure and seed relapse. To address this, we investigated the clonal origin and transcriptional dynamics of “CAR T tolerant persister cells” via time resolved clonal tracing of the progeny of individual B-ALL clones, using expressed molecular barcodes in an immunocompetent mouse model of CD19 targeting CAR T. We demonstrate that relapse is a pre-determined fate of rare B-ALL clones, which each adopt diverse, yet clone-specific, transcriptional phenotypes at relapse. Moreover, each diverse relapse phenotype appears to be underpinned by a shared, rare “origin of relapse” cell state that is common to all relapse-fated clones. Our immunocompetent mouse model of murine CAR T cells targeting CD19 (ID3-h41bb-3z) on a syngeneic, BCR::ABL1(p190) driven B-ALL recapitulates the clinical scenario of MRD-negative remission followed by CD19+ relapse. We labelled B-ALL cells with SPLINTR (Fennell &amp; Vassiliadis et al. Nature 2022), a lentiviral lineage tracing reagent comprising expressed molecular barcodes that are read out by single cell RNA sequencing (scRNAseq), to allow dynamic profiling of the clonal origin and transcriptome of individual B-ALL clones over time, across multiple therapeutic timepoints including pre-treatment, remission and relapse. Tumour initiating frequency in this model of B-ALL is high with 23% of transplanted clones able to establish fulminant B-ALL. Only 0.7% of clones, however, were able to persist following CAR-T pressure and seed relapse. In fact, &amp;gt;99% of post-CAR T relapsed disease was comprised by just 3 (0.3%) individual clones and in one mouse disease relapse was driven entirely a single clone. Remarkably, we found that the same clones were able to drive relapse in multiple mice, consistent with a the presence of pre-determined, heritable cell-intrinsic properties capable of causing relapse following CAR T. To further study this phenomenon, we performed scRNAseq on these murine B-ALL samples to examine the transcriptional profiles of these rare, relapse fated clones prior to and following CAR T. Whilst prior to therapy, relapse fated clones were transcriptionally identical to the CAR T sensitive clones, following CAR T we observed that relapse fated clones adopted distinct transcriptional profiles compared to their transcriptome in the absence of therapeutic pressure, suggesting transcriptional adaptation underpins their ability to survive therapy. We noted that each resistant clone had a unique adaptive response and consequent transcriptional signature. Remarkably however, the adaptive response of each clone in different mice was essentially identical, indicative of strong, conserved clone-intrinsic mechanisms of adaptation. Although each CAR T resistant clone adopted disparate transcriptional states in the bulk ALL, we identified a single rare cell state (~1% of the bulk B-ALL) that was shared between all clones, highly suggestive of a common point of origin from which transcriptional adaptation arises. This rare cell state demonstrates metabolic hallmarks of therapy resistance and a distinct developmental transcriptional profile most analogous to the recently characterised preBCR-dependant stage of normal B cell development, raising the prospect that these cells represent an “origin of relapse” cell state. Preliminary data suggests that this rare cell state may also be conserved in human Ph+ B-ALL. In summary, by modelling CD19+ B-ALL relapse following MRD negative remission after CAR T, we have identified a rare cell state that our analysis suggests serves as a common and necessary point from which a transcriptionally diverse range of B-ALL phenotypes can arise and be maintained. We have demonstrated that relapse following CAR T emerges due to clone-specific transcriptional differences from this rare cell state, a phenomenon which may extend to a diverse range of therapies in B-ALL.

SURG-04. FAST DETECTION OF GLIOMA INFILTRATION USING LABEL-FREE OPTICAL MICROSCOPY AND DEEP NEURAL NETWORKS

Abstract INTRODUCTION Fast and accurate detection of tumor infiltration is a central challenge in the comprehensive management of diffuse glioma patients. Despite our best real-time tumor detection strategies, such as intraoperative MRI and fluorescence-guided surgery, dense and safely resectable tumor infiltration remains at the surgical margin in over 85% of diffuse glioma patients. Patterns of treatment failure demonstrate that glioma recurrence occurs at the surgical margin in the majority of patients due to residual tumor burden. Objective Here, we present FastGlioma, an artificial intelligence (AI)-based intraoperative diagnostic system for fast (&amp;lt; 10 seconds) detection of diffuse glioma infiltration at microscopic resolution without the need for tumor-specific markers. Method FastGlioma is trained using large-scale, self-supervised visual feature learning on stimulated Raman histology (SRH), a rapid, label-free, optical microscopy technique, and a GPT-style whole slide SRH tumor infiltration scoring method. We pushed the performance limits of FastGlioma by investigating the trade-off between imaging speed versus accuracy for microscopic tumor detection. RESULTS In a large prospective external testing cohort of diffuse glioma patients (180 patients, 935 surgical margin specimens) who underwent intraoperative SRH imaging, we demonstrate that FastGlioma was able to detect and quantify microscopic tumor infiltration with an average AUROC of 92.1 +/- 0.0%, performing on par with three expert neuropathologists on the same task. FastGlioma is over 10X faster than previous SRH-based methods and 100X faster than conventional H&amp;E histology. Finally, we demonstrate that FastGlioma was &amp;gt; 20% more accurate at detecting dense tumor infiltration when compared to radiologic features or 5-aminolevulinic fluorescence (98.0% versus 77.8% accuracy) for both IDH-mutant diffuse gliomas and IDH-wildtype glioblastomas. CONCLUSION Our results demonstrate how intraoperative optical imaging and deep neural networks can achieve fast and accurate tumor detection, unlocking the role of AI in improving the surgical management of brain tumor patients.

Oligo-Residual Disease in PD-1/PD-L1 Inhibitors Treated Metastatic Non-Small Cell Lung Cancer: Incidence, Pattern of Failure and Clinical Value of Local Consolidative Therapy

Growing numbers of clinical trials are testing the efficacy of incorporating local therapy into programmed death receptor (ligand) 1 (PD-1/PD-L1) inhibitors in metastatic non-small cell lung cancer (NSCLC), but the optimal timing and patient selection are still controversial. We aimed to examine the patterns of maximum tumor response and treatment failure in PD-1/PD-L1 inhibitor-treated NSCLC, and explore the potential clinical value of local consolidative therapy (LCT) in those with oligo-residual disease (ORD). Metastatic NSCLC treated with PD-1/PD-L1 inhibitors in three academic centers from May 2018 to December 2021 were retrospectively reviewed and those derived clinical benefit, defined as having objective response or durable stable disease lasting≥6months, were finally enrolled. Patterns of tumor response and treatment failure were extensively analyzed. ORD was defined as residual tumor distribution limited to 3 organs and 5 lesions, otherwise was defined as multiple residual disease (MRD). Local therapies targeting the residual tumor lesions performed after PD-1/PD-L1 inhibitors initiation and before initial disease progression, were considered as LCT. The primary endpoints were the overall survival (OS) and progression-free survival (PFS). Of the 318 patients enrolled, ORD and MRD were documented in 122 (38.4%) and 196 (61.6%) patients, respectively. Those who developed ORD had a significantly longer OS than those with MRD (p = 0.006). The median time to best response was 4 months and more than 50% of the initial disease progression developed only from the residual tumor lesions, providing the preliminary rationale of LCT. Among the 122 patients with ORD, those receiving LCT (n = 39) had significantly longer PFS (p = 0.04) and OS (p<0.001) than those without LCT. Moreover, LCT remained one of the independent predictors of improved PFS and OS after Cox analyses. Local consolidative therapy seems to be feasible and may provide extra survival benefit for metastatic NSCLC patients with oligo-residual disease after PD-1/PD-L1 inhibitor treatment.

Patterns of Treatment Failure After Selective Rearranged During Transfection (RET) Inhibitors in Patients With Metastatic Medullary Thyroid Carcinoma.

Medullary thyroid cancer (MTC) harbors frequent mutations in RET oncogene. Selective RET inhibitors (RETi) have emerged as effective treatments. However, resistance almost invariably occurs. MTC patients who were initiated on RETi between 2018 and 2022 were included. Baseline characteristics, RET mutational status, RETi response, available tumor tissue and molecular profiles sampled pre- and post-RETi were analyzed. Among 46 MTC patients on RETi during the study period, 26 patients had discontinued at data cut-off because of progression (n = 16), death (n = 4), and toxicity (n = 6). The most frequent RET mutations at baseline were p.M918T (n = 29), and p.C634X (n = 6). Pre- and post-RETi molecular profiles were available in 14 patients. There was no primary resistance on pre-RETi samples. Post-RETi profiles revealed a bypass mechanism of resistance in 75% of the cases including RAS genes mutations (50%), FGFR2 and ALK fusions and and MYC p.P44L. RET solvent from and hinge region mutations was the only resistance mechanisms in 25% of the cases. Tumor samples from initial thyroidectomy, pre- and post-RETi, from six patients, showed an increase of the mean Ki 67-index of 7%, 17% and 40% respectively (P = 0.037) and a more aggressive poorly differentiated histology in three patients. Bypass resistance may be the most frequent mechanism of progression under RETi. A more aggressive histology may arise following RETi and warrants further investigation.

Patterns of treatment failure in patients with nasopharyngeal carcinoma and salvage treatment outcome: A retrospective analysis study

IntroductionIn Saudi Arabia, head and neck cancers represent 6 % of all malignancies. 33 % of these are nasopharyngeal. Thus, we aimed to distinguish patterns of treatment failure and salvage treatment outcomes among patients with nasopharyngeal carcinoma (NPC). MethodsA retrospective review of patients treated for NPC in a tertiary care hospital. From May 2012 to January 2020, we retrospectively reviewed 175 patients that fit our inclusion criteria. Those who did not complete their treatment, started treatment in another institution, or did not complete a 3-year follow-up were excluded. In addition, the primary treatment outcome and the salvage treatment for those who failed initial treatment were collected and analyzed. ResultsPatients were predominantly stage 4 disease. 67 % of the patients were alive without evidence of disease during their last follow-up. However, 75 % of failure occurs in the first 20 months of completing the treatment regimen. Neoadjuvant therapy and delays in referral play a significant role in treatment failure. For failed cases, concurrent salvage chemoradiotherapy showed the best survival. ConclusionAdvanced stage 4A and T4 nasopharyngeal carcinoma should receive the maximum treatment, with a close follow-up, particularly during the first 2 years after treatment. Furthermore, the excellent outcome from salvage chemoradiotherapy and radiotherapy alone would make physicians aware of the importance of aggressive primary treatment.

Evaluation of local control strategies on patterns of treatment failure in patients with localized ewing sarcoma treated on AEWS1031: A report from the children’s oncology group.

11529 Background: To evaluate clinical characteristics and patterns of treatment failure in patients with localized Ewing sarcoma (ES) treated on AEWS1031 according to local control (LC) strategies, tumor size, and tumor site. Methods: AEWS1031 was a phase 3 randomized trial comparing two interval compressed chemotherapy regimens. Patients who completed LC on AEWS1031 were analyzed. LC was with surgery alone (S), definitive radiation therapy (RT), or surgery plus radiation (S+RT), and determined by the treating investigator. Local failure (LF) and distant failure (DF) were defined as recurrence at primary tumor site or distant site, respectively. Fine and Gray method was used to estimate cumulative incidence of LF and DF from time LC was completed. P-values were calculated using logrank or Gray’s test, as appropriate. A two-sided p-value of ≤0.05 was considered significant. Results: 588 patients completed LC. Median age at enrollment was 13.0 years (range: 0.6- 33.9 years). Tumor sites were categorized as extremity (230; 39%), axial (142; 24%), extraosseous (110; 19%), and pelvis (106; 18%). At diagnosis, tumor volume (TV) was ≥200 mL in 170 patients (31%) and maximum tumor dimension (MTD) was ≥8 cm in 289 patients (52%). LC was with S in 320 patients (54%), RT in 160 (27%), and S+RT in 108 (18%). Eight patients received preoperative RT. Fifty-three patients (13.1%) who received S±RT had an R1 resection. LC with S was more likely for extremity (58%), RT for pelvis (38%) and S+ RT for axial (36%) and extraosseous (34%) primary tumors (p &lt;0.01). With median follow up of 67.6 months from LC, the 5-year cumulative incidences of LF and DF for the entire cohort were 6.0% (95% CI, 4.3-8.3%) and 11.0% (95% CI, 8.6-13.9%), respectively. Eleven patients experienced simultaneous LF and DF. LF incidence was 5.0% for S, 8.4% for RT, and 5.6% for S+RT (p=0.47). DF incidence was 11.8% for S, 6.4% for RT, and 15.1% for S+RT (p=0.16). LF incidence by tumor site was 3.6% for extremity, 8.7% for pelvis, 7.3% for axial, and 6.8% for extraosseous (p=0.08). LF incidence was higher for primary tumors ≥200 mL (11.3%) compared to tumors &lt; 200 mL (3.9%; p&lt;0.01) and for tumors ≥8 cm (7.8%) compared to tumors &lt; 8 cm (4.4%; p=0.02). Tumor size was associated with a higher LF incidence for S and RT, but not for S+RT (Table). LF incidence was 4.0% for R0, 7.5% for R1 with RT, and 16.7% for R1 without RT (p=0.02). Conclusions: We report the lowest LF incidence to date for prospective ES trials conducted. Both larger TV and MTD were associated with higher LF. Future investigations will aim to evaluate the impact of chemotherapy dose-intensity on LC and identify risk-stratification variables for improved LC. Five-year LF incidence by LC and tumor size. Clinical trial information: NCT01231906 . [Table: see text]

Oligo-residual disease in PD-1/PD-L1 inhibitor-treated metastatic non-small cell lung cancer: Incidence, pattern of failure and clinical value of local consolidative therapy.

e21143 Background: Growing numbers of clinical trials are testing the efficacy of incorporating local therapy into programmed death receptor (ligand) 1 (PD-1/PD-L1) inhibitors in metastatic non-small cell lung cancer (NSCLC), but the optimal timing and patient selection are still controversial. We aimed to examine the patterns of maximum tumor response and treatment failure in PD-1/PD-L1 inhibitor-treated NSCLC, and explore the potential clinical value of local consolidative therapy (LCT) in those with oligo-residual disease (ORD). Methods: Metastatic NSCLC treated with PD-1/PD-L1 inhibitors in three academic centers from May 2018 to December 2021 were retrospectively reviewed and those derived clinical benefit, defined as having objective response or durable stable disease lasting≥6months, were finally enrolled. Patterns of tumor response and treatment failure were extensively analyzed. ORD was defined as residual tumor distribution limited to 3 organs and 5 lesions, otherwise was defined as multiple residual disease (MRD). Local therapies targeting the residual tumor lesions performed after PD-1/PD-L1 inhibitors initiation and before initial disease progression, were considered as LCT. The primary endpoints were the overall survival (OS) and progression-free survival (PFS). Results: Of the 318 patients enrolled, ORD and MRD were documented in 122 (38.4%) and 196 (61.6%) patients, respectively. Those who developed ORD had a significantly longer OS than those with MRD (p = 0.006). The median time to best response was 4 months and more than 50% of the initial disease progression developed only from the residual tumor lesions, providing the preliminary rationale of LCT. Among the 122 patients with ORD, those receiving LCT (n = 39) had significantly longer PFS (p = 0.04) and OS (p &lt; 0.001) than those without LCT. Moreover, LCT remained one of the independent predictors of improved PFS and OS after Cox analyses. Conclusions: Local consolidative therapy seems to be feasible and may provide extra survival benefit for metastatic NSCLC patients with oligo-residual disease after PD-1/PD-L1 inhibitor treatment.

Investigating the patterns of treatment failure in patients with advanced stage III and IV melanoma receiving adjuvant therapy.

e21532 Background: The landscape of treatment of patients with resectable stage III melanoma has evolved considerably given studies demonstrating survival benefit of anti-PD-1 immunotherapy and BRAF/MEK-inhibitor (BRAF/MEKi) therapy in the adjuvant setting, as well as surgical changes relating to the Multicenter Selective Lymphadenectomy Trial (MSLT)-II trial. Currently, the decision to treat with anti-PD-1 or BRAF/MEKi therapy in the adjuvant setting is dependent upon patient, provider, and institutional preferences, but no comparative analysis has been done between adjuvant therapy options. Methods: Clinical data from 141 surgically-resected staged III and oligometastatic stage IV patients receiving adjuvant anti-PD-1 (n = 66), BRAF/MEKi (n = 36), or surgery only (n = 39) between 2017 and 2021 was analyzed retrospectively. Primary endpoints were overall survival (OS) and progression free survival (PFS) between the three treatment groups. Secondary endpoints include the duration of adjuvant treatment and reasons for termination of therapy. Results: During a mean follow-up period of 17 months, 33.3% of anti-PD-1 patients and 16.7% of BRAF/MEKi patients experienced recurrence, while 41.0% of the surgery only patients experienced recurrence. In univariate Cox regression analyses of the survival data, patients who received anti-PD-1 (HR = 0.46, 95% CI: 0.25-0.87, p = 0.016) or BRAF/MEKi (HR = 0.44, 95% CI:0.21-0.90, p = 0.024) had significantly improved PFS compared to patients treated with surgery only, but the OS was not significantly different with treatment. A multivariate Cox regression model was performed, adjusting for age, sex, and melanoma disease stage. In this model, anti-PD-1 was still associated with improved PFS (HR = 0.33, p &lt; 0.001), while BRAF/MEKi also trended towards improved PFS, but was not statistically significant (HR = 0.54, p = 0.13). Other associations include males having a significantly worse PFS (HR = 2.32, p = 0.009) and OS (HR = 5.86, p = 0.02), and patients with stage IIIC or worse disease having worse PFS (HR = 4.56, p &lt; 0.001), but not significantly worse OS (HR = 4.84, p = 0.05). The average duration of adjuvant therapy was similar between both groups (250-260 days) with approximately half of the patients completing the treatment course. A larger proportion of BRAF/MEKi patients stopped treatment due to intolerable side effects compared to anti-PD-1 patients (83.3% vs. 64.0%). Conclusions: Adjuvant treatment decreases the chance of recurrence compared to surgery alone, but the benefit on overall survival is still inconclusive. Male and more advanced stage III melanoma prior to initiating adjuvant therapy are factors associated with an increased likelihood of recurrence. Although it appears that more patients terminated BRAF/MEKi therapy early due to side effects compared to anti-PD-1, additional follow-up will be needed to confirm this finding.

Survival Outcomes for Patients with Relapsed/ Refractory Aggressive B Cell Lymphomas Following Receipt of High-Dose Chemotherapy/Autologous Stem Transplantation and/or Chimeric Antigen Receptor-Modified T Cells

Patients diagnosed with relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL) or high-grade B cell lymphoma (HGBL) may achieve prolonged survival following receipt of high-dose chemotherapy/autologous stem cell transplantation (HDC/ASCT) or CD19-directed chimeric antigen receptor modified T cell therapy (CART19). Although early results from randomized clinical trials suggest that assignment to CART19 versus salvage immunochemotherapy as second-line therapy results in improved survival, analysis of a large series of patients who actually received HDC/ASCT or CART19 has yet to be performed. Such an analysis may inform future research efforts to optimize the risk stratification of R/R DLBCL/HGBL patients who are candidates for either therapy. The aim of this study was to evaluate clinicopathologic factors predictive of freedom from treatment failure (FFTF) for R/R DLBCL/HGBL patients following receipt of HDC/ASCT or CART19, and to compare patterns of treatment failure (TF) in R/R DLBCL/HGBL patients receiving HDC/ASCT and those receiving CART19. THE STUDY GROUP COMPRISED: patients age ≤75 years with R/R DLBCL/HGBL who received HDC/ASCT demonstrating partial or complete metabolic response to salvage immunochemotherapy and/or CART19 in the standard of care setting at the University of Pennsylvania between 2013 and 2021. Survival analyses were performed from the time of infusion of either HDC/ASCT or CART19, as well as at landmark time points postinfusion for patients who achieved FFTF. For 100 HDC/ASCT patients with a median follow-up of 62.7 months, the estimated 36-month FFTF and overall survival (OS) rates were 59% and 81%, respectively. For 109 CART19 patients with a median follow-up of 37.6 months, the estimated 36-month FFTF and OS rates were 24% and 48%, respectively. HDC/ASCT patients had significantly higher rates of estimated 36-month FFTF when they achieved actual FFTF at 3, 6, 12 and 24 months. Additionally, the rates of baseline characteristics predictive of TF at 36 months for either HDC/ASCT or CART19 patients were either similar to or significantly lower for CART19 patients compared to HDC/ASCT patients who achieved actual FFTF at 3, 6, 12, and 24 months. Patients with R/R DLBCL/HGBL achieving response to salvage immunochemotherapy who received HDC/ASCT had a high rate of estimated FFTF regardless of whether they harbored features predictive of resistance to salvage immunochemotherapy, which may be more durable than that of R/R DLBCL/HGBL patients receiving CART19. These findings support further investigation of disease characteristics, such as molecular features, that may predict response to salvage immunochemotherapy in patients fit for HDC/ASCT.

Patterns of treatment failure for PD-(L)1 refractory extensive-stage small cell lung cancer in continued PD-(L)1 treatment

BackgroundAlthough immunotherapy greatly extends overall survival (OS) of patients with extensive-stage small cell lung cancer (ES-SCLC), a number of patients develop immunotherapy resistance (IR). Patterns of failure in ES-SCLC are not clarified. Our study aims to explore the clinical pattern of IR and prognostic factors for these patients. MethodsThe study was conducted from 117 ES-SCLC patients with immunotherapy between 2018 and 2022. Chi-square tests and Fishers' exact tests was used to explore failure patterns in different populations. Survival analyses of different progression patterns and subsequent treatment regimens were conducted by Kaplan–Meier curves and log-rank test. Results86 (73.5%) patients experienced IR. The patients with smoking (never smoker vs. current or ex-smoker, 59.5 % vs. 81.3%, P = 0.010), liver metastasis (extrahepatic metastasis vs. intrahepatic metastasis, 73.6 % vs. 90.9%, P = 0.050), and distant metastasis status (no distant metastasis vs. distant metastasis, 39.1 % vs. 81.9%, P<0.001) were associated with IR rates. Liver progression had a lower incidence in 1st line immunotherapy (1st line vs. ≥2nd lines, 14.0 % vs. 41.7%, P = 0.004) and a higher incidence in multiple progression (multiple progression vs. Oligo-progression, 39.4 % vs. 17.0%, P = 0.021). Cranial (41.7 % vs. 16.1%, P = 0.012) and distant lymph node (16.7 % vs. 3.2%, P = 0.049) progression were the main failure model for acquired IR in comparison to primary IR. Patients with new lesion progression only (17.73 vs. 9.17 months, P = 0.013) and non-hepatic progression (14.23 vs. 11.67 months, P = 0.042) had a longer OS. Patients in cross-line immunotherapy after IR had a favourable prognosis (17.07 vs. 11.93 months, P = 0.007). ConclusionThe most common failure pattern of immunotherapy for ES-SCLC was lung and regional lymph node progression. Brain and liver progression were the most common extra thoracic failure sites for 1st line and 2nd and more lines immunotherapy, respectively. There was a higher probability of primary IR in 2 lines and above immunotherapy. Patients with new only progression site and cross-line rechallenge immunotherapy had a better prognosis.

Dynamics of disease progression during treatment with Osimertinib in patients with EGFR T790M-positive non-small cell lung cancer.

Patterns of treatment failure and subsequent treatment in non-small cell lung cancer (NSCLC) patients treated with osimertinib are scarcely known. We analyzed the disease progression during osimertinib treatment to identify potential treatment strategies. We identified advanced NSCLC patients who commenced osimertinib treatment after progression on previous epidermal growth factor receptor (EGFR)-tyrosine-kinase inhibitor (TKI) from June 2014 to November 2018 from electronic records. Patients' tumor characteristics, efficacy outcomes, affected organs from radiology studies, and treatment modalities before and after osimertinib were analyzed. Eighty-four patients were included. At osimertinib initiation, bone (50.0%) and brain (41.9%) were the commonest single metastatic sites, whereas thoracic involvement (73.3%) was more frequent than bone (27.4%) or brain (20.2%) metastasis during disease progression on osimertinib. Oligo-progressive disease (PD) and central nervous system (CNS)-sanctuary PD were observed in 15 (17.9%) and 3 (3.6%) patients, respectively. Most patients without brain metastasis (BM) at osimertinib initiation remained BM-free (46/49, 93.9%), and 60% of patients (21/35) with pre-existing BM showed intracranial disease control despite extracranial PD. The resistance mechanisms to osimertinib were explored in 23 patients (27.4%), and T790M-loss was observed in 14 patients (60.9%) who had worse survival outcomes than those without T790M-loss (progression-free survival, 5.4 vs. 16.5 months, p = 0.02; overall survival, not reached, p = 0.03). PD during osimertinib treatment occurred preferentially in the thorax and pre-existing sites. Extracranial PD prevailed over intracranial PD regardless of baseline BM and prior brain radiation. These results support osimertinib's intracranial efficacy and may guide treatment strategies for EGFR-mutated NSCLC with BM.

Rationale and value of consolidative cranial local therapy in EGFR-mutant non-small cell lung cancer patients with baseline brain metastasis treated with first-line EGFR-TKIs.

To explore the rationale and value of consolidative cranial local therapy (CLT) in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) patients with brain metastases (BMs). EGFR-mutant NSCLC patients with baseline BMs who received first-line EGFR-tyrosine kinase inhibitors (TKIs) at two academic centers from May 2015 to June 2020 were retrospectively enrolled. Patterns of tumor response and treatment failure were extensively analyzed in order to explore the rationale of CLT. Cranial lesions with number ⩽3 and largest tumor size ⩽3 cm at baseline and best response to EGFR-TKIs were defined as oligo-BMs and oligo-residual cranial disease (ORCD), respectively. To provide preliminary data supporting CLT, survival outcomes were compared in patients with ORCD, stratified by CLT status. Of the 216 patients enrolled, 57.1% had oligo-BMs and 24.5% received first-line osimertinib. At best response to the first-line EGFR-TKIs, intracranial complete response, partial response, and stable disease occurred in 18.5, 31.9, and 44.4% of the whole population, respectively. For patients without CLT (n = 193), ORCD was observed in 78.1% of the 105 patients with baseline oligo-BMs and 10.2% of the 88 patients with baseline multiple-BMs. With a median follow-up of 22.8 months, 107 patients had cranial first progressive disease (PD); more than 60% developed their first PD solely from the residual tumor sites at best response to EGFR-TKIs. Moreover, among patients with ORCD (n = 108), patients who received CLT (n = 17) achieved significantly longer progression-free survival (13.4 versus 8.5 months, p = 0.001) and overall survival (58.9 versus 28.8 months, p = 0.021) than those without CLT. Meanwhile, CLT remained as an independent prognostic factor associated with improved survival after Cox regression analyses. Cranial progressive disease developed mostly at the residual cranial lesions in EGFR-mutant NSCLC patients with baseline BMs who received first-line EGFR-TKIs. Consolidative cranial local therapy targeting the oligo-residual cranial tumor lesions may provide survival benefit, which warrants future validation.

Pattern of failure and clinical value of local therapy for oligo-recurrence in locally advanced non-small cell lung cancer after definitive chemoradiation: Impact of driver mutation status.

Considerable differences of treatment response and pattern of failure may exist between definitive chemoradiation (CRT) treated locally advanced non-small cell lung cancer (LA-NSCLC) patients. The clinical value of additional tyrosine kinase inhibitors (TKIs) before disease recurrence and salvage local therapy after initial recurrent disease remain controversial. Consecutive LA-NSCLC patients receiving definitive CRT and having definite results about driver mutations (EGFR, ALK and ROS1) were retrospectively reviewed. Initial recurrent disease was classified as in-field recurrence, out-of-field recurrence and distant metastasis. Recurrent disease occurred only in the brain or limited to ≤3 extra-cranial organs and ≤5 extra-cranial lesions, was defined as oligo-recurrence. Progression free survival and overall survival (OS) were calculated from diagnosis to disease progression or death, and to death, respectively. OS2 was measured from initial disease recurrence to death among patients who had recurrent disease. Of the 153 enrolled patients, 39 had driver mutations and 13 received additional TKI therapy besides definitive CRT. Patients harboring driver mutations but without additional TKI therapy had a similar PFS and significantly longer OS (p=0.032) than those without driver mutations. Additional TKI therapy prolonged PFS (p=0.021) but not OS among patients with driver mutations. No significant difference of pattern of failure was observed between patient subgroups stratified by the status of driver mutations and the usage of additional TKI therapy. Furthermore, 57 of the 95 patients with initial recurrent disease developed oligo-recurrence and salvage local therapy significantly improved OS2 (p=0.01) among patients with oligo-recurrence disease. LA-NSCLC patients receiving definitive CRT generally had similar PFS and pattern of treatment failure, regardless of driver mutation status. Additional TKI therapy besides definitive CRT could prolong PFS but not OS. The majority of recurrent disease after definitive CRT belongs to oligo-recurrence and salvage local therapy may provide survival benefit.

Evaluating the relationship between vaginal apex “dog ears” and patterns of recurrence in endometrial cancer following adjuvant image guided vaginal cuff brachytherapy

PURPOSEThe aim of this investigation is to characterize vaginal apex “dog ears” and their association with patterns of treatment failure in patients with endometrial cancer treated with adjuvant high-dose-rate (HDR) single-channel vaginal cuff brachytherapy (VCB). METHODSA retrospective review of patients treated with HDR VCB from 2012 to 2021 for medically operable endometrial cancer at a single institution was conducted. Dog ears, defined as tissue at the apex extending at least 10 mm from the brachytherapy applicator were identified on CT simulation images. Fisher exact test and a multivariate logistic regression model evaluated the association between factors of interest with treatment failure. Vaginal cuff failure free survival (VCFFS) was calculated from first brachytherapy to vaginal cuff recurrence (VCR). RESULTSA total of 219 patients were reviewed. In this sample, 57.5% of patients met criteria for having dog ears. In total, 13 patients (5.9%) developed a VCR. There was no statistically significant difference in the rate of VCR between patients with and without dog ears (7.1% vs. 4.3%, p = 0.56). There was a trend toward increased risk of recurrence with higher grade histology identified in the multivariate logistic regression model (p = 0.085). The estimated 3-year probability of VCFFS was 86%. CONCLUSIONSVaginal apex dog ears are prevalent but are not found to statistically increase the risk of VCR after VCB in our single institution experience. However, while local failure remains low in this population, we report an absolute value of over twice as many VCRs in patients with dog ears, indicating that with improved dog ear characterization this may remain a relevant parameter for consideration in treatment planning.