Comparable Progression-free Survival Research Articles

Prognostic Significance of Double-Expresser Status in Diffuse Large B-cell lymphoma: Experience from a Tertiary Care Cancer Centre in India

Background: Diffuse large B-cell lymphoma (DLBCL) is a neoplasm of medium or large B lymphoid cells with a diffuse histopathologic growth pattern. Co-expression of MYC and BCL2 proteins in DLBCL by immunohistochemistry (IHC) is referred to as the double-expresser (DE) phenotype and is associated with inferior survival. Objectives of this study were to assess the DE status in DLBCL and to assess its utility in predicting the prognosis in DLBCL. Methods: This was a retrospective study conducted in a tertiary care cancer centre. Study population included all the cases of DLBCL, NOS diagnosed in the centre in 2012. MYC and BCL2 protein expression were analysed by immunohistochemistry. The prognostic significance of double-expressers was analysed by comparing progression free survival (PFS) and overall survival (OS) of double-expressers and non-double expressers using appropriate statistical methods. All the data were analysed using SPSS 11 software. Kaplan-Meier method was used to estimate the survival probability. A significant difference in survival between various prognostic factors was tested using the log-rank test. Prognostic factors were assessed using univariate and multivariate Cox-regression model. A P- value < 0.05 was considered to be statistically significant. Results: Double-Expresser lymphoma (DEL) constituted 22.2% (n=18) of all cases of DLBCL, NOS. DE status was associated with shorter PFS (P-value = 0.049) and OS (P-value = 0.015). Conclusion: DE status is associated with poor prognosis in DLBCL, NOS. Assessment of MYC and BCL2 by IHC represents a rapid and inexpensive approach to risk-stratify patients with DLBCL at the time of diagnosis.

Abstract PO5-04-01: Inetetamab combined with sirolimus and chemotherapy in HER2 positive metastatic breast cancer patients with abnormal activation of Pi3k/Akt/mTOR pathway after trastuzumab treatment

Abstract Objective: To explore the efficacy and safety of Inetetamab Combined with Sirolimus and Chemotherapy in the treatment of human epidermal factor receptor 2 (HER2) positive metastatic breast cancer patients with abnormal activation of Pi3k/Akt/mTOR (PAM) pathway after Trastuzumab treatment. Methods: This prospective multicenter clinical study enrolled HER2 positive metastatic breast cancer patients at the National Cancer Center in China from July 2021 to September 2022 with PAM pathway mutation confirmed by histology or peripheral blood genetic testing. The inclusion criteria included: 1) Recurrent and metastatic breast cancer patients with HER2 positive confirmed histologically; 2) ECOG PS score ≤ 2; 3) Patients who have progressed after previous treatment with Trastuzumab; 4) Patients with PAM pathway mutation confirmed by Genetic testing; 5) Patients' cardiac, pulmonary, liver and bone marrow functions are basically normal; 6) Patients voluntarily sign informed consent forms. The exclusion criteria included: 1) Patients previously treated with mTOR inhibitors or pyrotinib; 2) Patients who have used chronic Corticosteroid for more than 3 months or used Immunosuppressive drug within 4 weeks; 3) Patients with symptomatic central nervous system metastasis; 4) Patients with left ventricular Ejection fraction< 50% or clinical manifestations of obvious arrhythmia, myocardial ischemia, severe atrioventricular block, cardiac insufficiency, and severe valvular disease; 5)Diagnosed with other malignant tumors within five years. Patients were randomly divided into trial group and control group. The patients in the trial group received inetetamab combined with sirolimus and chemotherapy, and control group received pyrotinib and chemotherapy. RECISTv1.1 standard was used to evaluate the efficacy of patients. Descriptive statistics are used to summarize clinical pathological features. Kaplan Meier method was used to draw survival curves. Log-rank test was used to compare progression free survival (PFS) differences between groups. P< 0.05 was considered statistically significant. Results:A total of 59 HER2 positive metastatic breast cancer patients with abnormal activation of PAM pathway were included, of which 37 patients received the treatment of inetetamab group and 22 patients received the treatment of pyrotinib group. The median follow-up time was 5.33 months. In the intent-to-treat set, the median PFS of patients in the inetetamab group was 4.64 months, which was shorter than 5.69 months in the pyrotinib group. There was no statistically significant difference between the two groups (P=0.51; HR=0.41; 95% CI, 0.12-1.45). The objective response rate (ORR) of the inetetamab group and the pyrotinib group were 28.1% and 29.4%, respectively. In terms of safety, the incidence of adverse events (AE) in the experimental group was (33/37) 89.1%, while (16/21) 76.2% in the control group. The incidence of AE above level 3 in the inetetamab group and pyrotinib group were (13/37) 35.1% and (3/21) 14.3%, respectively. Conclusion:For the metastatic HER2 positive breast cancer patients with abnormal activation of PAM pathway treated with trastuzumab previously, the combination of inetetamab with sirolimus and chemotherapy regimen are equivalent to the combination of pyrotinib and chemotherapy regimen. It demonstrated that combination of inetetamab with sirolimus and chemotherapy could be one of the treatment options for the metastatic HER2 positive breast cancer patients. Citation Format: Qiao Li, Dan Lv, Xiaoying Sun, Mengyuan Wang, Li Cai, Feng Liu, Chenghui Li, Jiuda Zhao, Jing Sun, Yehui Shi, Fei Ma. Inetetamab combined with sirolimus and chemotherapy in HER2 positive metastatic breast cancer patients with abnormal activation of Pi3k/Akt/mTOR pathway after trastuzumab treatment [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-04-01.

The efficacy and safety of adding anlotinib in gradual progression on third-generation EGFR-TKIs for EGFR-mutant advanced nonsmall cell lung cancer.

Acquired resistance is unavoidable with the approval of third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for first-line therapy of advanced non small cell lung cancer (NSCLC). Some studies have found that combining antiangiogenesis medicines with EGFR-TKI may benefit clinical outcomes in EGFR-mutant NSCLC. However, it is unclear whether EGFR-TKI paired with antiangiogenesis therapy could further improve survival for patients with gradual progression. Thus, we comprised the clinical effectiveness and safety of continuous EGFR-TKI in combination with anlotinib and EGFR-TKI alone in patients who had gradual progression on third-generation EGFR-TKI treatment. The comparison of progression-free survival (PFS) and overall survival(OS) between two groups used the Kaplan-Meier method. Our study comprised 121 eligible patients in total. The objective response rates were 25.0% and 0%, and the disease response rate was 91.7% and 86.9% in the combination group and EGFR-TKIs monotherapy group. The median PFS of combined anlotinib and EGFR-TKI treatment was 6.7 months and the median PFS was 3.6 months in the EGFR-TKI monotherapy group ( P < 0.001). There were no significant differences between the two groups in OS. The common adverse reactions were diarrhea (21.7%), hypertension (21.6%) and proteinuria (20.0%) in the combination group. Seven patients experienced a grade 3 or higher adverse event, no patients discounted the treatment or died due to the toxicity. Our study indicated that, when combined with anlotinib following gradual progression on EGFR-TKIs, it was more efficacious for EGFR-mutant NSCLC patients than EGFR-TKI monotherapy. And the toxicity was clinically manageable.

Prevalence and prognosis of PIK3CA mutations in Bulgarian patients with metastatic breast cancer receiving endocrine therapy in first-line setting.

In approximately 40% of patients with HER2-negative/HR-positive breast cancer tumors, the PIK3CA gene is mutated. Despite this, clinical outcomes vary between studies in this cohort. We aimed to ascertain the prevalence of PIK3CA mutations in patients with metastatic HR+/HER2- breast in Bulgaria, as well the evaluation and comparison of progression free survival (PFS) between wild-type (WT) and mutation-positive groups in the real-world setting. Three oncology centers in Bulgaria collected 250 tissue samples between 2016 and 2022 for this multicentric retrospective study. PIK3CA mutations were identified using Real-Time qPCR. The median follow-up period was 35 months. The mean age of the mutant cohort was 57.6 ± 11.6 years, compared to 56.5 ± 12.2 years for the WT cohort (p = .52). The percentage of patients with visceral metastasis was 58.8% (n = 147). Approximately 84.3% (n = 210) of the patients had reached postmenopause. 29.2% (n = 73) of the patients had PIK3CA mutations. The predominant mutation was present in exon 20, H1047R (46.5%). We found a significant correlation only between the presence of a mutation and the metastatic diseases at diagnosis (p = .002). As first-line therapy, 67.1% of patients received endocrine therapy (ET) plus cyclin dependent kinase (CDK4/6) inhibitor, while the remainder received ET alone. The median PFS of patients in the group with the mutation was 32 months (95%, CI: 22-40) compared to 24 months in the WT cohort ((95%, CI: 21-36) (p = .45)); HR = 0.86 (95%, CI: 0.5-1.3) (p = .46). We corroborated our conclusion using propensity matching score analysis, (36 months [95% CI: 20-40] vs. 26 months [95% CI: 21-38], [p = .69]). We found that the prevalence of PIK3CA mutations in our patients was comparable to what has been reported in other nations. Our results suggest that PIK3CA mutational status has no bearing to ET efficacy in first-line setting.

Improved Survival of R/R Double Hit/Triple Hit Lymphoma in the Era of CD19 Chimeric Antigen T Cell (CART) Therapy

Introduction: DH/THL also classified as high-grade B cell lymphomas (HGBCL) with MYC and BCL2 and/or BCL6 rearrangements have higher risk of progression after initial treatment and poor response to salvage therapies compared to diffuse large B cell lymphoma (DLBCL), NOS. Recently, CART cell therapy has shown encouraging responses in treatment of relapsed refractory (R/R) DLBCL. In this retrospective study, we evaluated whether survival of (R/R) DH/THL is improved in the CART era. Methods: In this multicenter retrospective study, adult pts (pts) with R/R DH/THL after anthracycline-based therapy were included. Demographic and clinical variables were obtained from electronic health records. Study objectives was overall survival (OS) at 2 year landmark. We utilized full propensity score matching to compare progression free survival (PFS) and OS of CART with 2 nd line chemoimmunotherapy. Results: 278 DH/THL pts treated between 2010-2020 were included. Median age was 63 years (range 52-74), 163 (58%) were male, 119 (43%) were classified as DLBCL and 116 (42%) as HGBCL; 40 (14%) were transformed from follicular lymphoma. 225 (82%) had advanced stage, 161 (67%) had elevated LDH, 85 (33%) had bulky disease, 74 (59%) had B symptoms. 105 (38%) pts treated for relapsed disease before 2018 were included in the pre-CART era cohort. 168 (60%) pts treated from 2018 onwards were included in the CART era cohort. 102 (60%) pts in CART cell era received CART cells, 40 (14%) received polatuzumab vedotin (pola), 10 (3.5%) received loncastuximab tesirine, tafasitamab and bispecific antibody each. Characteristics at relapse were similar in both groups. Median follow up was 8.9 (0.2-146) months. 2-year OS estimate was 36% (CI 95: 30-42%) in entire population. Patients treated in CART cell era had significantly higher OS (2 yr OS: 43% [CI 95: 35-53]) compared to pts treated in pre-CART cells era (2-year OS: 24% [CI 95: 16-34], p=0.0006) (Figure 1). In multivariable analyses, increasing age (HR = 1.02 (CI 95: 1.01, 1.04), p=0.003), extranodal disease (HR = 1.41 (CI 95: 1.00, 1.99), p&amp;lt;0.001), elevated LDH (HR = 1.57 (CI 95: 1.11, 2.24), p=0.01) were associated with inferior OS. Increasing time to relapse (HR = 0.98 (CI 95: 0.97, 0.99), p&amp;lt;0.001) was associated with superior OS. BCL6 rearrangement did not affect OS. When adjusted for these factors, treatment with CART cells was associated with higher 2 yr OS (HR = 0.33 (CI 95: 0.22, 0.49), p&amp;lt;0.001). Treatment with polatuzumab (HR = 1.07 (CI 95: 0.71, 1.6), p=0.07) was not significantly associated with OS in univariable analysis. 102 pts underwent CART cell therapy at any point for relapse; 94 (93%) were refractory to prior chemotherapy. 62 (60%) responded and 52 (50%) had CR after CART cells. 2-year PFS and OS after CART cell therapy were 28% (CI 95: 19-40) and 40% (CI 95: 30-53), respectively. Increasing time to CART was associated with inferior OS (HR: 1.02 (CI 95: 1.0-1.03, p=0.03) but not PFS (HR: 1.02 (CI 95: 0.99-1.04), p=0.2). 219 (79%) pts received curative intent salvage chemotherapy for 2 nd line. 2-year PFS and OS were 15% (CI 95: 11-20) and 38% (CI 95: 31-45), respectively. 21 pts received CART cell therapy for 2 nd line. 2 year PFS and OS in this small number of pts were 52% (CI 95: 35-79) and 70% (CI 95: 52-94), respectively. Due in part to the small number of pts who received CART cells in 2 nd line, we utilized full propensity score matched analysis to compare each patient in CART cell group to all possible matched controls in salvage chemotherapy group. Variables matched were age, LDH, extra nodal disease and time to relapse. In propensity score matched analysis, pts who received CART cells had significantly higher 2 year PFS (HR: 10.5 (CI 95: 3.4-17.5), p=002) and 2 year OS (HR: 7.5 (CI 95: 1.4-13), p=0.01). Conclusions: Survival of r/r DH/THL appears to have improved in the era of CART cell therapy. About 2/3 of pts refractory to chemotherapy respond to CART cells, and in multivariable analysis, receipt of CART cells was associated with improved OS. Increasing time to CART cells was associated with inferior survival. In a propensity score matched analysis utilizing full matching, CART cell therapy in 2 nd line was associated with significantly higher 2 year PFS and OS compared to curative intent salvage therapy. Other CD 19 and CD 20 targeting agents approved after CART cell therapy might contribute to favorable survival, effect of these agents could not be assessed because of small numbers.

Evaluation of tumour size and rete testis invasion in progression free survival of our patients with stage i testicular seminoma. A retrospective observational study of a reference hospital center and literature review

IntroductionThe aim of this study was to evaluate the impact of tumour size and rete testis invasion in progression free survival of our patients with stage I testicular seminoma. A literature review is also made. Material and methodsA retrospective observational study was performed. We included patients with stage I seminoma between January 2010 and July 2022. Patients without factors of poor prognostic –Group A– were compared with patients with factors of poor prognostic –Group B–. Kaplan-Meier curves and log-rank testing were used to compare progression free survival (PFS) between these groups. Statistical significance was considered at P≤.05. Results55 patients were included in this study. 20 patients (36.4%) were of good prognostic –Group A– and 35 (63.6%) had factors of poor prognostic –Group B–. The mean age was similar in both groups (mean±standard deviation), 38.62±9.04 years. The mean follow-up time was 63.5±33.6 months. All the patients in group A and 25.7% of the patients in group B underwent active surveillance (AS). 26 patients (74.3%) of the patients in Group B were treated with one cycle of adyuvant carboplatin. Three patients suffered a relapse with retroperitoneal lymph nodes (10.3%), all of them were treated with three cycles of BEP, with a complete response of the disease. No statistical significant differences were found in PFS between Group A and B (log Rank P=.317). ConclusionIndividualization of adjuvant treatment in stage I seminoma is important, avoiding the adverse effects derived from them.

Severe hypertension development significantly improves progression-free survival in regorafenib treatment for metastatic colorectal cancer.

Regorafenib is the first multikinase inhibitor used for metastatic colorectal cancer (mCRC) treatment. Reports regarding other multikinase inhibitors have suggested that the development of hypertension is associated with improved clinical benefits. We aimed to reveal the relationship between the development of severe hypertension and regorafenib efficacy in an mCRC real-world setting. Patients with mCRC (n = 100) who received regorafenib were assessed retrospectively. The primary endpoint was a comparison of progression-free survival (PFS) between patients with and without ≥ grade 3 hypertension. The secondary endpoints were overall survival (OS), disease control rate (DCR), and adverse effects. Patients developing ≥ grade 3 hypertension accounted for 30%, and obtained significantly longer PFS than control patients (median PFS of 53 and 56days, 95% confidence interval [CI] of 46-144 and 49-63days, respectively; P = 0.04). In contrast, OS and DCR were not statistically different between the groups (P = 0.13 and P = 0.46, respectively). The incidence and severity of adverse effects were not significantly different, except for hypertension. Treatment interruption was significantly more frequent in patients with hypertension (P = 0.04). Multivariate Cox hazard analysis suggested that the development of ≥ grade 3 severe hypertension was an independent factor for improved PFS (adjusted hazard ratio 0.57, 95% CI 0.35-0.93; P = 0.02). In contrast, baseline hypoalbuminemia was associated with a worse PFS (1.85, 1.14-3.01; P = 0.01). We have revealed that patients who develop severe hypertension after regorafenib treatment for mCRC have improved PFS. Management of hypertension is important for effective treatment with less burden; therefore, further evaluation is needed.

Randomized phase 3 study of tarlatamab, a DLL3-targeting bispecific T-cell engager (BiTE),compared to standard of care in patients with relapsed small cell lung cancer (DeLLphi-304).

TPS8611 Background: Small cell lung cancer (SCLC) is an aggressive malignancy for which very few patients achieve long term disease control; response to most treatments is transient and second line treatment options are limited. Delta-like ligand 3 (DLL3) is a Notch ligand aberrantly expressed on the surface of up to 85% of SCLC cells and minimally expressed in normal tissues, making it an attractive therapeutic target. Tarlatamab is a bispecific T cell engager (BiTE) molecule designed to bind DLL3 on target cancer cells and CD3 on T cells, thereby driving T cell-dependent killing of tumor cells. Results from the first-in-human study in patients with relapsed/refractory SCLC (DeLLphi-300; NCT03319940) demonstrate tarlatamab efficacy in pretreated patients with confirmed responses in 23% of patients and median duration of response &gt; 12 months.1 Median overall survival (OS) was 13.2 months. Grade ≥ 3 treatment-related AEs (TRAEs) occurred in 31% of patients and TRAEs resulted in discontinuation in 4% of patients. This promising efficacy/safety profile is being evaluated further in a phase 2, open-label study in patients with relapsed/refractory SCLC after ≥2 lines of prior treatment (DeLLphi-301; NCT05060016). Methods: NCT05740566 is a randomized, open-label, phase 3 study of tarlatamab compared with standard of care (SOC) in ~700 patients with relapsed SCLC after platinum-based first-line chemotherapy. Patients will be randomized 1:1 to receive tarlatamab or SOC therapy (lurbinectedin or topotecan in US, Canada, Australia, Singapore, Korea; amrubicin in Japan; topotecan in all countries except Japan), stratified by prior anti-programmed cell death 1 (PD-1) or anti-programmed cell death ligand 1 (PD-L1) exposure, chemotherapy-free interval, presence of brain metastases, and SOC (topotecan/amrubicin vs lurbinectedin). The primary objective is to compare the efficacy of tarlatamab with SOC on prolonging OS. Key secondary endpoints include comparison of progression free survival (PFS) based on investigator assessment per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) and patient-reported outcomes (PRO) including disease-related symptoms, physical function, and global health status of quality of life. Key eligibility criteria include adults with histologically or cytologically confirmed relapsed SCLC who progressed following 1 platinum-based regimen. Patients must have measurable lesions as defined per RECIST 1.1 within the 21-day screening period and must have adequate organ function. Exclusions include untreated or symptomatic central nervous system metastases, history of immune checkpoint inhibitor use resulting in severe immune-mediated adverse event, and previous history of NSCLC. Enrollment is ongoing.

Impacto del tamaño tumoral y la invasión de la rete testis en la supervivencia libre de progresión de nuestros pacientes con seminoma testicular en estadio I. Estudio observacional retrospectivo en un hospital de referencia y revisión bibliográfica

IntroductionThe aim of this study was to evaluate the impact of tumour size and rete testis invasion in progression free survival of our patients with stage I testicular seminoma. A literature review is also made. Material and methodsA retrospective observational study was performed. We included patients with stage I seminoma between January 2010 and July 2022. Patients without factors of poor prognostic –Group A– were compared with patients with factors of poor prognostic –Group B–. Kaplan-Meier curves and log-rank testing were used to compare progression free survival (PFS) between these groups. Statistical significance was considered at P ≤ .05. Results55 patients were included in this study. 20 patients (36.4%) were of good prognostic –Group A– and 35 (63.6%) had factors of poor prognostic –Group B–. The mean age was similar in both groups (mean ± standard deviation), 38.62 ± 9.04 years. The mean follow-up time was 63.5 ± 33.6 months. All the patients in group A and 25.7% of the patients in group B underwent active surveillance (AS). 26 patients (74.3%) of the patients in Group B were treated with one cycle of adyuvant carboplatin. Three patients suffered a relapse with retroperitoneal lymph nodes (10.3%), all of them were treated with three cycles of BEP, with a complete response of the disease. No statistical significant differences were found in PFS between Group A and B (log Rank P = .317). ConclusionsIndividualization of adjuvant treatment in stage I seminoma is important, avoiding the adverse effects derived from them.

Ipilimumab with atezolizumab-bevacizumab in patients with advanced hepatocellular carcinoma: The PRODIGE 81-FFCD 2101-TRIPLET-HCC trial.

A substantial proportion of patients with hepatocellular carcinoma have to face up, sooner or later, to systemic therapy. The current standards as first line systemic therapies are either atezolizumab (anti-PD-L1) plus bevacizumab (anti-VEGF), or durvalumab (anti-PD-L1) plus tremelimumab (anti-CTLA-4). However, the median overall survival remains below 20 months, and a minority of patients become long-term survivors. Of interest in immune-oncology strategies for hepatocellular carcinoma, the objective response seems to be the most reliable surrogate marker of better overall survival. TRIPLET-HCC (NCT05665348) is a multicentre, randomised, open-label phase II-III trial designed to evaluate efficacy and safety of the triple combination by the addition of ipilimumab (anti-CTLA-4) to atezolizumab/bevacizumab, versus the double atezolizumab/bevacizumab combination. The main inclusion criteria are histologically proven BCLC-B/C HCC without previous systemic therapy. The primary objective of the phase II is the objective response rate in the triple arm, and OS in the triple versus double arms in the phase III. Secondary endpoints common to the phases II and III are the comparisons of progression-free survival, objective response rates, tolerance and quality of life. In addition, genetic and epigenetic studies from tissue and circulating DNA/RNA will be conducted to assess their prognostic or predictive value.

Real-world treatment and outcomes of patients with metastatic BRAF mutant colorectal cancer.

BRAF mutation occurs in 5%-10% of metastatic colorectal cancers (mCRCs). Patients with BRAF mutant mCRC exhibit a specific metastatic pattern and poor prognosis. Survival outcomes are heterogeneous in cases of mCRC with a BRAF mutation. The optimal first-line therapy is still controversial. We retrospectively reviewed the medical records of patients with mCRC between June 2010 and December 2021. Clinicopathologic characteristics, treatment and BRAF mutation testing results were collected. Patients with a BRAF mutation were included. Kaplan-Meier methods and log-rank tests were used to analyze and compare survival. Cox proportional hazards regression was used to establish the predictive nomogram model. Of the 4475 mCRC, 261 have a BRAF mutation, including 240 V600E and 21 non-V600E mutants. The median overall survival (OS) was 18.2months in the BRAF V600E mutant group versus 38.0months in the non-V600E mutant group (p=0.022). ECOG score, tumor differentiation, liver metastasis, bone metastasis and primary tumor resection were independent prognostic factors for the OS of BRAF V600E mutant mCRC. A nomogram model was established using these factors. The median OS was 39.3m, 18.2m and 10.7m for the low-risk, intermediate-risk and high-risk groups defined by this model, respectively (p < 0.0001). Patients who received first-line triplet chemotherapy ± bevacizumab had comparable progression free survival (PFS) and OS compared with those treated with doublets ± bevacizumab. BRAF V600E mutant mCRCs exhibit unfavorable and heterogeneous prognosis. The first-line intensive chemotherapy did not confer a marked impact on the PFS and OS.

Abstract P4-02-18: Impact of clonal hematopoiesis on disease progression following CDK4/6 inhibitor therapy

Abstract Background Clonal Hematopoiesis (CH) is a well-established risk factor for adverse clinical outcomes including all-cause mortality, cardiovascular disease, and progression to hematologic malignancies. The presence of CH has been shown to adversely impact overall survival in non-hematologic cancers, however whether CH modulates response to specific therapies in breast cancer is not known. Here we investigate the impact of CH mutations on disease progression in patients with metastatic estrogen receptor (ER) positive breast cancer undergoing treatment with first line CDK4/6 inhibitors and endocrine therapy (CDK4/6i+ET). Methods We analyzed data from a well annotated cohort of patients with ER+ breast cancer who received endocrine therapy and CDK4/6 inhibitors. All patients underwent prospective tumor and matched WBC sequencing utilizing the MSK-IMPACT assay. CH variants were detected in blood samples utilizing the well-validated variant detection and filtration pipeline of MSK-IMPACT. CH mutations were defined as putative drivers (CH-PD) or non-putative drivers (CH) as previously described. To ensure the presence of CH at the time of therapy initiation, only patients who had CH sampling performed from 6 months before through 4 months after initiation of CDK4/6i+ET were included. We compared progression free survival (PFS) in patients with and without CH, as well as by CH-PD status and DNMT3A CH mutations. We investigated clinical covariates including type of endocrine therapy, receipt of prior neoadjuvant or adjuvant chemotherapy, and age at start of CDK4/6i+ET. Results The final cohort was comprised of 378 patients, of whom 135 (35.7%) had CH. The median time between sample collection and CDK4/6i+ET initiation was 0 (IQR -0.79 to 0.47 months). Patients with CH were older at time of therapy initiation (median 63.0 versus 54.7 years, p &amp;lt; 0.001). There were no significant differences between groups in terms of endocrine therapy (aromatase inhibitor or fulvestrant), prior chemotherapy, and time from CH sample collection to CDK4/6i+ET start. Univariate Cox-proportional hazard analysis did not reveal a difference between progression free survival and overall CH (HR 0.96, 95% CI 0.75 – 1.23, p = 0.76), CH-PD (HR 1.05, 0.77 – 1.43, p = 0.77), or DNMT3A mutations (HR 1.12, 0.80 – 1.60, p = 0.52) compared to patients without CH. Interestingly, age less than 60 years was found to be associated with PFS outcome (univariate HR 1.57, 1.22 – 2.01, p = 0.0004). Multivariate analysis adjusted for endocrine therapy partner and age at CDK4/6i+ET therapy did not reveal an association between outcome and overall CH (HR 1.07, 0.83 – 1.39, p = 0.59). In patients younger than age 60, presence of overall CH did not confer a significant PFS difference (HR 0.90, 0.63 – 1.29, p = 0.57). In the subset of patients older than 60 (n = 168) presence of CH conferred numerically, but not statistically, significant shorter PFS (HR 1.41 [0.96 – 2.09], p = 0.08). In this population, CH-PD conferred a shorter PFS (HR 1.75, 1.12 – 2.72, p = 0.02). Conclusion We found that CH, CH-PD and DNMT3A CH mutations did not affect PFS among metastatic ER+ breast cancer patients treated with first line CDK4/6 inhibitors. Younger age was associated with increased risk of progression, warranting further investigation. In the subset of patients with age older than 60, CH-PD conferred a shorter PFS. Further data, incorporating records of dose reductions, will be presented at the meeting. Citation Format: Jacqueline Tao, Pablo Sanchez Vela, Anton Safonov, Emanuela Ferraro, Sebastia Franch Exposito, Kamal Menghrajani, Ryan Ptashkin, Elizabeth Comen, Lior Z. Braunstein, Mark E. Robson, Sarat Chandarlapaty, Jorge Reis-Filho, Michael Berger, Ahmet Zehir, Larry Norton, Ross Levine, Pedram Razavi. Impact of clonal hematopoiesis on disease progression following CDK4/6 inhibitor therapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-02-18.

Abstract OT3-26-01: CCTG MA40: DOUBLE-BLIND PLACEBO CONTROLLED PHASE III TRIAL OF FULVESTRANT AND IPATASERTIB FOR ADVANCED HER-2 NEGATIVE AND ESTROGEN RECEPTOR POSITIVE (ER+) BREAST CANCER POST FIRST LINE CDK 4/6 AND AROMATASE INHIBITOR THERAPY (FINER)

Abstract Background: The PI3K/AKT/mTOR pathway is a rational target in the metastatic disease setting for hormone receptor positive breast cancer based on preclinical and clinical data demonstrating that pathway inhibition improves outcome (Baselga 2012, Andre 2019, Jones 2019). Combining fulvestrant and AKT inhibition demonstrated efficacy in pts with HR+aBC (Howell 2022). Ipatasertib is a potent, highly selective, small-molecule inhibitor of three isoforms of serine/threonine kinase AKT. We hypothesize that Ipatasertib plus fulvestrant will improve PFS compared to fulvestrant in the second line setting post disease progression on aromatase inhibitor (AI) + CDK 4/6 inhibitor therapy. Methods: MA40 is a double blind, placebo-controlled trial in patients with hormone receptor positive, HER2-negative breast cancer with prior progression on AI plus CDK4/6 inhibitor therapy. Patients are randomized to fulvestrant/ipatasertib 400 mg po days 1-21 every 28 day or fulvestrant/placebo. The primary objective is to compare Progression Free Survival (PFS) between arms (RECIST 1.1, investigator assessed). Secondary objectives include comparisons between arms: PIK3CA/AKT1/PTEN altered cohort and non-altered cohorts; PFS by Blinded Central Radiology Review (all enrolled patients, PIK3CA/AKT1/PTEN altered and non-altered cohorts), Response rate; Duration of Response; Clinical Benefit Rate; Overall Survival; Time to Commencement of Subsequent Line of Systemic Therapy or Death; Safety and Tolerability (CTCAE version 5.0); QOL (EORTC QLQ-C30, NCI PRO-CTCAE); Economic Evaluation, (healthcare utilization and health utilities(EQ-5D-5L)). Statistical Design: Allocation 1:1 balanced for: PIK3CA/PTEN/AKT1 mutation status (ctDNA analysis using FoundationOne®Liquid Platform) (altered vs wildtype/unknown); prior treatment duration with CDK4/6 inhibitor (&amp;lt; 6 months vs &amp;gt; 6 months) and centre. Sample size is 250 to detect a benefit in PFS with the addition of ipatasertib. Eligibility Criteria: Histologically and/or cytologically confirmed ER positive and HER-2 negative breast cancer by local assessment that is advanced; postmenopausal status; clinical and/or radiographic progression during treatment with or within 28 days after discontinuation of first line of treatment with a CDK 4/6 inhibitor and an AI; only one prior line of chemotherapy in the advanced setting. Conduct to Date: Enrollment is ongoing. Supported by Hoffmann-La Roche Limited, CCS Citation Format: Stephen K. Chia, David W. Cescon, Andrew D. Redfern, Danielle Rodin, Christine Simmons, Jean-Pierre Ayoub, Haji Ibrahim Chalchal, Daniel Rayson, Moira Rushton-Marovac, Tracey Hay, Lisa Gallinaro, Bingshu Chen, Wendy Parulekar. CCTG MA40: DOUBLE-BLIND PLACEBO CONTROLLED PHASE III TRIAL OF FULVESTRANT AND IPATASERTIB FOR ADVANCED HER-2 NEGATIVE AND ESTROGEN RECEPTOR POSITIVE (ER+) BREAST CANCER POST FIRST LINE CDK 4/6 AND AROMATASE INHIBITOR THERAPY (FINER) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-26-01.

A randomized study of consolidation chemo-radiotherapy versus observation after first-line chemotherapy in advanced gall bladder cancers (RACE-GB Study): trial protocol

Background: Chemotherapy (CT) is the standard of care for advanced gall bladder cancer (GBC). However, after completion of 6 cycles of CT, a proportion of patients with good performance status progress within a few months. Retrospective data in locally advanced cases revealed that consolidation chemo-radiotherapy (CTRT) in responders to CT and with good performance status improves overall survival. Methods: FNA proven advanced GBC with predefined clinical-radiological features will be administered 4 cycles CT (cisplatin-gemcitabine combination). After completion of CT, those in good Karnofsky performance status (KPS) will be randomised to consolidation CTRT versus observation (standard of care). The primary end point of the study is to compare OS between the two arms. The secondary end point is to compare progression free survival (PFS), toxicity, and quality of life between the two study arms. The trial is designed to detect an improvement in 2-year overall survival (OS) from 8% in the control arm to 25% in study arm with 80.0% power at a 0.05 significance level. The resultant sample size to achieve this aim is 140 (70 in each arm) over a duration of 4-5 years with a 10% attrition rate. Accrual has been from January 2019 to October 2022. Conclusions: This trial aims to assess the incremental gain in outcomes with consolidation CTRT versus observation in responders to first-line CT in advanced GBCs. This is the first randomised study to evaluate role of consolidation chemoradiation. Trial Registration: The trial is registered with clinical trials registry India (CTRI/2019/04/025204) and clinical trials.gov (NCT05493956).

SWOG/NRG S1914: A Randomized Phase III Trial of Induction/Consolidation Atezolizumab + SBRT vs. SBRT Alone in High Risk, Early-Stage NSCLC (NCT#04214262)

<h3>Purpose/Objective(s)</h3> Stereotactic radiotherapy (SBRT) is the standard of care for early stage, medically inoperable non-small cell lung cancer (NSCLC). While rates of in-field control exceed 90% in prospective trials, rates of regional and distant control after SBRT remain suboptimal, and adjuvant chemotherapy is rarely used in this typically frail patient population. SWOG/NRG S1914 is a randomized phase III trial testing the addition of neoadjuvant, concurrent, and adjuvant atezolizumab to SBRT for early-stage NSCLC. <h3>Materials/Methods</h3> Eligible patients have T1-3N0M0 NSCLC ≤7cm and are medically inoperable or declined surgery. Patients must have at least one risk factor suggestive of increased risk of recurrence: tumor diameter ≥2 cm, SUV_max ≥6.2, or moderately/poorly/undifferentiated differentiated histology. Patients are randomized 1:1 to standard-of-care SBRT or to neoadjuvant, concurrent, and adjuvant atezolizumab 1200 mg IV Q3 week with SBRT initiated with cycle 3. Standard SBRT schedules of 3-5 fractions with a BED ≥100 are permitted. Stratification factors include location (central versus peripheral), size (<4 cm versus ≥4cm), and Zubrod performance status (0-1 vs 2). The primary objective of the study is to compare overall survival between the arms. The accrual goal is 480 patients to achieve 432 eligible patients based on a design with 80% power to rule out a null hazard ratio at the 1-sided 0.025 level, if the true hazard ratio were 0.70. The estimated duration of accrual and follow-up are 60 and 36 months, respectively and includes 4 interim analyses evaluating early stopping for futility or efficacy. Secondary objectives include comparisons of progression free survival (PFS), distant, locoregional and local failure rates, toxicity, and quality of life (EORTC QLQ-C30 and EORTC QLQ-LC13). <h3>Results</h3> Enrollment began 08/13/2020. As of 02/23/2022, 284 sites have been approved to enroll patients. 80 patients have enrolled and undergone randomization. <h3>Conclusion</h3> SWOG/NRG S1914 is a randomized phase III trial testing the addition of neoadjuvant, concurrent, and adjuvant atezolizumab to SABR in early-stage NSCLC.

Induction Anti-PD-1 Immunotherapy plus Chemotherapy Followed by Definitive Chemoradiation Therapy in Locally Advanced Esophageal Squamous Cell Carcinoma: A Real-World Retrospective Study

<h3>Purpose/Objective(s)</h3> The addition of immunotherapy to chemotherapy significantly improved survival in patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC). Neoadjuvant immunotherapy plus chemotherapy was safe and effective in locally advanced resectable ESCC. However, little is known about its role in the induction setting before chemoradiation therapy in unresectable locally advanced ESCC. This study evaluated the efficacy of induction anti-PD-1 immunotherapy plus chemotherapy followed by definitive chemoradiation therapy (dCRT) in locally advanced ESCC. <h3>Materials/Methods</h3> Patient and treatment characteristics were collected on all consecutive locally advanced ESCC patients from November 2017 to December 2021 at our institution who were treated with dCRT, with or without induction anti-PD-1 immunotherapy plus chemotherapy. We compared progression free survival (PFS) and overall survival (OS) between the treatment groups by using the Kaplan-Meier method and Cox proportional hazards regression. <h3>Results</h3> In a total of 137 unresectable locally advanced ESCC patients who completed the treatment of dCRT, 62 (45.3%) of whom underwent induction anti-PD-1 immunotherapy plus chemotherapy before dCRT, and 75 (54.7%) of whom underwent dCRT only. Overall, with a median follow-up of 19.0 months (range, 4.2-59.3 months) for survivors, the median PFS and OS were 20.0 and 30.4 months, respectively. Patients with locally advanced ESCC who received induction anti-PD-1 immunotherapy plus chemotherapy before dCRT had a marginally longer PFS than those who received dCRT alone (28.8 vs. 15.9 months; hazard ratio 0.68, 95% CI 0.42-1.11; P = 0.128), with the 1-year PFS rate of 72.6% and 60.0%, respectively. The median OS of the patients who received induction anti-PD-1 immunotherapy plus chemotherapy before dCRT and those who received dCRT alone were not reached and 25.2 months, with the 1-year OS rate of 85% and 81.3%, respectively (hazard ratio 0.57, 95% CI 0.32-1.01; P = 0.058). <h3>Conclusion</h3> Compared with dCRT alone, induction anti-PD-1 immunotherapy plus chemotherapy followed by dCRT yields more favorable survival outcomes in patients with unresectable locally advanced ESCC. More prospective clinical studies should be warranted.

Comparison of Simultaneous Integrated Boost IMRT for Dose Escalation (54 Gy) and Conventional IMRT (45 Gy) Twice Daily Combined with Concurrent Chemotherapy for Limited-Stage Small-Cell Lung Cancer: Analysis of Two Prospective Trials

<h3>Purpose/Objective(s)</h3> Twice-daily thoracic radiotherapy (TRT) with concurrent chemotherapy is standard for limited-stage small-cell lung cancer (LS-SCLC). However, the importance of twice-daily simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) has not been clearly defined in LS-SCLC. Therefore, we conducted a prospective single arm, multicenter phase II study of SIB-IMRT for dose escalation (54 Gy) to the gross tumor volume for LS-SCLC. Here, we compared SIB-IMRT for dose escalation (54 Gy) to the gross tumor volume versus conventional intensity-modulated radiotherapy (IMRT) of standard-dose (45 Gy) twice-daily combined with concurrent chemotherapy in patients with LS-SCLC. <h3>Materials/Methods</h3> Sixty patients with LS-SCLC were entered from 2015 to 2021 in the phase II study of SIB-IMRT, and all 60 patients were treated with SIB-IMRT to the postchemotherapy tumor volume, as the SIB-IMRT group. In the SIB-IMRT group, the prescribed dose was 54Gy at 1.8 Gy twice daily to PGTV, and 45 Gy at 1.5 Gy twice daily to PCTV. We previously conducted a prospective phase III study on thoracic radiotherapy (TRT) target volumes for LS-SCLC (Cancer, 2020, 126(4), 840-849). In that study, from 2012-2017, 85 patients received thoracic IMRT to the postchemotherapy tumor volume, as the IMRT group. In the IMRT group, the prescribed dose was 45 Gy at 1.5 Gy per twice-daily fraction to both the planning gross tumor volume (PGTV) and the planning clinical tumor volume (PCTV). All of the 145 patients in both groups received concurrent chemoradiotherapy (CCRT) after completion of 2 cycles of induction cisplatin-etoposide chemotherapy, and received chemotherapy for 4 to 6 cycles in total. We compared progression free survival (PFS) and overall survival (OS) between the treatment groups by using the Kaplan-Meier method. <h3>Results</h3> Overall, with a median follow-up of 34.6 months, the median PFS and OS were 11.9 and 23.7 months, respectively. The patients in the SIB-IMRT group showed marginal longer PFS than those in the IMRT group (13.3 months versus 11.5 months; <i>p</i> = 0.08). The median OS of the SIB-IMRT and IMRT groups were 35.0 and 20.3 months, with the 2-year OS rate of 66.1% and 38.8%, respectively (<i>p</i> =0.007). For radiotherapy toxicity, grade 2 acute esophagitis was more common in the SIB-IMRT group, but grade≥3 esophagitis and grade≥2 pneumonitis was no difference in both two groups. <h3>Conclusion</h3> For LS-SCLC patients, SIB-IMRT for dose escalation (54 Gy at 1.8Gy twice daily) to PGTV benefited survival greatly. Our results suggest that SIR-IMRT is safe and effective for patients with LS-SCLC and should be further evaluated in a large prospective clinical trial.

Immune checkpoint inhibitors and tyrosine kinase inhibitors in patients with advanced hepatocellular carcinoma: Does the sequence matter?

Combination therapy with immune checkpoint inhibitor (ICI) and antivascular endothelial growth factor (anti-VEGF) is currently the first line treatment for advanced hepatocellular carcinoma (aHCC). However, there are many patients who may not be able to receive combination therapy due to underlying comorbidities or resource limitations. For these patients, systemic treatment options include single agent tyrosine kinase inhibitors (TKIs) or ICI monotherapy. However, whether an optimal sequence of systemic therapy exists remains unknown. We aim to explore the impact of sequencing of TKI and ICI therapy in terms of response rates and to examine the safety of their use in sequential order. Patients with aHCC treated with both ICI and TKI between December 30, 2013 and June 13, 2018 were retrospectively identified. Patients were classified into two groups: those who received TKI in the first-line (TKI1), followed by ICI (ICI2) and those who received ICI (ICI1) in the first-line followed by TKI (TKI2). The primary objective of the study was to identify differences in objective response rate (ORR) and disease control rate (DCR), as evaluated based on response evaluation criteria in solid tumor v1.1 for TKI1, TKI2, ICI1, and ICI2. Secondary objectives included comparison of progression free survival (PFS) for each line of therapy, overall survival (OS) and adverse events (AEs). Twenty-seven and 23 patients were classified into group 1 and 2, respectively. Objective response rates of TKI1 and TKI2 were 3.8% and 17.6%, respectively (p=.28); DCR to TKI1 versus TKI2 was 23.1% versus 35.3% (p=.49). ORRs of ICI1 and ICI2 were 8.7% and 14.3%, respectively (p=.66); DCR to ICI2 versus ICI1 was 56.5% versus 42.9% (p=.37). Median PFS was not significant between TKI1 and TKI2 (PFS 3.06 versus 1.61 months, p=.097) as well as between ICI2 and ICI1 (PFS 1.84 versus 2.37 month, p=.32). Median OS was also not significantly different between both groups (OS 20.63 versus 13.93 months, p=.20) on univariable and multivariable analysis (OS adjusted hazard ratio [HR] 2.07, 95% CI .83-5.18, p=.118). The proportion of patients who experienced adverse events of any grade was similar in both groups (TKI1 59.3% versus TKI2 52.2%; ICI1 78.3% versus ICI2 70.4%). Our study suggests that the sequence of TKI versus ICI therapy in patients with aHCC may not matter, given similar efficacy and toxicity profile when either agent is received in the first or second-line setting. This finding is of value in the real-world setting, where patients may be frail or have comorbidities that render them unable to tolerate combination therapy (ICI and TKI/anti-VEGF). For these patients, sequential exposure to both classes of drugs (ICI and TKI) may be a suitable option.

Progression-free Survival of Advanced Pancreatic Cancer in Iraqi Patients Treated with First-line Chemotherapy

Background: Pancreatic cancer is a highly aggressive cancer. According to the latest data published by the World Health Organization, the number of new cases in 2020 in Iraq was 674 and represented 2% of all new cancer cases. Most of the pancreatic adenocarcinomas have spread outside the pancreas at the time of diagnosis. Progression free survival is the time between the date of diagnosis to disease progression or death. The current study aims to compare progression free survival between three chemotherapy regimens; Gemcitabine, Gemcitabine/Nab-paclitaxel and FOLFIRINOX of advanced and metastatic pancreatic cancer in Iraqi patients. Methods: Patients were divided into three groups; patients who will receive Gemcitabine, those who will receive Gemcitabine/Nab-paclitaxel, and patients who will receive FOLFIRINOX. The patients were observed for disease progression by computed tomography which was performed every three months for the tumor response and progression. Results: In the Gemcitabine, Gemcitabine/Nab-paclitaxel, and FOLFIRINOX groups, the median Progression Free Survivals were (4, 5, and 5.7 months, respectively; p is less than 0.05), where FOLFIRINOX was superior to Gemcitabine monotherapy and Gemcitabine/Nab-paclitaxel. In addition, neutropenia, febrile neutropenia, diarrhoea, nausea, vomiting, fatigue, hypokalaemia and neuropathy were highly in the FOLFIRINOX-treated patients than in both Gemcitabine and Gemcitabine/Nab-paclitaxel groups of patients. However, anaemia and thrombocytopenia were higher with Gemcitabine and Gemcitabine/Nab-paclitaxel than were with FOLFIRINOX. Conclusion: The median Progression free survival is better for the Gemcitabine/Nab-paclitaxel and FOLFIRNOX than for Gemcitabine alone. Also, adverse effects are more common with FOLFIRINOX than with other first-line chemotherapeutic agents.

Efficacy of osimertinib in patients with EGFR mutant lung cancer harboring the uncommon exon 19 deletion, L747_A750&gt;P.

e21112 Background: EGFR exon 19 deletions (del19) are largely considered to have uniform sensitivity to EGFR tyrosine kinase inhibitors (TKIs). Approximately 70% of del19 tumors harbor the most common deletion, E756_A750del; however, many “uncommon” variants comprise the remainder of this group. In preclinical studies, the uncommon del19, L747_A750 &gt; P, demonstrates diminished sensitivity to the third generation TKI, osimertinib [. Identifying differences in clinical outcomes with osimertinib treatment could have therapeutic implications for patients (pts) with EGFR del19 non-small cell lung cancer (NSCLC). Methods: We conducted a multi-center retrospective cohort study of pts with metastatic EGFR del19 NSCLC treated with osimertinib. We compared progression free survival (PFS, time from TKI initiation to clinically significant growth of existing lesions or new lesions on imaging or death) and overall survival (OS) of pts with tumors harboring E746_A750del and L747_A750 &gt; P who received osimertinib in the first line (1L) or in second or later lines of therapy and were T790M+ (≥2L). The Kaplan Meier method and Cox model were used to estimate PFS and OS, and multivariable logistic regression was used to estimate the odds of achieving PFS &gt; 12 months. Multivariable analyses adjusted for baseline covariates- age, sex, race, and smoking. Results: From March 2013 to December 2021, 86 pts with EGFR E746_A750del and 36 with L747_A750 &gt; P were treated with osimertinib. For 1L osimertinib, E746_A750del was associated with significantly prolonged PFS vs. L747_A750 &gt; P (median 21.3 months (95% CI 17.0-31.7) vs. 11.7 months (10.8-29.4)) in the adjusted analysis (hazard ratio [HR] 0.52 [95% CI, 0.28-0.98, p = 0.043]). Pts with the common del19 mutation were more likely to achieve PFS &gt; 12 months with 1L osimertinib than those with the L747_A750 &gt; P mutation (Odds Ratio 4.14 (1.41-12.15), p 0.0097). OS exhibited a similar trend with a median OS that that was not reached (NR) at 40 months of follow-up among those with E746_A750del vs 26 months for L747_A750 &gt; P (adjusted HR 0.52 [95% CI, 0.23-1.19], p = 0.120). For pts treated with ≥2L osimertinib, there was also a trend towards favorable PFS and OS for pts with tumors harboring E746_A750del. Conclusions: The del19 mutation L747_A750 &gt; P is associated with inferior PFS compared to the common E746_A750del mutation in pts treated with 1L osimertinib. Understanding differences in osimertinib efficacy among EGFR del19 subtypes could alter management of these pts in the future.[Table: see text]