Prolonged Prolonged Progression-free Survival Research Articles

Efficacy of immune-checkpoint inhibitors combined with cytotoxic chemotherapy in advanced or recurrent endometrial cancer: A systematic review and meta-analysis

BackgroundThe combination of immune checkpoint inhibitors (ICIs) and platinum-based chemotherapy has emerged as a highly promising primary option for advanced or recurrent endometrial cancer (EC). The study aimed to evaluate treatment efficacy of ICIs with cytotoxic chemotherapy in EC. MethodsWe conducted a comprehensive review of randomized controlled trials up to November 11, 2023, focusing on immunotherapy combined with chemotherapy versus chemotherapy alone for EC. The primary endpoint was the pooled hazard ratio (HR), which was further analyzed across subgroups based on mismatch repair (MMR) status, race, histology, and programmed death-ligand 1 (PD-L1) status. The protocol was registered in PROSPERO (CRD42023475669). FindingsFour trials with 2335 patients were analyzed. ICIs with chemotherapy significantly prolonged progression-free survival (PFS) (HR, 0.70; 95% CI, 0.62–0.79) and overall survival (OS) (HR, 0.75; 95% CI, 0.63–0.89) compared to chemotherapy alone. Stratification by MMR status showed substantial benefits for dMMR (PFS; HR, 0.33; 95% CI, 0.26–0.43; OS; HR, 0.37; 95% CI, 0.22–0.91) over pMMR cohorts in both PFS and OS. In the subgroup analysis, there was significant PFS advantage in Caucasian (HR, 0.63; 95% CI, 0.54–0.72) over non-Caucasian, in endometrioid histology (HR, 0.66; 95% CI, 0.56–0.78) over non-endometrioid, and in PD-L1 positive (HR, 0.39; 95% CI, 0.19–0.81) over PD-L1 negative population. InterpretationICIs combined with platinum-based chemotherapy significantly prolonged PFS and OS in patients with advanced or recurrent EC. Patients with dMMR status, Caucasians, endometrioid histology, and positive PD-L1 status showed significant PFS benefits, emphasizing the need for personalized treatment approaches to improve outcomes.

Efficacy and Safety of Taletrectinib in Chinese Patients With ROS1+ Non-Small Cell Lung Cancer: The Phase II TRUST-I Study.

Taletrectinib, a highly potent, CNS-active, ROS1 tyrosine kinase inhibitor (TKI), has demonstrated high and durable response rates, high intracranial objective response rate (ORR), prolonged progression-free survival (PFS), and activity against G2032R with a favorable safety profile. We report outcomes from the pivotal TRUST-I study (ClinicalTrials.gov identifier: NCT04395677) of taletrectinib for ROS1+ non-small cell lung cancer in China. TRUST-I evaluated TKI-naїve and crizotinib-pretreated patients. The primary end point was confirmed ORR (cORR) by independent review committee; key secondary end points included duration of response (DOR), PFS, and safety. As of November 2023, 173 patients were enrolled (median age, 55 years; 58% female; 73% never smoked; TKI naїve: n = 106; crizotinib pretreated: n = 67). In TKI-naїve patients, cORR and intracranial cORR were 91% and 88%, respectively, and 52% and 73% in crizotinib-pretreated patients. In TKI-naїve patients, median DOR and median PFS were not reached (NR) with 22.1-month and 23.5-month follow-up, respectively. In crizotinib-pretreated patients, the median DOR was 10.6 months (95% CI, 6.3 months to NR; 8.4-month follow-up), and the median PFS was 7.6 months (95% CI, 5.5 to 12.0 months; 9.7-month follow-up). Eight of 12 patients (67%) with G2032R mutations responded. The most frequent treatment-emergent adverse events (TEAEs) were increased AST (76%), diarrhea (70%), and increased ALT (68%), most of which were grade 1-2. Incidences of neurologic TEAEs were low (dizziness: 23%; dysgeusia: 10%) and mostly grade 1. Discontinuations (5%) and dose reductions (19%) due to TEAEs were low. Taletrectinib continues to show high and durable overall responses, prolonged PFS, robust activity against intracranial lesions and acquired resistance mutations including G2032R, and a favorable safety profile with a low incidence of neurologic TEAEs.

Factors associated with prolonged progression-free survival of patients treated with first-line afatinib for advanced epidermal growth factor receptor-mutated non-small cell lung cancer.

This study aimed to investigate the factors associated with prolonged progression-free survival (PFS) (>36 months) of advanced non-small cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutations treated with first-line afatinib. We performed a retrospective analysis of data of patients with advanced EGFR-mutated NSCLC receiving first-line afatinib at two tertiary care referral centers, Linkou and Kaohsiung Chang Gung Memorial Hospital, in Taiwan between June 2014 and April 2022. The data of 546 treatment-naïve EGFR-mutated advanced NSCLC patients were analyzed. Median PFS and overall survival were 14.5 months and 27.2 months, respectively. The PFS of 462 patients (84.6%) was less than 36 months and of 84 patients (15.4%) was more than 36 months. The PFS > 36 months group had a significantly higher percentage of patients with uncommon mutations (p = 0.002). The PFS ≤36 months group had significantly higher incidences of bone, liver, and adrenal metastases (all p < 0.05) and a higher rate of multiple distant metastases. Multivariate logistic regression analysis showed that liver metastasis was negatively and independently associated with prolonged PFS (adjusted odds ratio = 0.246 [95% CI: 0.067-0.908], p = 0.035). The median overall survival of the PFS >36 months group was 46.0 months and that of the PFS ≤36 months group was 22.9 months (log-rank test, p < 0.001). We found that EGFR-mutated NSCLC patients receiving first-line afatinib were prone to shorter PFS if they had distant organ metastasis, especially liver metastasis.

Novel Agents May be Preferable to Standard Chemotherapy in Second-Line for Early Relapsing Follicular Lymphoma (FL) Patients

Introduction Early progression of FL after first line treatment is associated with poor outcomes. Disease progression within 24 months of initial therapy (POD24) is well-established adverse prognostic factor, while maintaining a complete remission (CR) at 30 months after initiation of induction therapy is considered a good surrogate for a prolonged progression-free survival (PFS). Nevertheless, treatment strategies in the second-line setting for these early relapsing patients are not clearly established, being their management heterogeneous across centers. The aim of our study was to analyze treatment patterns in this setting and to compare outcomes for patients who received chemotherapy (CT)-based regimens and immunotherapy (IT) approaches. Methods We conducted a retrospective review of patients diagnosed with grade 1-3a FL treated with upfront (CT) that progressed within 30 months of initial therapy (POD30) in 9 centers from January 2015 to June 2023. Patients who received single agent monoclonal antibodies or radiotherapy as first line treatment, and patients with FL grade 3b or histological transformation were excluded from the analysis. We defined 2 groups of patients according to the second-line regimen: the CT group, comprised by patients who received bendamustine-based regimens or other CT combinations, and the IT group that included patients who received monoclonal antibodies with lenalidomide and/or CD20xCD3 bispecific antibodies. Outcomes of interest were overall and complete response rate (ORR/CRR), PFS and overall survival (OS). Results Among 114 POD30 FL patients, 93 received CT and 21 received IT as second line treatment. Median age for the overall cohort was 56 years, with no differences according to salvage therapy (57 vs 53 years, p=0.19). Fifty-nine patients (52%) were female and 104 (94%) presented an advanced stage disease. Most of the patients in both groups had a high-risk FL at diagnosis (68% vs 67%, p=0.89) and at the time of first relapse (51% vs 24%, p=0.03), respectively. Distribution of first line treatment was well balanced between both groups. CHOP-based regimens were administered in 81% patients from the CT group and 90% in the IT group while bendamustine-based regimens were administered in 6% patients from the CT group and 10% in the IT group. In terms of best response to frontline therapy, 28 patients (25%) attained a CR, 59 patients (52%) a partial response (PR), 7 patients (6%) a stable disease (SD) and 20 patients (18%) a progressive disease (PD). Maintenance treatment was administered in 78 patients (68%), 59 patients (63%) from the CT group and 19 patients (90%) from the IT group ( p=0.03). Second-line treatment in the CT group included bendamustine-based regimens (n=40, 43%), ESHAP (n=31, 33%), gemcitabine-based (n=7, 8%), and other regimens (n=15, 16%), while the IT cohort comprised patients treated with lenalidomide in combination with monoclonal antibodies (n=5, 24%) and bispecific antibodies (n=16, 76%). For the full set of patients, best response included CR in 47 patients (43%), PR in 23 patients (21%), SD in 10 patients (9%) and PD in 30 patients (18%). For the CT and IT groups, there were no significant differences in terms of ORR (64% vs 60%, p=0.66) or CRR (42% vs 45%, p=0.87), respectively. Autologous stem cell transplantation (ASCT) was performed as a consolidative strategy in 27 patients (24%) from the overall cohort (29% for the CT cohort and 5% for the IT, p=0.05). Median follow up was 39.2 from diagnosis and 15.4 months from second-line treatment. Median PFS for patients receiving CT as second line of treatment was 11 months (95% CI: 6.3 - 15.2), compared to 16 months (95% CI: 13.01 - NA) for patients receiving IT (HR: 0.5, CI 95% 0.25-1; p=0.05). Finally, median OS for patients receiving CT as salvage therapy was 45.6 months (95% CI: 24.15% - NA), while median OS was not reached for patients receiving IT (HR: 0.19, CI 95% 0.03-1.4; p=0.1). Conclusions Treatment approaches for early relapsing FL are heterogeneous across centers, with many patients receiving chemotherapy as salvage therapy. Nevertheless, in our study a trend to a prolonged PFS and OS is observed in the group of patients receiving immunotherapy as salvage treatment. Novel agents such as lenalidomide and bispecific antibodies alone or in combination seem to improve the outcome in this population of FL with poor prognosis.

ICOS DNA methylation regulates melanoma cell-intrinsic ICOS expression, is associated with melanoma differentiation, prognosis, and predicts response to immune checkpoint blockade

BackgroundInducible T cell costimulator ICOS is an emerging target in immuno-oncology. The aim of this study was to investigate the epigenetic regulation of ICOS in melanoma by DNA methylation.MethodsWe comprehensively investigate ICOS DNA methylation of specific CpG sites and expression pattern within the melanoma microenvironment with regard to immune correlates, differentiation, clinical outcomes, and immune checkpoint blockade (ICB) response.ResultsOur study revealed a sequence-contextual CpG methylation pattern consistent with an epigenetically regulated gene. We found a cell type-specific methylation pattern and locus-specific correlations and associations of CpG methylation with ICOS mRNA expression, immune infiltration, melanoma differentiation, prognosis, and response to ICB. High ICOS mRNA expression was identified as a surrogate for enriched immune cell infiltration and was associated with favorable overall survival (OS) in non-ICB-treated patients and predicted response and a prolonged progression-free survival (PFS) following ICB therapy initiation. ICOS hypomethylation, however, significantly correlated with poor OS in non-ICB patients but predicted higher response and prolonged PFS and OS in ICB-treated patients. Moreover, we observed cytoplasmic and sporadically nuclear tumor cell-intrinsic ICOS protein expression. Tumor cell-intrinsic ICOS protein and mRNA expression was inducible by pharmacological demethylation with decitabine.ConclusionOur study identified ICOS DNA methylation and mRNA expression as promising prognostic and predictive biomarkers for immunotherapy in melanoma and points towards a hitherto undescribed role of ICOS in tumor cells.

Plasma extracellular vesicle transcriptomics identifies CD160 for predicting immunochemotherapy efficacy in lung cancer.

Better biomarkers are needed to improve the efficacy of immune checkpoint inhibitors in lung adenocarcinoma (LUAD) treatment. We investigated the plasma extracellular vesicle (EV)-derived long RNAs (exLRs) in unresectable/advanced LUAD to explore biomarkers for immunochemotherapy. Seventy-four LUAD patients without targetable mutations receiving first-line anti-programmed cell death 1 (PD-1) immunochemotherapy were enrolled. Their exLRs were profiled through plasma EV transcriptome sequencing. Biomarkers were analyzed against response rate and survival using pre- and post-treatment samples in the retrospective cohort (n = 36) and prospective cohort (n = 38). The results showed that LUAD patients demonstrated a distinct exLR profile from the healthy individuals (n = 56), and T-cell activation-related pathways were enriched in responders. Among T-cell activation exLRs, CD160 exhibited a strong correlation with survival. In the retrospective cohort, the high baseline EV-derived CD160 level correlated with prolonged progression-free survival (PFS) (P < 0.001) and overall survival (OS) (P = 0.005), with an area under the curve (AUC) of 0.784 for differentiating responders from non-responders. In the prospective cohort, the CD160-high patients also showed prolonged PFS (P = 0.003) and OS (P = 0.014) and a promising AUC of 0.648. The predictive value of CD160 expression was validated by real-time quantitative PCR. We also identified the dynamics of EV-derived CD160 for monitoring therapeutic response. The elevated baseline CD160 reflected a higher abundance of circulating NK cells and CD8+ -naïve T cells, suggesting more active host immunity. In addition, increased CD160 levels of tumors also correlated with a favorable prognosis in LUAD patients. Together, plasma EV transcriptome analysis revealed the role of the baseline CD160 level and early post-treatment CD160 dynamics for predicting the response to anti-PD-1 immunochemotherapy in LUAD patients.

Abstract P1-11-01: Trastuzumab deruxtecan vs treatment of physician’s choice in patients with HER2-low unresectable and/or metastatic breast cancer: Subgroup analyses from DESTINY-Breast04

Abstract Background: DESTINY-Breast04 demonstrated that the HER2 targeting antibody–drug conjugate trastuzumab deruxtecan (T-DXd) significantly prolonged progression-free survival (PFS) and overall survival (OS) vs treatment of physician’s choice (TPC) in patients (pts) with HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization negative) metastatic breast cancer (mBC) in pts in the hormone receptor−positive (HR+) cohort and all pts (HR+ and HR-; median PFS, 9.9 vs 5.1 months [mo], hazard ratio: 0.50; median OS, 23.4 vs 16.8 mo, hazard ratio: 0.64; both P &amp;lt; 0.0001; Modi et al. N Engl J Med 2022). Objective response rate (ORR) with T-DXd was ≥50% across cohorts. These subgroup analyses examine pt history and disease characteristics that may correlate with response to therapy. Methods: N = 557 pts with centrally confirmed HER2-low mBC were randomized 2:1 to T-DXd or TPC. Randomization was stratified by HER2 status (IHC 1+ vs 2+), 1 vs 2 prior lines of chemotherapy, and HR+ (with vs without prior treatment with cyclin-dependent kinase 4/6 inhibitor [CDK4/6i]) vs HR−. With the exception of the PFS and OS analyses by prior CDK4/6i use, all other described efficacy analyses were assessed post-hoc. Results: Benefit of T-DXd vs TPC was consistent in pts with or without prior CDK4/6i use (Table 1). Pts with high disease burden (ie, ≥3 metastatic sites) also benefited from T-DXd vs TPC (Table 2). There was a small subgroup (n = 22) among all pts (HR+ [n = 18] and HR− disease [n = 4]) with rapid progression prior to enrollment (disease progression within 6 mo of concluding a prior course of chemotherapy in early breast cancer). T-DXd showed responses in 7/14 (50%) pts in this subgroup vs 0/8 with TPC; this subgroup also had prolonged median PFS with T-DXd vs TPC (Table 3). Efficacy data for HER2 IHC 1+ vs 2+ and prior chemotherapy subgroups will be presented. Median OS was not reached for many subgroups (insufficient events in each group [data not shown]); however, subgroups in general showed OS benefit consistent with the primary analysis. With T-DXd, rates of interstitial lung disease/pneumonitis were similar in pts with/without prior CDK4/6i use. Conclusions: T-DXd treatment for HER2-low mBC in the phase 3 study DESTINY-Breast04 showed consistent efficacy independent of disease burden, prior CDK4/6i treatment, or rapid progression status. ILD is an important identified risk and requires proactive monitoring and management. These data continue to support the use of T-DXd as the new standard of care across subgroups of pts with HER2-low mBC. Editorial Acknowledgment Under guidance of the authors, assistance in medical writing and editorial support was provided by Eileen McIver, PhD, and Soniya Patel, PhD, of ApotheCom, and was funded by Daiichi Sankyo. Funding This study was funded by Daiichi Sankyo and AstraZeneca. Table 1. Efficacy by Prior CDK4/6i Treatment in Pts With HER2-Low Breast Cancer, HR+ Cohort. Table 2. Efficacy by Disease Burdena in Pts With HER2-Low Breast Cancer, ITT. Table 3. Efficacy by Rapid Progressor Statusa in Pts With HER2-Low Breast Cancer, ITT. Citation Format: Nadia Harbeck, Shanu Modi, William Jacot, Toshinari Yamashita, Joo Hyuk Sohn, Maria Vidal, Junji Tsurutani, Naoto T. Ueno, Aleix Prat, Naoki Niikura, Binghe Xu, Hope Rugo, Konstantinos Papazisis, Javier Cortés, Ian Krop, Dhiraj Gambhire, Lotus Yung, Yibin Wang, Jasmeet Singh, David Cameron. Trastuzumab deruxtecan vs treatment of physician’s choice in patients with HER2-low unresectable and/or metastatic breast cancer: Subgroup analyses from DESTINY-Breast04 [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 P1-11-01.

Dose-dependent efficacy of bevacizumab in recurrent glioblastoma.

Bevacizumab (BEV), at a standard dose of 10mg/kg every 2weeks is associated with prolonged progression-free survival (PFS) but no improvement in overall survival (OS) in recurrent glioblastoma (rGBM). Few studies have examined the potential dose-dependent efficacy of BEV. In Ontario, reimbursement for the costs of BEV varies, and as a result, our practice began to routinely use lower dose regimens. The main aim of this study was to ensure that there was no harm to patients who received the low dose protocol. A single-center retrospective study of patients given BEV for rGBM between 2015 and 2020 was performed. Clinical and treatment data including BEV dose regimen [SD (10mg/kg every 2weeks) vs. LD (5mg/kg every 2-3weeks or 10mg/kg every 3weeks)] received at the time of rGBM diagnosis were captured. Overall survival (OS) and progression-free survival (PFS) on BEV were compared using the Kaplan-Meier product-limit method. Log-rank test was used to compare potential predictive factors. Cox regression model was performed for multivariable analysis of OS and PFS. A total of 96 patients were included with a median follow-up duration of 6.84months (range 1.12-50.63 months) from the date of the first infusion. The LD group consisted of 55 of the 96 patients. By virtue of funding mechanisms for BEV, the median age in the LD group was significantly higher (62 vs. 54years p = 0.009). There was no difference in MGMT status between the two groups (p = 0.60). The LD group had prolonged median PFS (5.89months versus 3.22months; p = 0.0112) and OS (10.23months versus 6.28months; p = 0.0010). Multivariable analysis including the dose of BEV, the extent of resection, gender, and age revealed that standard dose of BEV, subtotal resection, and female sex were associated with worse overall survival. Nine patients in the SD group vs. 18 patients in the LD group reported an adverse event related to BEV. For patients with recurrent GBM, we found that a low dose regimen of BEV was associated with prolonged OS and PFS compared to the standard dose regimen. Lower dose schedules may be a better and more cost-effective option for patients with rGBM. Lower costs might provide more equitable access to this very important palliative drug.

Adjuvant Therapy for Renal Cell Carcinoma: End Points, Outcomes, and Risk Assessments.

Targeted tyrosine kinase inhibitors (TKIs) and immune-checkpoint inhibitors (ICIs) revolutionized the treatment of metastatic renal cell carcinoma (RCC). Efforts to translate these therapies into the adjuvant setting for local and locoregional RCC have been pursued over the past decade. We sought to provide an updated review of the literature regarding adjuvant therapy in RCC, as well as an analysis of patient characteristics that may portend the most favorable responses. Using PubMed, Google Scholar, and Wiley Online Library, we reviewed articles between 2000 and 2022. Search terms included "tyrosine kinase inhibitors," "adjuvant," "immunotherapy," and "renal cell carcinoma." The articles included were original and published in English. Information on clinical trials was collected from ClinicalTrials.gov, accessed in June 2022. Landmark trials investigating adjuvant vascular endothelial growth factor (VEGF) inhibitors produced conflicting results, with only a single trial of sunitinib (S-TRAC) resulting in US Food and Drug Administration-approval on the basis of a slightly prolonged progression-free survival (PFS). Subsequent meta-analyses failed to show a benefit for adjuvant VEGF inhibitors. Several trials evaluating ICIs are currently ongoing, with pembrolizumab (KEYNOTE-564) earning US Food and Drug Administration-approval for a prolonged PFS, although overall survival data are not yet mature. Preliminary results from other adjuvant ICI trials have been conflicting. There remains a lack of clear benefit for the use of adjuvant VEGF inhibitors in local and locoregional RCC. Adjuvant ICI investigations are ongoing, with promising results from KEYNOTE-564. It remains to be seen if PFS is an adequate surrogate end point for overall survival. Selection of patients at greatest risk for recurrence, and identification of those at greatest risk of rare but serious adverse events, may improve outcomes.

Selinexor-Bortezomib-Dexamethasone: A Review in Previously Treated Multiple Myeloma.

Selinexor [Nexpovio® (EU); Xpovio® (USA)] is a first-in-class, selective exportin-1 inhibitor. Oral selinexor once weekly in combination with subcutaneous bortezomib once weekly and oral dexamethasone twice weekly (selinexor-bortezomib-dexamethasone) is approved in the EU and USA for the treatment of adult patients with multiple myeloma who have received at least one prior therapy. In the open-label, randomized, phase 3 BOSTON trial, this regimen significantly prolonged progression-free survival (PFS) compared with the standard bortezomib-dexamethasone regimen in patients with previously treated multiple myeloma. Selinexor-bortezomib-dexamethasone had a generally manageable tolerability profile and an acceptable safety profile in BOSTON, with a lower incidence of peripheral neuropathy (a bortezomib-induced toxicity) compared with bortezomib-dexamethasone. The triplet regimen uses less bortezomib and dexamethasone during the first 24 weeks of treatment. The efficacy and safety profiles of selinexor-bortezomib-dexamethasone, combined with its once-weekly administration of selinexor and bortezomib, make it a useful additional triplet therapy option for previously treated multiple myeloma.

Biomarker analysis from a phase II multi-institutional study of nivolumab in patients with advanced refractory biliary tract cancer

BackgroundOur previous phase II study demonstrated that nivolumab provides modest but durable clinical efficacy in patients with refractory biliary tract cancer, suggesting the significant clinical benefit of nivolumab in selected patients and the necessity of predictive biomarkers. We evaluated clinicopathological characteristics and tumour microenvironment of the patients who were enrolled the trial to identify potential biomarkers. MethodsBaseline clinicopathological characteristics and pretreatment tumour samples were collected. The obtained tumour samples were assessed for whole exome sequencing, RNA sequencing and immunohistochemistry. Their correlations with clinical outcome were analysed. ResultsPretreatment tumour evaluation revealed PD-L1 expression on tumour, CD8 T cell infiltration and high ratio of CD8 T cell/regulatory T cell in tumour microenvironment were significantly associated with prolonged progression-free survival (PFS), while PD-1 expression on lymphocytes and CD68 macrophages infiltration in tumour microenvironment had no predictive role. Asian patients (N = 3) had improved PFS and disease control rate compared with non-Asian (N = 54). A six-gene predictive model was constructed by evaluation of total 23,550 candidate genes from RNA sequencing of baseline tumour samples using LASSO-Cox regression analysis, and high score of the six-gene prediction model was associated with prolonged PFS. ConclusionThis study suggests that PD-L1 expression on tumour, CD8 T cell infiltration and high ratio of CD8/regulatory T cells and six-gene expression profile in tumour microenvironment may be potential predictive biomarkers of nivolumab in biliary tract cancers. Further studies are needed to confirm these findings.

Dose-dependent efficacy of bevacizumab in recurrent glioblastoma.

e14042 Background: Bevacizumab (bev), at a standard dose of 10 mg/kg every 2 weeks is associated with prolonged progression free survival (PFS) but no improvement in overall survival (OS) in recurrent glioblastoma (rGBM). While there are reports of lower dose regimens of bev being better tolerated and effective in rGBM, this has not been studied in comparison to a standard dose of bev. The main aim of this study is to report on the dose-dependent efficacy of bev by comparing PFS and OS in rGBM patients receiving standard dose (SD) vs lower dose (LD) of bev. Methods: A single-center retrospective study of patients with rGBM started on bev between 2015 – 2020 was performed. Clinical and treatment data including bev dose regimen (SD [10 mg/kg every 2 weeks] vs LD [5 mg/kg every 2-3 weeks or 10 mg/kg every 3 weeks]) received at the time of rGBM diagnosis were captured. Overall survival (OS) and progression-free survival (PFS) on bev were compared between the two groups using the Kaplan-Meier product-limit method. Log-rank test was used to compare potential predictive factors. Cox regression model was performed for multivariable analysis of OS and PFS. Results: A total of 96 patients were included with a median follow-up duration of 6.84 months (range 1.12-50.63 months) from date of the first infusion. The LD group consisted of 55/96 patients (57 %) and the age in the LD group was significantly older than the SD group (62 vs 54 years p = 0.009). There was no significant difference in MGMT status between the 2 groups (p = 0.73). Eight patients received lomustine with bev (3 from the standard and 5 from the low dose group). The LD group had prolonged OS (10.23 months versus 6.28 months; p-value = 0.0010) and PFS (5.89 months versus 3.22 months; p-value = 0.0112). Multivariable analysis including dose of bev, extent of resection, gender and age revealed that standard dose of bev, subtotal resection and female sex were associated with worse OS. Eleven patients in the SD group vs 15 patients in the LD group reported an adverse event related to bev. Conclusions: In this study we demonstrate that a reduced dose of bev (5 mg every 2-3 weeks) prolonged both the OS and PFS compared to a standard dose of 10 mg/kg every 2 weeks. This may represent a better and more cost-effective option for patients with rGBM in need of salvage therapy.

Subgroup analysis of patients with no prior chemotherapy in EMERALD: A phase 3 trial evaluating elacestrant, an oral selective estrogen receptor degrader (SERD), versus investigator’s choice of endocrine monotherapy for ER+/HER2-advanced/metastatic breast cancer (mBC).

1100 Background: EMERALD demonstrated significantly prolonged progression-free survival (PFS) and a manageable toxicity profile for elacestrant vs standard of care endocrine therapy (SOC) in patients with ER+/HER2- mBC following progression on prior endocrine and CDK4/6 inhibitor therapy. Benefit was observed in the overall study population and in patients with ESR1 mutations (mESR1). Here, we report a subgroup analysis from EMERALD in patients with no prior chemotherapy. Methods: EMERALD (NCT03778931) is a randomized, open-label, phase 3 trial that enrolled patients with ER+/HER2− mBC who had 1–2 lines of endocrine therapy, mandatory pretreatment with a CDK4/6 inhibitor, and ≤1 chemotherapy. Patients were randomized 1:1 to elacestrant (400 mg orally daily) or SOC (investigator’s choice of fulvestrant or aromatase inhibitor). Primary endpoints were PFS in all patients and patients with mESR1. In this analysis, we compared PFS between elacestrant and SOC in patients without prior chemotherapy. Results: Among the 477 patients enrolled in the trial, 77.8% (n = 371) had not received prior chemotherapy for mBC (median age = 64). Among patients without prior chemotherapy, treatment with elacestrant was associated with significantly prolonged PFS compared to SOC in both the overall population (hazard ratio [HR] = 0.68 [95% CI, 0.52-0.89] P = 0.004; median PFS 3.7 vs 2.0; 6-mo PFS 38% vs 23%; 12-mo PFS 27% vs 12%), and patients with mESR1 (HR = 0.54 [95% CI, 0.36-0.80] P = 0.002; median PFS 5.3 vs 1.9; 6-mo PFS 44% vs 24%; 12-mo PFS 31% vs 12%). Key treatment-related adverse events (AEs) in the no prior chemotherapy elacestrant group were nausea (25.9%), fatigue (12.7%), and hot flush (11.1%). There were no treatment-related deaths in either group. Conclusions: Among patients with ER+/HER2− mBC without prior chemotherapy, elacestrant significantly prolonged PFS compared to SOC endocrine therapy and showed favorable outcomes in this subgroup. Clinical trial information: NCT03778931.

Addition of Bevacizumab to Erlotinib as First-Line Treatment of Patients With EGFR-Mutated Advanced Nonsquamous NSCLC: The BEVERLY Multicenter Randomized Phase 3 Trial

IntroductionAdding bevacizumab to erlotinib prolonged progression-free survival (PFS) of patients with EGFR-mutated advanced NSCLC in the Japanese JO25567 trial, but limited data were available in non-Asian patients. BEVERLY is an Italian, multicenter, randomized, phase 3 investigating the addition of bevacizumab to erlotinib as first-line treatment of advanced EGFR-mutated NSCLC. MethodsEligible patients were randomized 1:1 to erlotinib plus bevacizumab or erlotinib alone. Investigator-assessed PFS and blinded independent centrally reviewed PFS were coprimary end points. With 80% power in detecting a 0.60 hazard ratio and two-sided α error of 0.05, 126 events of 160 patients were needed. The trial was registered as NCT02633189 and EudraCT 2015-002235-17. ResultsFrom April 11, 2016, to February 27, 2019, a total of 160 patients were randomized to erlotinib plus bevacizumab (80) or erlotinib alone (80). At a median follow-up of 36.3 months, median investigator-assessed PFS was 15.4 months (95% confidence interval [CI]: 12.2–18.6) with erlotinib plus bevacizumab and 9.6 months (95% CI: 8.2–10.6) with erlotinib alone (hazard ratio = 0.66, 95% CI: 0.47–0.92). Blinded independent centrally reviewed PFS analysis confirmed this result. A statistically significant interaction with treatment effect was found for smoking habit (p = 0.0323), with PFS prolongation being clinically significant only among current or previous smokers. Hypertension (grade ≥3: 24% versus 5%), skin rash (grade ≥ 3: 31% versus 14%), thromboembolic events (any grade: 11% versus 4%), and proteinuria (any grade: 23% versus 6%) were more frequent with the combination. ConclusionsThe addition of bevacizumab to first-line erlotinib prolonged PFS in Italian patients with EGFR-mutated NSCLC; toxicity was increased with the combination but without unexpected safety issues.

Updated Overall Survival Data and Predictive Biomarkers of Sintilimab Plus Pemetrexed and Platinum as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC in the Phase 3 ORIENT-11 Study

IntroductionSintilimab plus chemotherapy significantly prolonged progression-free survival (PFS) compared with chemotherapy alone in nonsquamous NSCLC in the ORIENT-11 study. Updated overall survival (OS) and PFS data and corresponding biomarker analyses are reported here. MethodsIn this study, a total of 397 patients with previously untreated, locally advanced or metastatic nonsquamous NSCLC were assigned to sintilimab plus chemotherapy combination treatment (combo) group or placebo plus chemotherapy treatment group. The patients were stratified by programmed death-ligand 1 (PD-L1) expression levels. Immune signature profiles from tumor RNA sequencing and PD-L1 immunohistochemistry were correlated with clinical outcome to identify predictive biomarkers. ResultsAs of January 2021, with median follow-up of 22.9 months, median OS was significantly improved in the combo group compared with the placebo plus chemotherapy treatment group (not reached versus 16.8 mo; hazard ratio [HR] = 0.60, 95% confidence interval [CI]: 0.45–0.79, p = 0.0003). High or medium immune cell infiltration was strongly associated with improved PFS in the combo group, in contrast to absent or low immune cell infiltration, which suggests that chemotherapy could not prime “immune deserts” to obtain benefit from programmed cell death protein-1 inhibition. In particular, high major histocompatibility complex (MHC) class II presentation pathway expression was significantly correlated with prolonged PFS (HR = 0.32, 95% CI: 0.19–0.54, p < 0.0001) and OS (HR = 0.36, 95% CI: 0.20–0.64, p = 0.0005) in the combo group. Importantly, patients with low or absent PD-L1 but high MHC class II expression could still benefit from the combo treatment. In contrast, MHC class I antigen presentation pathway was less relevant in this combination setting. ConclusionsThe addition of sintilimab to chemotherapy resulted to significantly longer OS in nonsquamous NSCLC. Expression of MHC class II antigen presentation pathway could identify patients benefiting most from this combination.

Efficacy and safety of palbociclib in patients with estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer with preexisting conditions: A post hoc analysis of PALOMA-2

ObjectiveIn the PALOMA-2 trial, palbociclib in combination with letrozole prolonged progression-free survival (PFS) and exhibited an acceptable safety profile in patients with estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer (ABC). This post hoc analysis of PALOMA-2 evaluated the efficacy and safety of palbociclib plus letrozole in patients with preexisting conditions grouped by Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC). MethodsPostmenopausal patients without prior treatment for ABC were randomized 2:1 to receive palbociclib (125 mg/d on a 3 weeks on/1 week off schedule) plus letrozole (2.5 mg/d, continuous) or placebo plus letrozole. Patients were grouped by the following MedDRA SOC preexisting conditions: gastrointestinal, musculoskeletal, metabolic, and vascular/cardiac. Median PFS was estimated by the Kaplan-Meier method, and treatment emergent adverse events (AEs) were compared between treatment arms within each preexisting condition subgroup. ResultsAt baseline, 276 (41.4 %) patients had preexisting gastrointestinal disorders, 390 (58.6 %) had musculoskeletal disorders, 259 (38.9 %) had metabolic disorders, and 382 (57.4 %) had vascular/cardiac disorders. Baseline characteristics were similar between subgroups and between each arm within subgroups. Regardless of baseline preexisting condition, palbociclib plus letrozole prolonged PFS compared with placebo plus letrozole. Treatment-emergent AEs associated with palbociclib plus letrozole and dose modifications due to AEs were similar across preexisting condition subgroups. ConclusionThis post hoc analysis of PALOMA-2 demonstrated a favorable effect of palbociclib on PFS and a safety profile consistent with previous observations, regardless of underlying preexisting condition. Pfizer Inc (NCT01740427).

Rituximab Maintenance Versus Observation After Immunochemotherapy (R-CHOP, R-MCP, and R-FCM) in Untreated Follicular Lymphoma Patients: A Randomized Trial of the Ostdeutsche Studiengruppe Hämatologie und Onkologie and the German Low-Grade Lymphoma Study Group.

The German study groups, the German Low-Grade Lymphoma Study Group (GLSG) and Ostdeutsche Studiengruppe Hämatologie und Onkologie (OSHO), initiated in 2007 a double randomized trial to investigate efficacy and safety of rituximab maintenance versus observation in remission after randomly assigned induction treatment in the first-line follicular lymphoma. Previously untreated patients with stage II–IV follicular lymphoma in need of therapy were randomized to receive 6 cycles of R-CHOP, R-MCP, or R-FCM. Responding patients were subsequently randomized to 2 years rituximab maintenance or observation, stratified by type of immunochemotherapy, quality of remission, and Follicular Lymphoma International Prognostic Index (FLIPI). Recruitment was stopped in 2011 after the PRIMA results had been published. Median age of the 206 recruited patients was 66 years (range, 24–86), and (FLIPI) was low in 13%, intermediate in 28%, and high in 60%. High and comparable overall response rates were observed after R-CHOP (88%), R-MCP (89%), and R-FCM (91%). Rituximab maintenance substantially prolonged progression-free survival (PFS) in comparison to observation in remission (hazard ratio 0.39, P = 0.0064). In the rituximab maintenance group, the 3-year PFS was 89% compared with 69% in the observation group. No differences in overall survival were observed for maintenance vs. observation (hazard ratio 1.04, 95% confidence interval 0.32–3.43, P = 0.95). In this randomized trial, 2 years of rituximab maintenance was associated with significantly prolonged PFS in comparison to observation after response to first-line immunochemotherapy in follicular lymphoma. Our data represent an independent confirmation of the PRIMA trial results.(Clinical Trial EudraCT Number: 2005-005473-29, 2006-09-26)

High Expression of Programmed Death-Ligand 1 (PD-L1) Correlates with Macrophage Gene Expression and Is Associated with Prolonged Progression-Free Survival (PFS) in Patients (pts) with First-Line (1L) Diffuse Large B-Cell Lymphoma (DLBCL)

▪Introduction PD-L1 and its receptor PD-1 are both expressed on multiple cell types, including antigen-presenting cells, T cells and tumor cells. In DLBCL, PD-L1 expression on non-malignant immune cells is common, whereas tumor-cell PD-L1 expression is restricted to a small percentage of pts. Because PD-L1/PD-1 are expressed on macrophages after in vitro activation, and activated macrophages contribute to antibody-dependent cellular phagocytosis (ADCP), high PD-L1 expression may identify tumors enriched with activated tumor-infiltrating macrophages primed for ADCP. Considering the role of ADCP in clinical responses to anti-CD20 (rituximab/obinutuzumab), we hypothesized that PD-L1 expression could reflect abundance of activated tumor-infiltrating macrophages and may be associated with prolonged PFS in 1L DLBCL. We leveraged 2 large Phase 3 trials and cell-line immune gene expression to better understand the biological and clinical relevance of PD-L1 expression in 1L DLBCL.Methods We used clinical, genomic and pre-treatment immunohistochemistry (IHC) data from 1L DLBCL pts treated in the MAIN (NCT00486759) and GOYA (NCT01287741) trials. Pre-treatment tissue microarray cores from 201 MAIN pts were stained for PD-L1 (clone SP263), with 21 uninvolved lymph node FFPE sections used as controls. PD-L1+ samples were defined as IHC > 1+ (> 1% tissue area occupied by PD-L1+ cells). Tumor cells were identified based on morphological/cytological features, and PD-L1 tumor expression was scored as a percentage. Activated B-cell (ABC), germinal center B-cell (GCB) and unclassified DLBCL prognostic subtypes were determined by the NanoString Lymph2Cx cell-of-origin (COO) assay. We quantified mRNA expression of PD-L1, macrophage and B-cell genes using TruSeq (Illumina) RNAseq among 702 DLBCL pts (GOYA, n = 552; MAIN, n = 150), with 28 DLBCL cell lines and 15 purified normal B-cell samples as comparators. High/low expression of each gene signature was determined by median cutoffs. Median follow-up durations were 24 and 29 mo in MAIN and GOYA, respectively (≈ 30% of PFS events in both cohorts). We used Cox regression to examine associations between these markers and PFS, adjusting for IPI, age, COO, sex and treatment arm.Results Among 201 DLBCL pts in MAIN, PD-L1 was primarily detected on inter-follicular cells with myeloid/dendritic morphology, similar to the PD-L1 staining pattern of normal lymph nodes. In samples with evaluable germinal centers (GCs), a subset of GC cells expressed PD-L1 with a punctate and granular pattern consistent with a myeloid origin. Overall, there were significantly more pts with high PD-L1 expression by IHC (IHC 3+) and mRNA among ABC vs GCB DLBCL pts. A minority of DLBCL pts (10%) had PD-L1+ tumor cells, consistent with low/undetectable CD274 (PD-L1) mRNA in the majority of DLBCL cell lines and purified normal B-cell samples tested. Additionally, among the 702 evaluable pts in both studies, CD274 mRNA inversely correlated with a B-cell gene signature (MAIN, r= −0.55; GOYA, r= −0.32). High PD-L1 expression (IHC 2+/3+) correlated with prolonged PFS (HR, 0.44 [0.24, 0.80]; P < 0.01) among the 201 evaluable pts in MAIN. Among 552 evaluable pts in GOYA, CD274 expression was higher in pts with a PET-CR (P= 0.02), particularly in pts with ABC DLBCL (P= 0.0001), with a trend toward prolonged PFS in the ABC subtype (HR, 0.80 [0.63, 1.0]; P= 0.054). CD274 mRNA positively correlated with macrophage gene expression in both cohorts (MAIN, r= 0.61; GOYA, r= 0.57); pts with high PD-L1 expression (IHC 2+/3+) also demonstrated high mRNA expression of the macrophage marker CD68. Consistent with PD-L1 reflecting abundance of activated tumor-infiltrating macrophages relevant to anti-CD20 response, high expression of a macrophage signature correlated with prolonged PFS (HR, 0.63 [0.45, 0.87]; P= 0.003) in GOYA and a trend toward prolonged PFS among DLBCL pts treated in MAIN (HR, 0.64 [0.35, 1.16]; P= 0.10), although statistical significance was not reached.Conclusions In 1L DLBCL, most pts expressed PD-L1 on immune cells with myeloid/dendritic morphology, potentially reflecting activated macrophages primed for ADCP and supportive of the correlation between high PD-L1 expression and improved clinical outcomes among pts treated with immunochemotherapy. In the context of anti-CD20, the biology of PD-L1 expression on macrophages and the impact of PD-L1/PD-1 blockade on ADCP merit further study. DisclosuresMcCord:Genentech, Inc.: Employment. Bolen:Genentech: Employment, Equity Ownership. Koeppen:Genentech, Inc.: Employment. Kadel:Genentech, Inc.: Employment. Fingerle-Rowson:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Oestergaard:F. Hoffmann-La Roche Ltd: Employment. Venstrom:Genentech, Inc.: Employment.

Rituximab Maintenance after First-Line Immunochemotherapy in Mantle Cell Lymphoma: Long-Term Follow-up of the Randomized European MCL Elderly Trial

Rituximab Maintenance after First-Line Immunochemotherapy in Mantle Cell Lymphoma: Long-Term Follow-up of the Randomized European MCL Elderly Trial

Abstract PS10-14: Efficacy and safety of palbociclib (PAL) in patients (pts) with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) with preexisting conditions: A post hoc analysis of PALOMA-2

Abstract Background: In the PALOMA-2 trial, PAL + letrozole (LET) significantly prolonged progression-free survival (PFS) vs placebo (PBO) + LET in pts with ER+/HER2– ABC. This post hoc analysis assessed efficacy and safety of PAL + LET in pts from PALOMA-2 with baseline preexisting conditions grouped by Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC). Methods: Postmenopausal pts with ER+/HER2– ABC received PAL (125 mg/d, 3/1 schedule) + LET (2.5 mg/d, continuous) or PBO + LET. Pts were grouped by the following MedDRA SOC preexisting conditions: Gastrointestinal, Musculoskeletal, Metabolism, and Vascular/Cardiac. Baseline characteristics, PFS, and safety were assessed. Results: At baseline, 41.4% of pts had preexisting gastrointestinal disorders, 58.6% musculoskeletal disorders, 38.9% metabolism disorders, and 57.4% vascular/cardiac disorders. Baseline characteristics were similar between treatment arms within each subgroup and also between subgroups. Within each subgroup, ≥40% of pts also had ≥1 of the other coexisting conditions. Median PFS (mPFS) was significantly longer with PAL + LET vs PBO + LET regardless of preexisting condition (Table). In general, adverse events (AEs) were more frequent with PAL + LET in all subgroups; neutropenia was most common. Within each treatment arm, AEs and dose modifications due to AEs were similar regardless of preexisting condition. Conclusion: PAL + LET showed prolonged PFS and a consistent safety profile regardless of baseline preexisting condition in pts with ER+/HER2– ABC. Clinical trial identification: Pfizer Inc (NCT01740427) TablePreexisting ConditionPAL + LETPBO + LETPAL + LET vs PBO + LETnmPFS (95% CI)nmPFS (95% CI)HR (95% CI)P ValueGastrointestinal17627.6 (17.5–33.1)10013.6 (11.0–18.5)0.57 (0.42–0.78)&amp;lt;0.001Musculoskeletal25227.6 (21.4–33.1)13816.3 (11.2–19.1)0.53 (0.41–0.69)&amp;lt;0.001Metabolism18627.6 (19.3–30.6)7313.8 (8.3–27.4)0.62 (0.44–0.87)0.003Vascular/Cardiac25430.4 (25.1–36.2)12814.5 (11.0–18.5)0.51 (0.39–0.66)&amp;lt;0.001 Citation Format: Karen Gelmon, Janice M Walshe, Reshma Mahtani, Anil A Joy, Meghan Karuturi, Patrick Neven, Dongrui Ray Lu, Sindy Kim, Patrick Schnell, Eustratios Bananis, Lee Schwartzberg. Efficacy and safety of palbociclib (PAL) in patients (pts) with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) with preexisting conditions: A post hoc analysis of PALOMA-2 [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-14.