Terms Of ORR Research Articles

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.

Matching-Adjusted Indirect Comparison (MAIC) of Brexucabtagene Autoleucel (Brexu-cel) and Pirtobrutinib in Patients with Relapsed/Refractory (R/R) Mantle Cell Lymphoma (MCL) Previously Treated with a Covalent Bruton Tyrosine Kinase Inhibitor (cBTKi)

Introduction: Patients with MCL often require multiple lines of therapy and exhibit a generally unfavorable prognosis, particularly following failure of cBTKi therapy. Therapies such as chimeric antigen receptor (CAR) T-cell therapies and non-covalent BTKi therapies have shown promise in improving outcomes. Brexu-cel (formerly known as KTE-X19) is the only CAR T-cell therapy approved in the US for R/R MCL based on results from a phase 2 multicenter, single-arm trial (ZUMA-2; NCT02601313) in patients with R/R MCL who had 1-5 prior therapies, including a BTKi. Pirtobrutinib, a highly selective, non-covalent BTKi, was recently approved in the US for treatment of R/R MCL after at least two lines of systemic therapy including a BTKi, based on ongoing results from a multicenter phase 1/2 study (BRUIN; NCT03740529). In the absence of a direct head-to-head trial comparing brexu-cel and pirtobrutinib, we performed an unanchored MAIC to estimate the relative treatment effects of these therapies in the post-BTKi setting for R/R MCL. Methods: Individual patient-level data were available for ZUMA-2 (N=68; 35.8 months median follow-up as of July 24, 2021 data cut-off) whereas study-level data were available for BRUIN (N=90 in the BTKi pre-treated cohort; 23.5 months median follow-up as of July 29, 2022 data cut-off). Longer-term overall survival (OS) data for ZUMA-2 from the July 23, 2022 data cut-off (46.1 months median follow-up) were available and used. Logistic propensity score models were used to weight the brexu-cel infused population from ZUMA-2 to match the aggregate baseline characteristics of the BTKi pre-treated cohort in BRUIN. These baseline characteristics represented clinically relevant prognostic factors which were pre-specified based on input from clinical experts and data availability. The base-case model incorporated the top five most pertinent factors, which were reported in at least 50% of patients in both trials: blastoid morphology, MCL International Prognostic Index, number of prior lines of therapy, disease stage, and prior autologous stem cell transplantation. A sensitivity analysis additionally incorporated TP53 mutation (missing in >50% of patients in ZUMA-2 and BRUIN) and Ki-67 proliferation index (missing in >50% of patients in BRUIN). Several prognostic factors (response to prior BTKi therapy, response to last therapy, and duration on prior BTKi therapy) could not be considered due to not being reported for BRUIN. The effective sample size was calculated as a measure of the degree of precision after weighting, reflecting the extent of overlap in the distribution of covariates between the trial populations. Relative treatment effects were expressed as odds ratios or hazard ratios with 95% confidence intervals. Outcomes included objective response (ORR), complete response (CR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results: In the base-case MAIC, a significant difference in the odds of ORR and CR in favor of brexu-cel versus pirtobrutinib was observed (Table 1). Similarly, brexu-cel demonstrated a significant improvement in PFS (Table 2). OS and DOR point estimates were in favor of brexu-cel when compared to pirtobrutinib, although not statistically significant. These findings were consistent with unadjusted naïve analyses as well as the sensitivity analyses including adjustment for TP53 mutation and Ki-67 proliferation index. Conclusions: While acknowledging the inherent limitations of an unanchored indirect comparison, our findings suggest that brexu-cel offers clinically and statistically significant efficacy benefits in terms of ORR, CR, and PFS compared to pirtobrutinib in patients with R/R MCL after prior cBTKi therapy. Both treatments were not statistically different in terms of OS and DOR although the estimated hazard ratios indicated a favorable trend for brexu-cel; however, given the relatively shorter follow-up and the high degree of censoring in BRUIN, an updated analysis incorporating longer follow-up data with more events from BRUIN could provide more reliable results. Although efforts were made to ensure a robust approach to the selection of prognostic factors for inclusion in the model, the possibility of some residual confounding variables cannot be completely ruled out. Nevertheless, these results provide valuable insights that may help inform treatment decisions for this population.

Different doses of bevacizumab in combination with chemotherapy for advanced colorectal cancer: a meta-analysis and Bayesian analysis.

The aim of the present study was to explore the incremental benefit of bevacizumab (Bev) in the treatment of advanced colorectal cancer (CRC) with different doses. A literature search of eight electronic databases (China National Knowledge Infrastructure, Wanfang databases, Chinese Biomedical Database, VIP medicine information, Cochrane Library, MEDLINE, PubMed, and EMBASE) was conducted from database creation to December 2022. Randomized controlled trials (RCTs) that compared Bev at various dosages + chemotherapy (CT) versus placebo (or blank control) + CT were selected. The overall survival (OS), progression-free survival (PFS), overall response rate (ORR; complete response [CR] + partial response [PR]), and grade ≥ 3 adverse events (AEs) were integrated first by pooled analysis. The likelihood of ideal dosage of Bev was then ranked using random effects within Bayesian analysis. Twenty-six RCTs involving 18,261 patients met the inclusion criteria. OS increased significantly after using 5mg (HR: 0.87, 95% CI 0.75 to 1.00) and 10mg dosages of Bev (HR: 0.75, 95% CI 0.66 to 0.85) with CT, but statistical significance was not attained for the 7.5mg dose (HR: 0.95, 95% CI 0.83 to 1.08). A significantly increased in PFS with doses of 5mg (HR: 0.69, 95% CI 0.58 to 0.83), 7.5mg (HR: 0.81, 95% CI 0.66 to 1.00), and 10mg (HR: 0.60, 95% CI 0.53 to 0.68). ORR distinctly increased after 5mg (RR: 1.34, 95% CI 1.15 to 1.55), 7.5mg (RR: 1.25, 95% CI 1.05 to 1.50), and10mg (RR: 2.27, 95% CI 1.82 to 2.84) doses were administered. Grade ≥ 3 AEs increased clearly in 5mg (RR: 1.11, 95% CI 1.04 to 1.20) compared to 7.5mg (RR: 1.05, 95% CI 0.82 to 1.35) and 10mg (RR: 1.15, 95% CI 0.98 to 1.36). Bayesian analysis demonstrated that 10mg Bev obtained the maximum time of OS (HR: 0.75, 95% CrI 0.58 to 0.97; probability rank = 0.05) indirectly compared to 5mg and 7.5mg Bev. Compared with 5mg and 7.5mg Bev, 10mg Bev also holds the longest duration for PFS (HR: 0.59, 95% CrI 0.43 to 0.82; probability rank = 0.00). In terms of ORR, 10mg Bev holds the maximum frequency (RR: 2.02, 95% CrI 1.52 to 2.66; probability rank = 0.98) in comparison to 5mg and 7.5mg Bev clearly. For grade ≥ 3 AEs, 10mg Bev has the maximum incidence (RR: 1.15, 95% CrI 0.95 to 1.40, probability rank = 0.67) in comparison to other doses of Bev. The study suggests that 10mg dose Bev could be more effective in treating advanced CRC in efficacy, but 5mg Bev could be more safer in terms of safety.

Therapeutic efficacy of platinum/etoposide regimens in the treatment of advanced poorly differentiated neuroendocrine carcinomas of the lung: A retrospective analysis.

Lung neuroendocrine neoplasms (NENs) are rare malignancies developed from bronchial mucosa. Because of its rarity and complex histopathology, there is limited data on the role of chemotherapy in this subset of tumors. Few studies regarding the treatment of poorly differentiated lung NENs, known as neuroendocrine carcinomas (NECs), are available and many limits are detectable as heterogeneity of tumor samples including different origins and different clinical behaviors, moreover, no evidence of therapeutic advances have been achieved along the last thirty years. We performed a retrospective analysis of 70 patients affected by poorly differentiated lung NECs: half of patients underwent a first line therapy with a combination of cisplatin plus etoposide; the remaining patients receiving carboplatin instead of cisplatin, plus etoposide. Results: In our analysis, the outcomes of patients treated with either cisplatin or carboplatin schedule are similar in terms of ORR (44% versus 33%), DCR (75% versus 70%), PFS (6.0 versus 5.0 months) and OS (13.0 versus 10 months). Median number of chemotherapy cycles was 4 (range 1-8). The 18% of patients required a dose reduction. Main toxicities reported were hematological (70.5%), gastrointestinal (26.5%) and fatigue (18%). Survival rate in our study suggests that high grade lung NENs are characterized by an aggressive behavior and a poor prognosis, despite the treatment with platinum/etoposide according to available data. Clinical results of present study contribute to strengthen available data on the usefulness of platinum/etoposide regimen in the treatment of poorly differentiated lung NENs.

An immune-related gene expression profile to predict the efficacy of adding atezolizumab to first-line FOLFOXIRI plus bevacizumab in metastatic colorectal cancer: A translational analysis of the phase II randomized AtezoTRIBE study.

3581 Background: The phase II randomized AtezoTRIBE study demonstrated that the addition of atezolizumab (atezo) to first-line FOLFOXIRI plus bevacizumab (bev) prolongs PFS of mCRC patients, but benefit is limited among patients with proficient mismatch repair (pMMR) tumours. Among these patients, identifying a subgroup able to achieve benefit from immune-checkpoint inhibitors is a crucial challenge of translational research. To this end, we investigated the potential predictive role of an immunomodulatory gene expression signature (IO score), measuring the presence of infiltrating inflammatory cells and differentiated stromal microenvironment. Methods: AtezoTRIBE was a phase II comparative trial in which mCRC patients, unselected for MMR status, were randomized 1:2 to receive first-line FOLFOXIRI/bev (control arm) or FOLFOXIRI/bev/atezo (experimental arm). RNA was obtained from FFPE blocks of tumour specimens collected at baseline from 142 (65%) out of 218 enrolled patients. RT-qPCR was performed using DetermaIO™, to assess mRNA expression of a targeted panel of 27 genes. The established pan-cancer IO score and threshold were applied to dichotomize tumours as IO-positive (IO+) or IO-negative (IO-). Results: IO score was successfully determined in 122 (86%) cases, and 33 tumours were defined as IO+ (27%). No differences in terms of baseline clinical and molecular features were observed between IO+ and IO- tumours. Patients with IO+ and IO- tumours showed similar PFS (median PFS: 14.4 vs 13.6; HR 0.84 [95%CI: 0.53-1.33], p = 0.468). An interaction between IO status and treatment effect was reported (p for interaction = 0.066), with higher PFS benefit in favour of the experimental arm among patients with IO+ tumours (HR 0.39 [95% CI:0.15-1.02]) than among those with IO- tumours (HR 0.83 [95% CI 0.50-1.35]). A similar trend was observed in the pMMR subgroup (n = 110) (IO+ tumours: HR for PFS 0.47 [95% CI 0.18-1.25]; IO- tumours: HR for PFS 0.93 [95% CI 0.56-1.55]) (p for interaction = 0.139). No differences in terms of ORR were reported between arms according to the IO status. Conclusions: The investigated immunomodulatory signature (IO score) may be helpful to predict benefit from the addition of atezolizumab to first-line FOLFOXIRI/bev in metastatic colorectal cancer, also in the cohort of pMMR tumours. Our results support the hypothesis that a deeper characterization of tumour immune microenvironment may help identifying mCRC patients more likely to benefit from ICI-based therapeutic strategies. These findings are worthy of further investigation in independent cohorts.

CIMUC: Chemotherapy following Immune checkpoints inhibitors in patients with locally advanced or metastatic urothelial carcinoma (la/mUC).

492 Background: Immune checkpoints inhibitors (ICIs) have recently changed therapeutic landscape of la/mUC. Recent studies suggested an improvement of response to salvage chemotherapy (CT) after ICIs in several cancer types including urothelial carcinoma. We assumed that efficacy of CT rechallenge after ICIs may be improved compared to second-line CT without previous ICIs in patients (pts) with la/mUC. Methods: CIMUC is a French multicentric retrospective study including all pts with la/mUC initiating second or third-line CT from January 1st 2015 to June 30th 2020. Two groups of pts were defined: pts in group 1 (G1) were treated with a second-line CT without previous ICIs; pts in group 2 (G2) were treated with third line CT after ICIs. Primary endpoint was objective response rate (ORR: proportion of patients with complete or partial response, according to RECIST 1.1 criteria) in G2 versus G1. Secondary endpoints were progression-free survival (PFS), defined as time from initiation of second or third-line CT to disease progression or death from any cause, and toxicities. This study is supported by the French Genito Urinary Group (GETUG). Results: 553 pts were included. Baseline characteristics of the 2 groups are summarized in the Table. ORRs were 31% (95%CI [26.5-35.5]) and 29.2% (95%CI [21.9-36.6]) respectively in G1 and G2, without statistically significant difference (p=0.617), even after adjustment for Bellmunt risk factors (p=0.3214). In subgroups analysis, no difference in ORR was observed by type of CT (platinum or taxanes), duration of response (DOR) to first-platinum-based CT (< 12 months or ≥ 12 months) and FGFR-status. We did not identify any predictive factor of OR in G2 in multivariate analysis. Median PFS were 4.6 months (95%CI [3.88; 5.06]) and 4.86 months (95%CI [4.11; 5.45]), respectively in G1 and G2. Grade 3/4 hematologic toxicity occurred in 35% and 22.4%, respectively in G1 and G2. Conclusions: While ORR was not superior in G2 versus G1, pts derive comparable benefit in a further line of treatment (G2) in terms of ORR and PFS. Despite limits inherent to any retrospective study, CIMUC represents one of the largest retrospective studies in this setting.[Table: see text]

C-MET Inhibitors as New Members of the NSCLC Treatment Armamentarium—A Pooled Analysis

Objective: Capmatinib and tepotinib, two recently FDA-approved and highly specific small-molecule inhibitors of c-MET exon 14 skipping mutations are new and important therapeutic options for the treatment of NSCLC patients harbouring c-MET alterations. However, the precise role of these molecules as a new treatment option is still not fully defined. Methods: In an attempt to further evaluate the contributions of c-MET inhibitors to the armamentarium of treatment options for advanced and metastatic NSCLCs, relevant phase II and III studies were retrospectively analyzed in terms of ORR and mPFS (mOS numbers are still not available for current c-MET trials and therefore not considered for statistical purposes). Results: Treatment of advanced and metastatic NSCLC patients harbouring c-MET exon 14 skipping mutations with the novel and highly selective c-MET inhibitors is significantly superior (p < 0.0001) when compared with standard chemotherapy. However, when c-MET inhibitors are compared with immunotherapy or the combination of immunotherapy and chemotherapy, no significant differences in terms of ORR and PFS were found, but treatment with c-MET reported be much more tolerable. Conclusion: The novel and highly selective c-MET inhibitors capmatinib and tepotinib are promising novel treatment options for patients with c-MET-dysregulated NSCLC primarily in the first-line setting, albeit a clear mOS benefit has not yet been established. Since immunotherapy did not appear to be particularly effective in NSCLC patients harbouring c-MET alterations, the vast majority of these patients are treated with immunotherapy plus chemotherapy. C-Met inhibitors appear to be equally effective and thereby sparing patients from the toxic effects of the chemotherapy. The routine testing of c-MET exon 14 skipping mutations should be performed as the GEOMETRY mono-1 data clearly showed higher response rates with capmatinib in treatment-naive than in pretreated patients, indicating that c-MET exon 14 skipping mutations should preferably be molecularly assessed at baseline. C-MET exon 14 skipping mutations are, therefore, clear biomarkers of response to c-MET inhibitors.

Tre-O2-10 - Ifosfamide and etoposide in advanced-stage, relapsed or refractory primary cutaneous T-cell lymphomas

Prolonged complete remissions (CRs) are rare in advanced-stage cutaneous T-cell lymphomas (CTCLs). Ifosfamide + etoposide (I+E) have been used to treat lymphomas, combined with platinum-based agents in Hodgkin disease or non-Hodgkin lymphomas including peripheral T-cell lymphomas. Monoclonal antibodies have induced long-term remissions in CTCL but are usually poorly effective in transformed disease Allogeneic haematopoietic stem cell transplantation (alloHSCT) holds a potential for cure but relies on the existence of a pretransplant CR, which may require the use of chemotherapeutic regimens. To our knowledge, to date there are no published data on I+E efficacy and tolerance in advanced refractory CTCL. We performed a retrospective monocentre study on 28 patients with mycosis fungoides (MF, n=15) or Sézary syndrome (SS, n=13) treated with I+E between 2012 and 2019. In this study, I+E showed antitumor activity in these heavily pretreated patients with CTCL, with an ORR of 43%, and no significant difference between the full-dose and reduced-dose regimens in terms of ORR or SAE frequencies, indicating that the reduced regimen may be a suitable option in fragile patients. In conclusion, I+E is a valuable therapeutic option in patients with advanced, refractory CTCL.

Obinutuzumab (Gazyva) and High-Dose Methylprednisolone (HDMP) Combination for Patients with Chronic Lymphocytic Leukemia (CLL) - a Phase Ib/II Study

Obinutuzumab (Gazyva) and High-Dose Methylprednisolone (HDMP) Combination for Patients with Chronic Lymphocytic Leukemia (CLL) - a Phase Ib/II Study

In Situ‐Grown Nitrogen‐Doped Carbon‐Nanotube‐Embedded Two Phases of Bimetal CoFe Alloy and CoFe2O4 Spinel Oxide as Highly Efficient Bifunctional Catalyst for Oxygen Reduction and Evolution Reactions in Rechargeable Zinc–Air Batteries

The pedestal of the rechargeable zinc–air battery (ZAB) is based on high‐performance bifunctional oxygen reduction/evolution reactions (ORR/OER) electrocatalysts. Herein, without any template or surfactant, in situ grown nitrogen‐doped carbon‐nanotube (NCNT)‐embedded with two phases of bimetal CoFe alloys and CoFe2O4 spinel oxide are constructed, using inexpensive materials of glucose, urea, and cobalt/iron acetates by programing the pyrolysis temperature. The obtained catalyst with optimal cobalt/iron acetates mass ratio (1:1) denoted as CoFe–CoFe2O4–NCNT not only exceeds Pt–Ru/C in terms of ORR half‐wave potentials [(0.88 vs 0.84 V versus reversible hydrogen electrode (RHE)] and limiting current densities (6.40 vs 5.40 mA cm−2), but also manifests superior OER activity with the potentials of (1.58 vs 1.67 V versus RHE) at 10 mA cm−2. Therefore, CoFe–CoFe2O4–NCNT exhibits a smaller value of (0.70 V versus RHE), surpassing that of Pt–Ru/C (0.85 V versus RHE) and shows excellent stability as well as outstanding methanol tolerance compared with the Pt–Ru/C commercial catalyst. In addition, CoFe–CoFe2O4–NCNT applied as a bifunctional air electrode in rechargeable ZAB displays a promising rechargeability performance with high‐discharge and low‐charge potentials and a relatively stable potential gap under 550 cycles, outperforming those of Pt–Ru/C.

Abstract PS4-38: Association of tumor infiltrating lymphocytes (TILs) density and PD-L1 expression with pembrolizumab (P) plus gemcitabine (Gem) efficacy in patients with HER2-negative advanced breast cancer (ABC) from the GEICAM/2015-04 (PANGEA-Breast) study

Abstract Background Immune cells (ICs) infiltration and immune checkpoints have been shown to be important for BC patients’ (pts) prognosis and response to immunotherapy. We aimed to analyze the relation between TILs prevalence and PD-L1 expression with efficacy to an immunostimulatory combination with P and Gem in ABC HER2-negative pts previously treated with ≤4 chemotherapy and/or ≥2 hormone therapy lines from the PANGEA-Breast trial (NCT03025880). Methods Pre-treatment (ttm) metastatic BC samples were assessed for TILs density [% of occupied stromal area upon H&amp;E staining] and for PD-L1 immunohistochemistry expression using monoclonal anti-PD-L1 antibody clone 22C3 (Merck) by calculating ICs score (% of positive infiltrated ICs) and combined positive score [CPS; PD-L1 stained cells (tumor cells, lymphocytes, macrophages) divided by total viable tumor cells, multiplied by 100]. Cut-offs ≥5%, ≥10%, ≥30% were explored for TILs. PD-L1 scores were considered positive if ≥1%. Cut-offs (≥5%, ≥20%, ≥50%) were additionally assessed for PD-L1 as CPS. Logistic regression models were used to evaluate association between TILs density and PD-L1 expression with ttm efficacy in terms of Objective Response Rate [ORR; Complete + Partial Response (CR + PR)], Clinical Benefit Rate [CBR; CR + PR + Stable Disease ≥24 weeks] and Progression Free Survival (PFS), according to RECIST v1.1. Results Thirty-six pts were included, 58% had triple negative BC and 98% ECOG score ≤1. Median number of prior ttm lines was 4. ORR and CBR were 15.2% and 17%, respectively; median PFS was 3.1 months. TILs and PD-L1 were evaluated in 30 and 29 pts, respectively. No association was found between TILs density and ttm efficacy in terms of ORR, CBR and PFS. Analysis of PD-L1 ICs score did not reveal any significant association with ORR, CBR or PFS. However, pts with negative PD-L1 expression by CPS (&amp;lt;1%) had a significantly prolonged PFS [p-value=0.031; HR 0.39 (95%CI 0.16; 0.95)], not maintained at CPS &amp;lt;20% cut-off [p-value=0.062; HR 0.42 (95%CI 0.17; 1.08)]. Conclusions Our findings support that: 1) P plus Gem ttm in heavily pre-treated HER2-negative ABC pts obtains a modest ORR of 15.2%; 2) TILs density and PD-L1 expression in ICs does not predict its benefit; 3) PD-L1 in tumor cells scored as CPS impacts in worse outcome (PFS) but not in ORR, suggesting an eventual prognostic role in this population; 4) no long-term responders were observed with P plus Gem in this trial. Citation Format: Luis De la Cruz, María Gion, Josefina Cruz, Jose Luis Alonso, Vanesa Quiroga, Fernando Moreno, Marta Santisteban, Raquel Andrés, Esther Holgado, Natalia Palazón, Luz Milva Rodríguez, Asunción Soto, Javier Cortés, Alfonso Cortés, Manuel Ramos, Maribel Casas, Massimo Chiesa, Susana Bezares, Rosalía Caballero, Federico Rojo. Association of tumor infiltrating lymphocytes (TILs) density and PD-L1 expression with pembrolizumab (P) plus gemcitabine (Gem) efficacy in patients with HER2-negative advanced breast cancer (ABC) from the GEICAM/2015-04 (PANGEA-Breast) study [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 PS4-38.

Azacitidine and Lenalidomide in Higher-Risk Myelodysplastic Syndromes. Long-Term Results of a Randomized Phase II Multicenter Study and Impact of Cytogenetic Scores and Mutational Status on Long-Lasting Responses

Azacitidine and Lenalidomide in Higher-Risk Myelodysplastic Syndromes. Long-Term Results of a Randomized Phase II Multicenter Study and Impact of Cytogenetic Scores and Mutational Status on Long-Lasting Responses

Efficacy and Safety of Ixazomib Induction and Maintenance in Newly Diagnosed Multiple Myeloma Patients According to the IMWG Frailty Score: A Post-Hoc Analysis of the EMN10-Unito Trial

Efficacy and Safety of Ixazomib Induction and Maintenance in Newly Diagnosed Multiple Myeloma Patients According to the IMWG Frailty Score: A Post-Hoc Analysis of the EMN10-Unito Trial

Novel approaches in marginal zone lymphoma: Systematic review.

e20089 Background: Marginal zone lymphoma represents no more than 17% of NHLs and there is no standard of care. We reviewed the efficacy of novel drugs with main focus on ORR and PFS/OS (when available). Methods: Literature search was performed based on PRISMA guidelines in PubMed, Cochrane, EMBASE, Clinicaltrials.gov. Studies which did not give separate results for MZL were excluded. Results: 23 trials (n = 1491 patients) were included. 57% were refractory to previous line of therapy. 9 studies were conducted specifically in MZL (n = 440). The most common intervention was Rituximab and its combinations. PFS and OS were inconsistently reported. 1. Monotherapy in untreated MZL: In a phase III study, ORR was reported at 82.8% vs 81.3% with PFS of 75% vs 78% at 3 years in Obinutuzumab vs Rituximab. In Phase II Ibritumumumab tiuxetan showed 100% ORR in 11 patients with 5-year PFS of 82%. Most common grade 3-4 AE were hematological. Lenalidomide was studied in 18 EMZL patients, with 60% being untreated. In this study, ORR was reported at 61% with CR 33%. 2. Combination therapy in untreated MZL: Lenalidomide+Rituximab showed 93% ORR and median PFS 59.8 months with manageable toxicities. Ibrutinib in combination with Rituximab and Lenalidomide produced ORR of 90% with CR 60%. The addition of Bendamustine to Rituximab showed ORR and CR of 91% and 73% with 3-year PFS of 93% in a study of only SMZL (n = 56). 3. Monotherapy in R/R MZL: Ibrutinib demonstrated ORR of 50%, 54% and 41% in EMZL, SMZL and NMZL, respectively with median PFS of 14.2 months. Less hematologic toxicity was seen in MZL patients receiving Ibrutinib monotherapy compared to other regimens. In 30 patients receiving Everolimus, ORR was reported at 25%. Bortezomib has significant activity in EMZL with ORR of 48%. PI3Kδ inhibitors Idelalisib, Copanlisib and Duvelisib showed clinical activity. Umbrelisib and Ofatumumab demonstrated ORR &gt; 50%. Vorinostat demonstrated an ORR of 22%. 4. Combination therapy in R/R MZL: Rituximab+Lenalidomide had a higher ORR (39.4 vs. 14.1%) and higher PFS (58 vs. 36% at 2-year) compared to Rituximab monotherapy. Combination of Tirabrutinib and Entospletinib showed 20% ORR in a small group of MZL patients. Addition of Idelalisib to Tirabrutinib demonstrated ORR 40%. Ibrutinib and Venetoclax combination demonstrated ORR &gt; 50%. Ublituximab and Umbralisib showed clinical activity. Conclusions: With expanding armamentarium of targeted agents, our review has demonstrated positive results especially in terms of ORR in patients with MZL. Further studies are required to explore the role of these drugs and their impact on survival.

Oligometastatic colorectal cancer: Prognostic implications of tumor load, role of locoregional treatments, and of first-line therapy intensification—A pooled analysis of TRIBE and TRIBE2 studies by GONO.

12 Background: According to the ESMO guidelines a metastatic spread involving up to 2 or occasionally 3 sites with 5 or sometimes more metastases (mts) is defined as oligometastatic disease (OMD) and the possibility to offer locoregional treatments (LRTs) should be carefully considered. Tumor load and treatment’s objective (cytoreduction vs disease control) are included among factors affecting the choice of the intensity of the upfront chemotherapy (CT). Nevertheless, no data from clinical trials adopting this definition are currently available, so that the prognostic effect of tumor load, the impact of LRTs and the magnitude of benefit from the CT-intensification in OMD remain unclear. Here we assess the effect of FOLFOXIRI/bev compared to doublets (FOLFOX or FOLFIRI)/bev and the impact of LRTs according to tumor load (OMD vs non-OMD) in a pooled analysis of two randomized phase III studies (TRIBE and TRIBE2). Methods: Subgroup analyses for ORR, PFS and OS were performed according to tumor load at baseline. OMD was defined as up to 5 mts, up to 3 mts in one organ, up to 3 affected organs, mts size ≤ 3 cm, absence of ascites and peritoneal, bone and central nervous system mts. Results: Among 1187 patients (pts) enrolled, 1158 were classifiable: 126 as OMD (11%) and 1032 as non-OMD (89%). Pts with OMD had longer PFS (14.3 vs 10.5 months (mos); p &lt; 0.01) and OS (44.3 vs 24.0 mos; p &lt; 0.01) compared with those with non-OMD. These results were confirmed in multivariable models (p &lt; 0.01). Also among pts who underwent LRTs with curative intent during first line (N = 202), those with OMD at baseline (N = 35) reported longer OS than those with non-OMD (59.6 vs 50.6 mos; p = 0.04). The benefit provided by FOLFOXIRI/bev compared to doublets/bev was confirmed in the OMD subgroup with no interaction effect between treatment arm and tumor load in terms of ORR, PFS and OS (p for interaction = 0.10, 0.58 and 0.23, respectively). Conclusions: OMD is confirmed as a positive prognostic factor and is associated with a higher magnitude of long-term benefit from LRTs than non-OMD. The positive impact of the intensification of the upfront CT is independent of tumor load.

Stereotactic ablative radiotherapy versus conventionally fractionated radiotherapy in the treatment of hepatocellular carcinoma with portal vein invasion: a retrospective analysis

BackgroundThis study aimed to compare the clinical outcomes of stereotactic ablative radiotherapy (SABR) and conventionally fractionated radiotherapy (CFRT) in hepatocellular carcinoma (HCC) patients with portal vein invasion (PVI).MethodsHCC patients with PVI treated with radiotherapy from 2007 to 2016 were analysed. CFRT was administered at a median dose of 51.5 Gy (interquartile range, 45–54 Gy) with 1.8–3 Gy per fraction. SABR was administered at a median dose of 45 Gy (interquartile range, 40–48 Gy) with 6–12.5 Gy per fraction. Treatment efficacy, toxicity, and associated predictors were assessed.ResultsAmong the 104 evaluable patients (45 in the SABR group and 59 in the CFRT group), the overall response rate (ORR, complete and partial response) was significantly higher in the SABR group than the CFRT group (62.2% vs. 33.8%, p = 0.003). The 1-year overall survival (OS) rate (34.9% vs. 15.3%, p = 0.012) and in-field progression-free survival (IFPS) rate (69.6% vs. 32.2%, p = 0.007) were also significantly higher in the SABR vs. CFRT group. All 3 rates remained higher in the SABR group after propensity score matching. Multivariable analysis identified SABR and a biologically effective dose ≥65 Gy as favourable predicators of OS. There was no difference between treatment groups in the incidence of radiation-induced liver disease or increase of Child-Pugh score ≥ 2 within 3 months of radiotherapy.ConclusionsSABR was superior to CFRT in terms of ORR, OS, and IFPS. We suggest that SABR should be the preferred technique for HCC patients with PVI.

Family history of cancer as surrogate predictor for immunotherapy with anti-PD-1/PD-L1 immune checkpoint inhibitors: The FAMI-L1 study.

2559 Background: In the preliminary analysis of the FAMI-L1 study, we found a significant association between family history of cancer (FHC) and better clinical outcomes with anti-PD1/PD-L1 inhibitors. Methods: We retrospectively evaluated advanced cancer patients treated with single agents PD1/PD-L1 inhibitors. Patients were categorized as follow: FHC-high (in case of at least one cancer diagnoses in both straight and collateral family line), FHC-low (in case of a cancer diagnoses in only one family line) and FHC-negative. FHC was collected till the second degree of relatedness. Results: Between September 2013 and May 2018, 772 consecutive patients were evaluated. Median age was 68 years; male/female ratio was 521/251. Primary tumors were: NSCLC (58.3%), melanoma (22.1%), renal cell carcinoma (16.6%) and others (3%). 114 patients (14.9%) had ECOG-PS ≥ 2. 341 patients (44.3) were FHC-positive: 268 of them (34.75) were FHC-low while 74 (9.6%) were FHC-high. FHC-high patients had a significantly higher incidence of irAEs compared to FHC-negative (55.4% vs 35.6%; p = 0.0012) and to FHC-low (41.4%; p = 0.0323). No significant differences were found in terms of ORR among subgroups (data not shown). At median follow-up of 15.8 months, median PFS was 9.1 months (95%CI: 8.1-10.4; 452 events) and median OS was 19.7 months (95%CI: 15.7-24.4; 436 censored). No significant differences were found regarding PFS (data not shown). Median OS of FHC-high patients was 31.6 months (95%CI: 26.2-31.6; 50 censored patients), which was significantly longer than 18.2 months (95%CI: 14.7-21.3; 229 censored patients) of FHC-negative patients (HR = 0.60 [95%CI: 0.39–0.92), p = 0.0213). No significant differences in terms of OS were found between FHC-high/low patients (data not shown). After adjusting for primary tumor, sex, treatment-line, number of metastatic sites and ECOG-PS, FHC-high was confirmed an independent predictor of longer OS compared to FHC-negative (HR: 0.57 [95%CI: 0.37-0.88], p = 0.0098). Conclusions: FHC-high seems to be an independent predictor for longer OS in cancer patients treated with anti-PD-1/PD-L1. DNA damage and response (DDR) genes alterations may underlie that results.

Fierce-21: Phase II study of vofatmab (B-701), a selective inhibitor of FGFR3, as salvage therapy in metastatic urothelial carcinoma (mUC).

409 Background: Patients (pts) with mUC who have failed platinum-based chemotherapy have a poor prognosis. About 20% of them usually respond to immune checkpoint inhibitors (ICI). Also, 20% of pts with mUC harbor FGFR3 mutations or fusions (M/F), and this feature may be associated with lower sensitivity to ICI. Vofatamab (B-701) is a fully human monoclonal antibody against FGFR3 that blocks activation of the wildtype and genetically activated receptor. FIERCE-21 is a Phase 1b/2 study designed to evaluate vofatamab monotherapy (VM) or in combination with docetaxel (VD). Methods: The study consists of a P 1b lead-in (P1b with VD), previously reported followed by P2 expansion cohort in FGFR3 M/F+ pts (identified with the FoundationONE CDx™ assay on archival samples). The study enrolled mUC pts with failure to ≥ 1 line prior chemotherapy (including prior taxane treatment) or ≤12 months of (neo)adjuvant chemotherapy, measurable disease and ECOG ≤ 1. Treatment consisted of vofatamab at 25 mg/kg alone (VM) and in combination with D (VD) at 75 mg/m2 q3w. Efficacy was assessed by investigators (RECIST 1.1). Primary objectives were safety and activity (objective response-rate [ORR]). Results: 55 pts have received treatment. In the Ph 2 study, 21 pts received VM, 15 pts received VD. 35% of pts were included as 2nd line therapy, 65% in 3rd or later line of treatment. For pts receiving VD, safety was consistent with Ph 1B data. For pts receiving VM, median age was 67 yrs, ECOG 1 = 71.4%, Hgb &lt; 10 gm/dL 13%, liver metastases 19%, ≥ 2 prior regimens 57%, (best response to prior therapy PD 31%). TEAEs occurring in ≥5% patients were asthenia (19%), diarrhea (9.5%), flushing 14%, chills (9.5%), hypotension (9.5%), decreased appetite (19%) and creatinine increased (9.5%). The majority of TEAS were grade 1 and 2. Only 1 patient on MF had a grade 3 TEAE and only 1 patient discontinued treatment due to an AE. The ORR have been seen in 7 pts to date including those receiving both VM and VD. Conclusions: Vofatamab both alone and combined with D in an every 3-week schedule are well tolerated with a low frequency of grade 3 TEAEs. Both VM and VD have demonstrated efficacy in terms of ORR, and mature results with PFS data will be presented. Clinical trial information: NCT02401542.

Sulfur bridges between Co9S8 nanoparticles and carbon nanotubes enabling robust oxygen electrocatalysis

Electrocatalytic active species, for example, metal sulfides, have been widely combined with carbon nanomaterials for enhanced performance because of the synergetic effect arising from the interaction between different components. However, the binding between metal sulfides and carbon nanomaterials, which plays a key role in determining their interaction, has not been clearly elucidated. Herein, we reported the sulfur bridges between sulfur-doped carbon nanotubes (S-CNTs) and Co9S8 nanoparticles and their significant effect on the practical electrochemical performance. Compared to the physically mixed composites, the one with sulfur bridges between CNTs and Co9S8 shows much better performance in terms of oxygen evolution (overpotential of 0.331 V at 10 mA cm−2) and oxygen reduction (half-wave potential of 0.810 V). Demonstrating that the sulfur bridges facilitate fast electron hopping from conductive support to active species, thus contributing to the outstanding electrochemical performance. Moreover, a rechargeable Zn-Air battery based on our electrocatalyst with strong sulfur bridges delivers an outstanding performance in terms of ORR and OER bifunctional performances. The clear understanding of the sulfur bridges between CNTs and Co9S8 is believed to shed substantial light on the development of other high-performance electrocatalysts.

Comparison of Two Different Therapeutic Regimens with Azacitidine and Lenalidomide (Combined versus Sequential) in Higher-Risk Myelodysplastic Syndromes. Update of Long-Term Results of a Randomized Phase II Multicenter Study

Comparison of Two Different Therapeutic Regimens with Azacitidine and Lenalidomide (Combined versus Sequential) in Higher-Risk Myelodysplastic Syndromes. Update of Long-Term Results of a Randomized Phase II Multicenter Study