Progression-free Survival In Subgroups Research Articles

Avelumab First-line Maintenance for Advanced Urothelial Carcinoma: Analysis from JAVELIN Bladder 100 by Duration of First-line Chemotherapy and Interval Before Maintenance

BackgroundIn the JAVELIN Bladder 100 phase 3 trial, avelumab first-line maintenance + best supportive care (BSC) prolonged overall survival (OS) and progression-free survival (PFS) versus BSC alone in patients with advanced urothelial carcinoma (advanced UC) without progression after first-line platinum-based chemotherapy. ObjectiveTo report post hoc analyses of subgroups defined by the duration of first-line chemotherapy and interval before maintenance. Design, setting, and participantsPatients with advanced UC without progression after four to six cycles of platinum-based chemotherapy and a 4–10-wk interval after chemotherapy (n = 700) were randomized to receive avelumab + BSC or BSC alone. Subgroups were defined by duration (quartile [Q]) and estimated number of cycles of chemotherapy, and interval between chemotherapy and maintenance. The median follow-up was >19 mo in both arms. Outcome measurements and statistical analysisOS (primary endpoint), PFS, and safety were assessed. Results and limitationsHazard ratios (95% confidence interval) for OS with avelumab + BSC versus BSC alone were as follows: by chemotherapy duration—<Q1: 0.65 (0.42–1.02), Q1–Q2: 0.79 (0.50–1.27), Q2–Q3: 0.74 (0.50–1.10), and >Q3: 0.63 (0.39–1.00); by number of cycles—four cycles: 0.69 (0.48–1.00), five cycles: 0.98 (0.57–1.71), and six cycles: 0.66 (0.47–0.92); and by interval—4–<6 wk: 0.75 (0.54–1.04), 6–<8 wk: 0.67 (0.43–1.06), and 8–10 wk: 0.69 (0.47–1.02). Results were similar for PFS. Safety was similar across subgroups. All analyses were exploratory. ConclusionsPost hoc analyses of OS and PFS in subgroups defined by first-line chemotherapy duration and interval before maintenance were generally consistent with the results in the overall population, with similar safety findings. Prospective trials are warranted to confirm these findings. Patient summaryAvelumab maintenance treatment helped patients with advanced urothelial cancer without disease progression after at least four cycles of prior chemotherapy, and who started maintenance treatment at least 4 wk after chemotherapy, to live longer.

Efficacy of tucatinib+trastuzumab+capecitabine (TTC) after trastuzumab-deruxtecan (T-DXd) exposure in Her2-positive metastatic breast cancer: A French multicentre retrospective study.

1014 Background: Recent guidelines have positioned T-DXd as a preferred treatment in the second line setting for HER2+ metastatic breast cancer (MBC). TTC is the preferred treatment in third line, however little is known on the efficacy of this combination after T-DXd exposure. Methods: We conducted a retrospective study in 12 French comprehensive cancer centers. All patients with HER2+ MBC treated with TTC after prior exposure to T-DXd were included. The primary end point was progression-free survival (PFS) in the whole population. Secondary end-points included overall survival (OS), PFS in subgroups and objective response rate. Results: Between 08/2020 and 12/2022, 101 patients were included. Median age was 56.4 y.o. (range 30.8 - 84.8). Median number of prior line of treatment for metastatic disease at TTC start was 4 (2 - 15). 82% and 95% of patients had received previous pertuzumab and T-DM1 respectively. The median duration of previous exposure to T-DXd was 8.9 months (1.4 - 31.4) and 82/101 (81%) patients had progressed under T-DXd while 19 had stopped T-DXd for toxicity or other reasons. TTC regimen was given as a 3rd line or 4th line for metastatic disease in 37/101 (37%) and beyond for the remaining patients. TTC was the immediate subsequent therapy to T-DXd for 86/101 pts (85%). With a median follow-up of 8.5 m (95%CI [7.7; 9.4]), 68/101pts (67%) have stopped TTC for progressive disease. Median PFS was 4.7 m (95%CI [3.8; 5.6]) and median OS not reached (95%CI [10.6; NA]) in the whole population. Patients treated with TTC as the immediate subsequent therapy to T-DXd, had a median PFS of 5.0 m (95%CI [4.0; 6.0]) and a median OS not reached (95%CI [11.9; NA]). Best response to TTC, evaluated by investigators in the 87/101 RECIST evaluable patients, was progressive disease, stable disease, partial response and complete response in 34%, 34%, 30% and 2% of patients respectively. At TTC initiation, 39 (39%) of patients had known brain metastases. Out of the 62 patients without known brain metastases at the initiation of TTC, 2 had brain metastases documented as a site of progression during TTC. Conclusions: In this large retrospective cohort, TTC shows significant efficacy for patients with HER2+ MBC previously exposed to T-DXd. Data and subgroup analyses will be updated for the meeting.

Safety and effectiveness of continuous denosumab for unresectable or advanced giant cell tumor

Introduction. Giant cell tumor of bone is a relatively rare, locally aggressive osteolytic skeletal neoplasm with uncertain behavior: recurrence rates up to 70 % and distant metastases occur 2–6 % of cases. Nowadays denosumab is the choice of therapy for patients with unresectable or advanced disease. However, the efficiency, duration or administration and most of all safety of continuous denosumab are not established.Materials and methods. Fourty advanced or unresectable giant cell tumor cases were observed from 2005 till 2020 in N.N. Blokhin National Medical Research Center of Oncology. The average age of pts was 33,6 ± 13,1 years (18–64), and the women and men ratio was about 2,1 : 1. The most commonly affected sites were long bones of the lower extremities (22,5 %), sacrum (22,5 %), long bones of the upper extremities (17,5 %), spine (17,5 %), pelvis (10 %) and others. 70 % of cases were anatomically compounded due to tumor localization and 27,5 % of cases were primary disease. 37,5 % of cases were with pulmonary metastases. Patients underwent computed tomography / magnetic resonance imaging every 3 months during the first three years and then once every six months. Patient received subcutaneous denosumab 120 mg every 4 weeks with a loading dose of 120 mg subcutaneous on study days 8 and 15. After 2 years monthly therapy and confirmed stabilization effect patient then received maintenance therapy: once in three months injection. All patients received daily calcium and vitamin D supplement.Results. Median follow-up was 52,8 ± 41,3 months (3–219 months). The average denosumab injections were 25 ± 16 (4–85). Clinical and radiographically stabilization of the effect occurred on average at 12 ± 8 (4–32) injections. Hypocalcemia was registered in one case (2.5 %). There was significant improvement of Karnofsky scale, Visual analogue scale (VAS) and Watkins scale (p &lt;0.001). 5-year progression-free survival for was 70.1 % (95 % confidence interval 55.7–88.0), the median was not reached. Progression of disease was observed only in subgroup with violations in denosumab administration or its cancellation (32,5 %). 3-year progression-free survival in subgroup with violations in denosumab administration or its cancellation was 10 % (95 % confidence interval 15.5–64.1). In subgroup with continuous denosumab and once in three months injection after 2 years monthly therapy there was no signs of progression.Conclusions. In this study we showed evidence of safety and effectiveness of continuous denosumab for unresectable or advanced giant cell tumor even with once in three months injection therapy. Denosumab for advanced giant cell tumor of bone became a choice of treatment, but we need further investigation for observation long term denosumab effectiveness and complications.

Treatment patterns and prognosis of patients with inoperable stage III NSCLC after completion of concurrent chemoradiotherapy ± immune checkpoint inhibition: a decade-long single-center historical analysis

PurposeTo investigate the impact of treatment time and patterns in inoperable stage III non-small cell lung cancer (NSCLC) following concurrent chemoradiotherapy (cCRT) ± immune checkpoint inhibitors (ICIs).MethodsPatients were stratified by treatment year: A (2011–2014), B (2015–2017) and C (2018–2020). Tumor- and treatment-related characteristics regarding locoregional recurrence-free survival (LRRFS), progression-free survival (PFS) and overall survival (OS) were investigated.ResultsOne hundred and thirty-six consecutive patients were analyzed. All patients completed thoracic radiotherapy (TRT) to a total dose ≥ 60.0 Gy; 36 (26%) patients received ICI. Median PFS in subgroups A, B and C was 8.0, 8.2 and 26.3 months (p = 0.007). Median OS was 19.9 months, 23.4 months and not reached (NR), respectively. In group C, median LRRFS and PFS were 27.2 vs. NR; and 14.2 vs. 26.3 months in patients treated with and without ICI. On multivariate analysis planning target volume (PTV) ≥ 700 cc was a negative prognosticator of LRRFS (HR 2.194; p = 0.001), PFS (HR 1.522; p = 0.042) and OS (HR 2.883; p = 0.001); ICI was a predictor of LRRFS (HR 0.497; p = 0.062), PFS (HR 0.571; p = 0.071) and OS (HR 0.447; p = 0.1). In the non-ICI cohort, multivariate analyses revealed PTV ≥ 700 cc (p = 0.047) and a maximum standardized uptake value (SUVmax) ≥ 13.75 (p = 0.012) were predictors of PFS; PTV ≥ 700 cc (p = 0.017), SUVmax ≥ 13.75 (p = 0.002) and a total lung V20 ≥ 30% (V20 ≥ 30) (p < 0.05) were predictors of OS.ConclusionsPatients treated after 2018 had improved survival regardless of ICI use. Implementation of ICI resulted in further significant increase of all tested survival endpoints. PTV ≥ 700 cc and ICI were only prognosticators for LRRFS, PFS and OS in the analyzed cohort.

Efficacy and safety of rezivertinib (BPI-7711) in patients with locally advanced or metastatic/recurrent EGFR T790M-mutated NSCLC: A phase IIb, multicenter, single-arm, open-label study.

9098 Background: Rezivertinib (BPI-7711) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) targeting both EGFR-sensitizing mutations and EGFR T790M mutation. This study aimed to evaluate the efficacy and safety of Rezivertinib in patients with locally advanced or metastatic/recurrent EGFR T790M mutated non-small cell lung cancer (NSCLC). Methods: Locally advanced or metastatic/recurrent NSCLC patients with histologic or cytologic or plasmatic confirmation of EGFR T790M mutations who progressed after first/second generation EGFR-TKIs therapy or primary EGFR T790M mutations were enrolled. Patients received Rezivertinib at 180mg orally once daily until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was objective response rate (ORR) assessed by blinded independent central review (BICR) per RECIST1.1. The efficacy for patients with central nervous system (CNS) metastases was measured by BICR according to the Response Assessment in Neuro-Oncology Brain Metastases. Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. Safety was assessed as per CTCAE 4.03. Results: A total of 226 patients were enrolled from Jul 5, 2019, to Jan 22, 2020. 91 (40.3%) patients had brain metastases. The tissue sample and plasma sample were positive for EGFR T790M in 120 (53.1%) and 116 (51.3%) patients, respectively. By the data cutoff date on Dec 23, 2021, the ORR by BICR was 64.6% (95%CI:58.0-70.8) and DCR was 89.8% (95%CI:85.1-93.4). The median DoR was 12.5 (95%CI:10.0-13.9) months and median PFS was 12.2 (95%CI:9.6-13.9) months. The median OS was 23.9 (95%CI:20.0-NC) months. Subgroup ORR: exon 19 deletion 72.4% (95%CI:64.4-79.5), L858R 51.9% (95%CI:40.4-63.3), tissue T790M positive 70% (95%CI:61.0-78.0), plasma T790M positive 56.9% (95%CI:47.4-66.1). Subgroup PFS: exon 19 deletion 12.4 (95%CI:8.8-15.1) months, L858R 10.3 (95%CI:8.3-13.9) months, tissue T790M positive 13.9 (95%CI:11.3-17.9) months, plasma T790M positive 9.6 (95%CI:7.0-11.0) months. Among 91 patients with CNS metastases, 29 patients had at least one brain target lesion whose CNS-ORR and CNS-DCR were 69.0% (95%CI:49.2-84.7) and 100% (95%CI:88.1-100), respectively. Time to progression of CNS was 16.5 (95%CI:9.7-NC) months. 188 of 226 (83.2%) patients had at least one adverse drug reaction, with the most common being white blood cell count decreased (27.9%), platelet count decreased (23.0%), anemia (22.6%). No interstitial lung disease was reported. Conclusions: Rezivertinib demonstrated promising efficacy and favorable safety for locally advanced or metastatic/recurrent NSCLC patients with EGFR T790M mutation. Clinical trial information: NCT003812809.

Progression-Free Survival (PFS) According to the Presence of Adverse Cytogenetic Abnormalities in Patients (pts) with Multiple Myeloma (MM) Receiving Ixazomib (ixa)-Based vs Placebo (pbo)-Based Therapy: A Pooled Analysis of the TOURMALINE-MM1, MM2, MM3, and MM4 Phase 3 Studies

Progression-Free Survival (PFS) According to the Presence of Adverse Cytogenetic Abnormalities in Patients (pts) with Multiple Myeloma (MM) Receiving Ixazomib (ixa)-Based vs Placebo (pbo)-Based Therapy: A Pooled Analysis of the TOURMALINE-MM1, MM2, MM3, and MM4 Phase 3 Studies

1390P - Diabetes is associated with pancreatic neuroendocrine tumours growth and metastasis

BackgroundPrevious studies have demonstrated an association between type 2 diabetes mellitus (T2DM) and several types of cancers. However, the role of T2DM in pancreatic neuroendocrine tumors (pNETs) has not been systemically studied. MethodsA retrospective, follow-up cohort analysis including 299 patients with pNETs was performed. The clinicopathologic characteristics between diabetics and nondiabetic were compared. The overall survival (OS) and progression-free survival (PFS) separated by diabetics and nondiabetic status were analyzed. The association between metformin use and survival was assessed to confirm whether metformin has an impact on prognosis of pNETs. ResultsThe prevalence of T2DM was 20.7% (n=62) in the cohort. For both OS and PFS, diabetic status was associated with a dismal outcome in univariate analyses, and the association was not exist when controlled by stage. The proportion of grade 3 tumor, distant metastasis and nerve invasion was higher in pNETs patients with T2DM than that of patients without T2DM. According to the result of logit regression, pNETs patients with T2DM were at high risk of tumor metastasis (OR=2.81, P=0.001), nerve invasion (OR=2.43, P=0.029) and grade 3 tumor (OR=4.97, P=0.010). Multivariate analysis demonstrated that T2DM was not an independent predictor of OS (P=0.742) and PFS (P=0.917). In subset analysis, no significant differences were observed for OS and PFS in subgroup according to their metformin usage. ConclusionsT2DM is associated with pNETs growth and metastasis, and is not an independent risk factor of poor prognosis in patients with pNETs. No significant association is found between metformin use and survival in pNETs patients. Legal entity responsible for the studyXianjun Yu. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Efficacy of vinorelbine combined with low-dose methotrexate for treatment of inoperable desmoid tumor and prognostic factor analysis.

To assess the efficacy of conservative chemotherapy for inoperable desmoid tumor (DT) and analyze the prognostic factors. From November 2008 to April 2016, 71 patients of inoperable DT were treated with vinorelbine and low-dose methotrexate in the Department of Bone and Soft Tissue Tumors, Peking University Cancer Hospital & Institute, and enrolled in this retrospective study. The chemotherapy duration is one year. The efficacy of chemotherapy and the prognosis were observed. Of the 71 patients, 55% were female. Age of onset varied from 1 to 47 years, and the median age was 14 years. Only 11 (15.5%) cases suffered primary tumor. The distribution of the site of tumors was: 31 (43.7%) in the trunk, 36 (50.7%) in the limbs, and 4 (5.6%) in the peritoneal and pelvic cavity. The size of tumor (the maximum diameter) differed from 2 to 37 cm with a mean of 9.3 cm. The median follow-up duration was 28 (range, 6-87) months. Common side effects included: nausea and vomiting, liver injury, bone marrow suppression and oral ulcers. When the chemotherapy finished, 1 (1.4%) case achieved complete response, 24 (33.8%) achieved partial response, 37 (52.1%) achieved stable disease and 9 (12.7%) had progressive disease. The overall response rate was 87.3%. The progression-free survival (PFS) of the participants were from 6 to 87 months, and the 2-, 3- and 5-year PFS was 79.9%, 68.4% and 36.3%, respectively. No significant difference was identified in PFS in subgroups of gender, age of onset, age of chemotherapy, tumor site and tumor size. For recurrent, inoperable and progressive DT, enough course of chemotherapy with vinorelbine combined with low-dose methotrexate was an optional choice for local control.

Synergistic effects of metformin in combination with EGFR-TKI in the treatment of patients with advanced non-small cell lung cancer and type 2 diabetes

BackgroundAcquired resistance has become the bottleneck affecting the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment. Studies have shown that the antidiabetic drug metformin could effectively increase the sensitivity of TKI-resistant lung cancer cells to EGFR-TKI. This study aimed to evaluate the effect of metformin in combination with EGFR-TKI on the prognosis of non-small cell lung cancer (NSCLC) patients with diabetes mellitus type 2 (DM2). MethodsData of NSCLC patients with DM2 who received treatment in six hospitals in China between January 2006 and January 2014 were reviewed retrospectively. They were divided into two groups: Group A, where the patients (n = 44) received EGFR-TKI plus metformin; and Group B, where the patients (n = 46) received EGFR-TKI plus hypoglycemic agents other than metformin. Prognostic differences between the two groups were assessed. ResultsThe median progression-free survival (PFS) and median overall survival (OS) in Group A were significantly longer than those in Group B (19.0 months vs. 8.0 months, P = .005; 32.0 months vs. 23.0 months, P = .002). The objective response rate (ORR) and disease control rate (DCR) in Group A were significantly higher than those in Group B (70.5% vs. 45.7%, P = .017; 97.7% vs. 80.4%, P = .009). Secondary data analysis showed that metformin use significantly prolonged the median PFS in subgroups using either first-line EGFR-TKI or second-line EGFR-TKI. ConclusionsMetformin and EGFR-TKI have a synergistic effect in the treatment of DM2 NSCLC patients harboring EGFR-activating mutations. Metformin use is associated with improved survival and delayed onset of acquired resistance to EGFR-TKI.

Final results from the large sunitinib global expanded-access trial in metastatic renal cell carcinoma.

Background:We report final results with extended follow-up from a global, expanded-access trial that pre-regulatory approval provided sunitinib to metastatic renal cell carcinoma (mRCC) patients, ineligible for registration-directed trials.Methods:Patients ⩾18 years received oral sunitinib 50 mg per day on a 4-weeks-on–2-weeks-off schedule. Safety was assessed regularly. Tumour measurements were scheduled per local practice.Results:A total of 4543 patients received sunitinib. Median treatment duration and follow-up were 7.5 and 13.6 months. Objective response rate was 16% (95% confidence interval (CI): 15–17). Median progression-free survival (PFS) and overall survival (OS) were 9.4 months (95% CI: 8.8–10.0) and 18.7 months (95% CI: 17.5–19.5). Median PFS in subgroups of interest: aged ⩾65 years (33%), 10.1 months; Eastern Cooperative Oncology Group performance status ⩾2 (14%), 3.5 months; non-clear cell histology (12%), 6.0 months; and brain metastases (7%), 5.3 months. OS was strongly associated with the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model (n=4065). The most common grade 3/4 treatment-related adverse events were thrombocytopenia (10%), fatigue (9%), and asthenia, neutropenia, and hand–foot syndrome (each 7%).Conclusion:Final analysis of the sunitinib expanded-access trial provided a good opportunity to evaluate the long-term side effects of a tyrosine kinase inhibitor used worldwide in mRCC. Efficacy and safety findings were consistent with previous results.

Body mass index and exon 19 mutation as factors predicting the therapeutic efficacy of gefitinib in patients with epidermal growth factor receptor mutation-positive non-small cell lung cancer.

Many randomized clinical trials have demonstrated that epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are advantageous over standard chemotherapy, either as front-line treatment or as further management of patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC). However, which subgroup of these patients could benefit more from EGFR-TKIs needs to be further explored. In the present study, we explored the predictive factors in such cohorts of patients who received gefitinib. The study included 95 patients with EGFR mutation-positive advanced NSCLC who received gefitinib treatment. Multivariate analysis of progression-free survival (PFS) was performed using classification and regression tree (CART) analysis to assess the effect of specific variables on PFS in subgroups of patients with similar clinical features. The median PFS in patients with EGFR mutation-positive advanced NSCLC who received gefitinib treatment was 13.3 months (95% confidence interval 9.4-17.2). CART analysis showed an initial split on body mass index (BMI); subsequently, three terminal subgroups were formed. The median PFS in the three subsets ranged from 8.2 to 15.2 months, in which the subgroup with a BMI less than or equal to 20.8 kg/m(2) had the longest PFS (15.2 months). In addition, PFS in the EGFR exon 19 mutation group was better than in the other mutation site group (10.3 vs. 8.2 months). BMI and exon 19 mutation may be predictors of PFS in patients with EGFR mutation-positive advanced NSCLC who receive gefitinib treatment. Both active EGFR mutation and patient-specific factors may be used to predict the therapeutic efficacy of EGFR-TKIs.

ERCC1 Cys8092Ala and XRCC1 Arg399Gln Polymorphisms Predict Progression-Free Survival after Curative Radiotherapy for Nasopharyngeal Carcinoma

BackgroundSingle nucleotide polymorphisms (SNPs) in DNA repair genes can alter gene expression and activity and affect response to cancer treatment and, correspondingly, survival. The present study was designed to evaluate the utility of the XRCC1 Arg399Gln and ERCC1 Cys8092Ala SNPs, measured in pretreatment biopsy samples, as predictors of response to radiotherapy in patients with non-metastatic nasopharyngeal carcinoma (NPC).Materials and methodsThe study included 75 consecutive patients with stage II-IVA-B NPC. XRCC1 Arg399Glu and ERCC1 Cys8092Ala SNPs were identified from paraffin-embedded biopsy specimens via Sanger sequencing. Expression of p53 and pAkt protein was analyzed by immunohistochemical staining. Potential relationships between genetic polymorphisms and progression-free survival (PFS) were analyzed by using a Cox proportional hazards model, the Kaplan-Meier method, and the log-rank test.ResultsMultivariate analysis showed that carriers of the ERCC1 8092 Ala/Ala genotype [hazard ratio (HR) 1.882; 95% confidence interval (CI) 1.031–3.438; P = 0.039] and heavy smokers (≥20 pack-years) carrying the XRCC1 Arg/Arg genotype (HR 2.019; 95% CI 1.010–4.036; P = 0.047) had significantly lower PFS rates. Moreover, combined positive expression of p53 and pAkt led to significantly increased PFS in subgroups carrying the XRCC1 Gln allele (HR 7.057; 95% CI 2.073–24.021; P = 0.002) or the ERCC1 Cys allele (HR 2.568; 95% CI 1.056–6.248; P = 0.038).ConclusionsThe ERCC1 Cys8092Ala polymorphism is an independent predictor of response to radiotherapy for NPC, and the XRCC1 Arg399Glu mutation combined with smoking status seems to predict PFS as well. Our results further suggest a possible correlation between these genetic polymorphisms and p53 protein status on survival.