Objective Disease Progression Research Articles

A call for objectivity: Radiologists' proposed wishlist for response evaluation in solid tumors (RECIST 1.1).

The Response Evaluation in Solid Tumors (RECIST) 1.1 provides key guidance for performing imaging response assessment and defines image-based outcome metrics in oncology clinical trials, including progression free survival. In this framework, tumors identified on imaging are designated as either target lesions, non-target disease or new lesions and a structured categorical response is assigned at each imaging time point. While RECIST provides definitions for these categories, it specifically and objectively defines only the target disease. Predefined thresholds of size change provide unbiased metrics for determining objective response and disease progression of the target lesions. However, worsening of non-target disease or emergence of new lesions is given the same importance in determining disease progression despite these being qualitatively assessed and less rigorously defined. The subjective assessment of non-target and new disease contributes to reader variability, which can impact the quality of image interpretation and even the determination of progression free survival. The RECIST Working Group has made significant efforts in developing RECIST 1.1 beyond its initial publication, particularly in its application to targeted agents and immunotherapy. A review of the literature highlights that the Working Group has occasionally employed or adopted objective measures for assessing non-target and new lesions in their evaluation of RECIST-based outcome measures. Perhaps a prospective evaluation of these more objective definitions for non-target and new lesions within the framework of RECIST 1.1 might improve reader interpretation. Ideally, these changes could also better align with clinically meaningful outcome measures of patient survival or quality of life.

Tivozanib plus nivolumab versus tivozanib monotherapy in patients with renal cell carcinoma following an immune checkpoint inhibitor: results of the phase 3 TiNivo-2 Study

Immune checkpoint inhibitors (ICIs) and vascular endothelial growth factor receptor tyrosine kinase inhibitors are cornerstones of first-line treatment for advanced renal cell carcinoma; however, optimal treatment sequencing after progression is unknown. This study aimed to assess clinical outcomes of tivozanib-nivolumab versus tivozanib monotherapy in patients with metastatic renal cell carcinoma who have progressed following one or two lines of therapy in the post-ICI setting. TiNivo-2 is a multicentre, randomised, open-label, phase 3 trial at 190 sites across 16 countries, in Australia, Europe, North America, and South America. Patients with advanced renal cell carcinoma and progression during or after one to two previous lines of therapy (including one ICI) were randomised 1:1 to tivozanib (0·89 mg per day, orally) plus nivolumab (480 mg every 4 weeks, intravenously) or tivozanib (1·34 mg per day, orally). Randomisation was stratified by immediate previous therapy (ICI or non-ICI) and International Metastatic Renal Cell Carcinoma Database Consortium risk category. The primary endpoint was progression-free survival (PFS), defined as the time from randomisation to first documentation of objective progressive disease according to RECIST 1·1 or death from any cause, whichever came first, by independent radiology review. Efficacy was evaluated in the intention-to-treat population, and safety was assessed in patients who received one or more doses of the study drug. This trial was registered on ClinicalTrials.gov (NCT04987203) and is active and not recruiting. From Nov 4, 2021, to June 16, 2023, 343 patients were randomly assigned to tivozanib-nivolumab (n=171) or tivozanib monotherapy (n=172). Median follow-up was 12·0 months. Median PFS was 5·7 months (95% CI 4·0-7·4) with tivozanib-nivolumab and 7·4 months (5·6-9·2) with tivozanib monotherapy (hazard ratio 1·10, 95% CI 0·84-1·43; p=0·49). Among those with an ICI as their immediate previous therapy (n=244), median PFS was 7·4 months (95% CI 5·6-9·6) with tivozanib-nivolumab and 9·2 months (7·4-10·0) with tivozanib monotherapy. With non-ICIs as the most recent therapy, lower median PFS was observed, with no difference between groups (tivozanib-nivolumab 3·7 months [95% CI 2·7-5·4] and with tivozanib monotherapy 3·7 months [1·9-7·2]). Serious adverse events occurred in 54 (32%) of 168 patients receiving tivozanib-nivolumab and 64 (37%) of 171 patients receiving tivozanib monotherapy. One (<1%) treatment-related death occurred (tivozanib group). These data further support that ICI rechallenge should be discouraged in patients with advanced renal cell carcinoma. Furthermore, these data suggest that tivozanib monotherapy has efficacy in the post-ICI setting. Aveo Pharmaceuticals.

Comparing Ribociclib versus Palbociclib as a Second Line Treatment in Combination with Fulvestrant in Metastatic Breast Cancer: A Randomized Clinical Trial.

Assessment of CBR, PFS, QOL and toxicity profile of palbociclib and ribociclib. This is an interventional concurrent randomised phase III open label clinical trial. It took place at the Oncology Centre Mansoura University, Egypt from July 2022 till December 2023. Patients with pathologically proved ER+ HER2- metastatic breast cancer who either progressed on adjuvant hormonal or progressed on 1st line hormonal for metastatic disease. Patients in arm A received palbociclib 125 mg/day orally for 3 weeks and 1 week rest, plus fulvestrant. Patients in Arm B received ribociclib at a dose of 600 mg, administered orally once daily for 3 weeks and 1 week rest, plus fulvestrant. Pre- and peri-menopausal women received the LHRH agonist goserelin. Patients who lost their endorsement and were considered to be lost to follow up. Quality of life was analysed using the (EORTC) quality-of-life questionnaire (QLQ)-C30 V3.0. Patients were asked to complete the questionnaires at screening; at the 2nd and 6th month. Toxicity was assessed and graded using (CTCAE) v5.0. Patients were evaluated clinically for response and toxicity monthly and radiologically by CT and tumor markers/ 3 months. Treatment continued until objective Progressive Disease (PD), symptomatic deterioration, unacceptable toxicity or death. Both arms had similar baseline characteristics. There was no statistically significant difference regarding the CBR (58.6% for both arms at 6 months and 13.8% in the palbociclib VS 17.2% in the ribociclib arm at 12 months). The median PFS to the whole population was 13 months. COX multivariate analysis revealed that postmenopausal had 2.85 more likely to survive than premenopausal patients. Patients with ECOG performance status 2 and 3 are 0.13 and 0.39 less likely to survive compared to patients with PS 1. Dose reduction increased the likelihood of survival 3.36 compared with no dose reduction. The median PFS was 13.67 months in the palbociclib arm and 12.69 months in the ribociclib arm with no statistically significant difference. During follow up, there was statistically significant improvement in insomnia in both arms and constipation in the palbociclib arm alone. Comparing the two arms, no statistically significant deterioration in the QOL domains except in fatigue and financial difficulties, with more deterioration in the palbociclib arm. Regarding common toxicities there was no statistically significant difference between the 2 arms. Both Ribociclib and palbociclib have similar CBR, PFS and toxicity profile.

Abstract PO4-05-05: Immune Activation Signatures for predicting CDKi primary response in advanced breast cancer patients

Abstract Background Cyclin Dependent Kinase inhibitors (CDKi’s) in combination with Endocrine Therapy (ET) have changed the first line management of patients with the most common subtype (HR+, HER2-) of metastatic breast cancer (MBC), improving progression-free survival (PFS) and overall survival. However, in approved indications for advanced breast cancer, approximately 20% of patients have been observed to have no response to CDKi’s and ET, and to progress after starting these therapies. Unlike other targeted therapeutics, there is no companion diagnostic or other clinically reliable biomarker for clinical decision support to indicate which patients will and will not benefit from CDKi therapy. Methods We have developed a novel platform that measures the Immune Activation Signature of patient plasma samples. Via simple measurements of the total concentration of protein-incorporated amino acid residues within patient plasma samples, the platform is designed to reveal changes in the proportion of immunoglobulins and albumin, and class-switching among immunoglobulins. For that purpose, we use Bioorthogonal chemical labelling reactions to label the protein-incorporated amino acids residues within the plasma. We measured the plasma samples of N=30 HR+, HER2- MBC patients, median age 54 years old, who were baseline naïve for CDKi’s treatment (16 on palbociclib, 11 on ribociclib, and 3 on abemaciclib) and ET. Eighteen patients had metastatic visceral disease and 12 patients had bone-only MBC. All patients were prospectively followed, and response assessed according to RECIST criteria on a CT scan every 3-months. Results Non-responding patients developed objective progressive disease during the first 6 months after starting CDKis and ET. In this cohort, 4 patients (13%) were classified as non-responders. The median PFS in non-responding patients was 4.5 months (4.03-5.02) and the median PFS in the cohort of responding patients was 16.6 months (6.8 – 40.9). The Immune Activation Signatures of the Responding and Non-Responding patients are shown in table 1. We analyzed the results with classical statistics and machine learning. A multivariate analysis of variance (MANOVA) test of the null hypothesis that the Immune Activation Signatures of Non-Responders and Responders are the same gave p = 0.00388. We analyzed the measured Immune Activation Signatures using a supervised machine learning classifier and observed in a held-back validation set correct prediction of 100% of non-responding patients and 95% accurate predictions overall. Conclusions According to these results, this platform may provide a clinically helpful biomarker for clinical decision support in the advanced or aggressive breast cancer context (patients with visceral metastasis bordering on visceral crisis), or for patient stratification in new indications. Table. Immune Activation Signature measurements (mean values in Clinical Outcome) Citation Format: Luis Costa, Cong Tang, Emma Yates, Qi Shi, Wesley Sukdao, Patricia Corredeira, Gonçalo Costa, Helena Pais, Catarina Abreu, Leonor Ribeiro, Rita Teixeira de Sousa, Sofia Torres, André Mansinho, Sandra Casimiro, Ana Cavaco, Patricia Alves, Angela Rodrigues, Lisiana Szeneszi, Gonçalo Bernardes. Immune Activation Signatures for predicting CDKi primary response in advanced breast cancer patients [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-05-05.

Real-world experience and outcomes of hepatocellular carcinoma (HCC) treated with transarterial radioembolization (TARE).

463 Background: TARE has been the preferred choice of locoregional therapy to advanced HCC in recent years. We attempted to identify factors contributing to the success of TARE in this retrospective review. Methods: HCC patients who received at least one TARE between 1/1/2015 and 8/30/22 at Ohio State University were included in this study. The patient's baseline characteristics at diagnosis (BLC) were extracted by chart review with post-procedural complications and survival outcomes. Descriptive statistics and log-rank test for survival outcomes were conducted using JMP Pro 16 (SAS Institute Inc., Cary, NC). Results: Our cohort had 144 patients with median age of diagnosis (dx) of 65 years, 81 % Caucasians, 81% males, 5% and 51% with hepatitis B and C, respectively; 24% and 21% ascites (As) and hepatic encephalopathy (HE) at dx, respectively; 72% (n=125) had just one procedure (24 had two planned procedures which were considered as 1), 12% (17) and 1% (2) had second and third procedures for recurrence, respectively. Immune checkpoint inhibitor (ICI) and other systemic therapy (tyrosine kinase inhibitor (TKI) or ramucirumab (Ram)) were given to 27% (5 before and 34 after TARE) and 24% (5 before and 30 after TARE), respectively. Other HCC-related BLC includes the number of lesions 1 vs 2-3 vs multiple = 45% vs 33% vs 22%; single lobe vs two lobes = 66 vs 33%; portal vein tumor thrombosis (PVTT) = in main portal vein vs. non-main veins (left or right or lower level) vs no PVTT = 14% vs 10% vs 76%. Median overall survival (OS) and time to recurrence after the first TARE (TTR) were 11 and 4 months (m), respectively. The only BLC that significantly influenced TTR was As (3 vs 4 m, p=0.008). Factors impacting OS were discussed in the table. Follow-up imaging (median = 3m) was available for response evaluation in 107/144 (indeterminate response (IR) reported in 25), and the response noted was reflective of OS (objective response vs. disease progression vs indeterminate, 22 vs 6 vs 8.5 m, p&lt;0.001). Conclusions: Careful patient selection based on BLC and the use of ICI (before or after) could improve the outcomes in HCC patients treated with TRAE. Larger prospective studies are needed to validate the study. [Table: see text]

Niraparib in Japanese patients with heavily pretreated, homologous recombination-deficient ovarian cancer: final results of a multicenter phase 2 study.

To evaluate the long-term efficacy and safety of niraparib in Japanese women with heavily pretreated ovarian cancer. This was the follow-up analysis of a phase 2, multicenter, open-label, single-arm study in Japanese women with homologous recombination-deficient, platinum-sensitive, relapsed, high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who had completed 3-4 lines of chemotherapy and were poly(ADP-ribose) polymerase inhibitor naïve. Participants received niraparib (starting dose, 300 mg) once daily in continuous 28-day cycles until objective disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was confirmed objective response rate (ORR), as assessed using Response Evaluation Criteria in Solid Tumors version 1.1. Safety evaluations included treatment-emergent adverse events (TEAEs). 20 patients were enrolled in the study and included in both efficacy and safety analyses. Median total study duration was 759.5 days. Median dose intensity was 201.3 mg/day. Confirmed ORR was 60.0% (90% confidence interval [CI]=39.4-78.3); 2 patients had complete response and 10 patients had partial response. Median duration of response was 9.9 months (95% CI=3.9-26.9) and the disease control rate was 90.0% (95% CI=68.3-98.8). The most common TEAEs were anemia (n=15), nausea (n=12), and decreased platelet count (n=11). TEAEs leading to study drug dose reduction, interruption, or discontinuation were reported in 16 (80.0%), 15 (75.0%), and 2 patients (10.0%), respectively. The long-term efficacy and safety profile of niraparib was consistent with previous findings in the equivalent population in non-Japanese patients. No new safety signals were identified. ClinicalTrials.gov Identifier: NCT03759600.

Efficacy of continuous arterial perfusion chemotherapy combined with transarterial chemoembolization regional arterial thermal perfusion in the treatment of pancreatic cancer with liver metastases

Abstract Background The aim of the study was to investigate the efficacy of continuous transcatheter arterial infusion chemotherapy combined with transarterial chemoembolization (TACE) for the treatment of advanced pancreatic cancer with liver metastasis. Methods Sixty patients with advanced pancreatic cancer and liver metastases were enrolled in this study. In the treatment group, 31 patients underwent continuous transcatheter arterial infusion chemotherapy combined with TACE regional arterial thermal perfusion, whereas 29 patients included in the control group received intravenous chemotherapy with gemcitabine and S-1. All patients received maintenance chemotherapy with S-1 after 4 cycles of the study regimen. Treatment efficacy, quality of life, survival, and toxicity were evaluated. Results Efficacy was better in the treatment group than in the control group, as reflected by the objective remission, partial remission, and disease progression rates (all P &lt; 0.05). The Eastern Cooperative Oncology Group and Numerical Rating Scale pain scores were also higher in the treatment group (both P &lt; 0.05). In survival analysis, the 1-year overall survival rates in the treatment and control groups were 64.516% and 10.345%, respectively, whereas the median overall survival times were 16 and 6 months, respectively (both P &lt; 0.05). The 6-month progression-free survival rates in the treatment and control groups were 77.419% and 13.790%, respectively, and the median progression-free survival times were 12 and 3 months, respectively (both P &lt; 0.05). The rates of hematological and nonhematological toxicological adverse effects were also lower in the treatment group (both P &lt; 0.05). Although the rate of liver dysfunction was higher in the treatment group, this finding had no adverse effects on prognosis. Conclusions Continuous transcatheter arterial infusion chemotherapy combined with TACE regional arterial perfusion chemotherapy resulted in better efficacy and safety outcomes in patients with pancreatic cancer and liver metastasis, suggesting its utility as a reference method for the clinical treatment of advanced pancreatic cancer.

Primary outcome analysis of the phase 3 SONIA trial (BOOG 2017-03) on selecting the optimal position of cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors for patients with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC).

LBA1000 Background: The phase-3, randomized, investigator-initiated, nationwide SONIA trial is evaluating the efficacy, safety and cost-effectiveness of CDK4/6i added to either first- or second-line endocrine therapy (ET) in patients with HR+, HER2- ABC who have received no prior therapy for ABC. The addition of CDK4/6i to ET improves progression-free (PFS) and overall survival (OS) in HR+, HER2- ABC, as initial treatment (first-line) and after prior endocrine monotherapy (second-line). Most international guidelines advice first-line use, despite prolonged toxicity and a steep increase in costs compared to use in second-line. Evidence of superiority of first-line use over second-line based on a head-to-head comparison is lacking. Methods: Pre- and postmenopausal women (N=1050), who received no prior therapy for ABC, with measurable or evaluable disease and WHO performance status 0-2 were enrolled in 74 Dutch hospitals. (Neo)adjuvant therapy was allowed (disease-free interval after non-steroidal aromatase inhibitor (NSAI) &gt;12 months). Patients were randomized 1:1 to receive strategy A (first-line treatment with an NSAI + CDK4/6i, followed on progression by fulvestrant (F)) or strategy B (first-line treatment with an NSAI, followed on progression by F + CDK4/6i). Choice between one of the available CDK4/6i (abemaciclib, palbociclib, ribociclib) was a stratification factor and left to the discretion of the treating physician. The primary endpoint is time from randomization to second objective disease progression, as assessed by local investigators, or death (PFS2). Secondary endpoints include OS, safety, quality of life, and cost-effectiveness. Results: After a median follow-up of 37.3 months (data cut-off 1 December 2022), median PFS2 was 31.0 months in strategy A versus 26.8 months in strategy B (hazard ratio 0.87; 95% confidence interval, 0.74 to 1.03; P=0.10). The treatment effect was consistent across the levels of pre-defined subgroups. The safety profile was characteristic for ET + CDK4/6i. Median time on CDK4/6i was 24.64 months in strategy A and 8.08 months in strategy B (Δ 16.56 months). The number of grade ≥3 adverse events was 2782 for strategy A and 1620 for strategy B. Conclusions: First-line use of CDK4/6i + ET does not provide statistically significant, nor clinically meaningful PFS benefit compared to second-line use in women with HR+, HER2- ABC. Use in first-line prolongs the time on CDK4/6i by 16.56 months and increases toxicity and costs. Second-line use may thus be a preferred option for the majority of patients. (Funded by The Netherlands Organisation for Health Research and Development and Dutch Health Insurers; ClinicalTrials.gov number, NCT03425838). Clinical trial information: NCT03425838 .

Safety and clinical activity of TTI-621 in combination with doxorubicin in patients with unresectable or metastatic high-grade leiomyosarcoma: Results from the low-dose expansion cohort.

11508 Background: TTI-621 is a recombinant fusion protein combining the Fc region of human IgG1 with a fragment of human SIRPα, designed as a decoy receptor for CD47 on tumor cells to interrupt CD47-SIRPα signaling and promote macrophage-mediated phagocytosis of tumor cells as well as activation of NK cells. Preclinical studies suggest TTI-621 may enhance the response to doxorubicin in macrophage-rich tumors that express CD47, such as leiomyosarcoma (LMS). A phase 1/2 dose escalation study with high- and low-dose expansion cohorts evaluating TTI-621 + doxorubicin in patients (pts) with advanced LMS is ongoing (NCT04996004); results from the low-dose expansion cohort are presented. Methods: This open-label study enrolled anthracycline-naïve pts aged ≥18 y with evaluable unresectable or metastatic high-grade LMS and ≤1 prior line of therapy for advanced disease. Pts in the low-dose expansion cohort received TTI-621 0.2 mg/kg on Days 1 and 8 in combination with doxorubicin 75 mg/m2 on Day 1 of 21-day cycles for a maximum 6 cycles, followed by TTI-621 monotherapy on Days 1 and 15 of 28-day cycles until objective disease progression. Primary objectives for the expansion phase were evaluation of safety and investigation of clinical activity via assessment of overall response and clinical benefit rates as defined by RECIST v1.1 criteria. Results: At data cut-off (Oct 3, 2022), 23 pts were evaluable for safety and 20 for clinical response. In the safety population, 39% had received prior treatment for advanced disease. Two pts (9%) experienced Grade ≥3 AE assessed as related to TTI-621 treatment: pancreatitis (n = 1, 4%) and platelet count decreased (n = 1, 4%). Seven pts (30%) experienced Grade ≥3 AE related to the combination of TTI-621 and doxorubicin, including two pts (9%) each with platelet count decreased and white blood cell count decreased and three pts (13%) with neutrophil count decreased. Grade ≥3 doxorubicin-related AEs were more common (n = 17, 74%); most frequent were neutrophil count decreased (n = 8; 35%), white blood cell count decreased (n = 7; 30%), and neutropenia (n = 6; 26%). One pt experienced an infusion-related reaction (Grade 1 chills) assessed as related to TTI-621. No pts attained complete response, but one pt had a complete resolution of all target lesions. Five pts (25%) attained partial response for an overall response rate of 25%; 11 pts (55%) attained stable disease for a disease control rate of 80%. Conclusions: Addition of TTI-621 to doxorubicin showed promising clinical activity and a favorable safety profile among pts with advanced LMS, including those with prolonged exposure to TTI-621 ( &gt; 360 d). Clinical trial information: NCT04996004 .

Real-life efficacy of nivolumab plus ipilimumab combination in untreated, unresectable malignant pleural mesotheliomas: Result of French early access program—MESOIMMUNE – GFPC 04-2021.

8536 Background: The SOC for unresectable malignant pleural mesothelioma (MPM) has changed in 2020 with the combination nivolumab plus ipilimumab (NIVO+IPI) results of CheckMate 743 study. As CheckMate 743 was therapeutic trial in selected MPM patients (pts), additional data would be of interest to confirm the results in real-life setting. Methods: The present multicenter, retrospective study assessed the outcomes of NIVO+IPI, via an early access program (EAP) in France, in pts with treatment naïve unresectable MPM. The primary objective was investigator-assessed real world progression-free survival (rwPFS) from initiation of NIVO+IPI, defined as time from first dose of NIVO+IPI to first documentation of objective disease progression or death from any cause. The secondary objectives were real world OS (rwOS), objective response rate (ORR), and safety of NIVO+IPI combination. Results: From April 1, 2021 to Feb 15, 2022 (last day of EAP) there were 143 pts included out of 350 pts treated by EAP for unresectable MPM in 44 centers. Population characteristics are described in the table. With a median follow-up of 14.1 months, median rwPFS was 7.8 months (95%CI 6.2-9.5). rwPFS rates no differ according to histological subtypes: rwPFS for epithelioid MPM was 8.1 months (95%CI 6.0-12.6) and 7.4 months (95% CI 5.3-11.2) for other histological subtypes. The median rwOS was not reached (NR), 1-year survival rate was 65% (95% CI 57-75%). Median rwOS was NR and 13.1 (95% CI 7.8- NA) in epithelioid and non-epithelioid MPM, respectively. At 1 year, 71.2% of pts with epithelioid MPM are still alive versus 51.2% in pts with other histological subtypes. ORR was 23.9% (95% CI 16.9-32.0%) with median time to response of 3.68 months (2.33-5.09) after introduction of NIVO+IPI. Disease control rate was 80.4%. Grade 3-4 adverse events (AE) occurred in 37.8%. Severe immune-related AE occurred in 13.9% of patients. Five deaths were associated with treatment-related AEs according to investigators judgment. Conclusions: While pt’s characteristics differed from the pivotal trial, notably with older and unselected patients, efficacy outcomes that we observed here compares favorably with CheckMate 743 results. Tolerance looks acceptable in real-life setting despite 5 toxic deaths reported. Extended follow-up of our cohort will allow consolidation of the results. Clinical trial information: NCT05308966 . [Table: see text]

Clinical Trials of Solid Tumor Drugs Approved in Europe: Evidence-Based-Medicine

The Response Evaluation Criteria in Solid Tumors (RECIST) were introduced to determine response to therapy by evaluation of change from baseline while on the treatment of the solid tumor. These criteria are used mainly in clinical trials where tumor objective response (tumor shrinkage) or disease progression is the primary endpoint. RECIST is widely used by academic institutions, cooperative groups, and industry for oncology clinical trials. Regulatory authorities use RECIST as an appropriate guideline for risk-benefit assessments of oncology drugs. This study aimed to assess the impact on pivotal clinical trial designs due to adopting the RECIST for assessing the risk-benefit ratio for oncology drugs approved in Europe for treatment of solid tumors (2000–2019). The Summary of Product Characteristics for all oncology drugs was reviewed to identify the pivotal clinical trials. Results: There were 78 pivotal clinical trials for 38 oncology drugs approved, by the European Medicines Agency (EMA), for treatment of solid tumors. Open-label randomized controlled trials (RCTs) account for 62.82% of the pivotal clinical trials compared to 37.18% blinded RCTs. A total of 6,721 patients (average=1,120) participated in 78 pivotal clinical trials. Around sixty-three percent (4,211 out of 6,721) of patients participated in blinded RCTs, and 37.34% (2,510 out of 6,721) of patients participated in open-label RCTs. Conclusion: Less restrictive rules for oncology drugs approval were applied by the regulatory agency. Over 19 years, EMA had approved oncology drugs based on open-label trials, especially when an oncology drug was compared to an active comparator, with results of few or no clinical improvement over existing therapy. The approval process of oncology drugs should be supported by clear evidence about the clinical effects of the new oncology drugs compared to the existing effective oncology therapies using clinical trial designs that are methodologically rigorous.

Survival benefits from afatinib compared with gefitinib and erlotinib among patients with common EGFR mutation in first-line setting.

BackgroundEpidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKIs) are recommended as first‐line treatment in non‐small cell lung cancer (NSCLC) patients with sensitizing EGFR mutations. The sequential use of different EGFR‐TKIs has been reported to demonstrate improvement in overall survival of NSCLC patients with EGFR mutations. There are limited reports on comparisons between regimens with first‐line use of afatinib, gefitinib or erlotinib, followed by osimertinib upon disease progression with acquired T790M mutation.MethodsA retrospective cohort study of Chinese patients with metastatic NSCLC harboring EGFR mutations who received first‐line gefitinib, erlotinib or afatinib treatment, followed by osimertinib upon disease progression with acquired T790M mutation, was conducted. The differences in overall survival (OS) and progression‐free survival (PFS) with first‐line EGFR‐TKI (PFS1) and time to second objective disease progression (PFS2) were compared among patients on different first‐line EGFR‐TKIs.ResultsAmong 155 patients, 101 (65.2%), 38 (24.5%) and 16 (10.3%) patients were on first‐line gefitinib, erlotinib or afatinib, respectively. Patients treated with afatinib in the first‐line setting had significantly longer OS compared with those on gefitinib or erlotinib, while the PFS1 and PFS2 were longer for patients on afatinib but did not reach statistical significance.ConclusionsFirst‐line afatinib, followed by osimertinib upon disease progression with T790M mutation, demonstrated significantly longer OS compared to that using other EGFR‐TKI in the first‐line setting.

Timing of onset of systemic treatment in asymptomatic patients with metastatic pancreatic cancer: An international expert survey and case-vignette study.

e16256 Background: The number of asymptomatic patients diagnosed with metastatic pancreatic cancer (mPDAC) is increasing, mostly due to increased use of imaging. Traditionally, systemic therapy is started immediately on disease detection. However, one perspective is that delaying therapy may preserve/maintain quality of life for longer. The impact on survival is unknown. The aim of this study was to gain further insights into current perspectives and clinical decision making regarding timing of start of systemic treatment in asymptomatic patients with mPDAC. Methods: An online survey (11 questions and 9 case vignettes) was sent to all first and last authors of published clinical trials on mPDAC over the past 10 years and medical oncologists of the Dutch Pancreatic Cancer Group. Differences in preferred treatment (i.e. immediate vs. delayed) between continents and years of experience (i.e. &lt; 5 years, 5-10 years, &gt; 11 years) were analyzed using the Fisher’s exact test. Results: Seventy-eight of 291 (27%) medical oncologists responded from 15 countries over 4 continents (62% Europe, 23% North America, 10% Asia, and 5% Australia). Most respondents worked in an academic hospital (73%) and reported more than 11 years’ experience (76%). The majority (63%) preferred immediate start of chemotherapy after diagnosis of metastastic disease. Thirty-two percent favored delayed treatment; 5% at symptom occurrence, 5% at objective disease progression, and 22% either at symptom occurrence or objective disease progression (whichever comes first). For the case vignettes, immediate treatment was preferred in 6/9 cases (67%). In the 3 remaining cases, delayed treatment was favored (case context: just one small lung metastasis, older age, significant comorbidities). The recommended timing of treatment (i.e. immediate or delayed treatment) was different between continents in 1/9 cases (11%, p = 0.012) and between years of experience in 5/7 cases (56%, all p &lt; 0.001); medical oncologists from Europe and with &lt; 5 years of experience preferred delayed treatment more often. Conclusions: This international survey based on case-vignettes indicated that immediate treatment was mostly preferred in asymptomatic patients with mPDAC. However, in one-third of cases, delayed treatment initiation was favored (e.g., due to patient selection and oncologists preference). The relation between timing of systemic treatment initiation and outcome in mPDAC is unknown and warrants further investigation.

Provider Perspectives on and Access to Palliative Care for Patients With Interstitial Lung Disease

Interstitial lung disease (ILD) results in profound symptom burden and carries high mortality. Palliative care (PC) is dedicated to improving quality of life in patients with serious illness. Early PC provision improves rates of advance care planning and symptom management in patients with ILD. What are the current perspectives on PC among ILD providers, and what are the barriers to PC in ILD specialty centers? A 24-question electronic survey was disseminated to providers at the 68 Pulmonary Fibrosis Foundation Care Centers across the United States from October 2020 to December2020. The survey was completed by 128 participants representing all 68 Pulmonary Fibrosis Foundation Care Center Network sites. Most respondents were physicians. Most providers exhibit good knowledge of, feel comfortable assessing a patient's readiness for, and agree with the need for PC for patients with ILD. Providers are most likely to refer to PC at objective disease and/or symptomatic progression rather than at initial diagnosis. In comparison with providers who report referring their patients to PC, providers who report rare referral are more likely to cite lack local PC availability (P< .01) and less likely to feel comfortable discussing prognosis/disease trajectory (P= .03) or feel it is important to address advance directives in ILD clinic (P= .02). There is a lack of standardized measures used to assess specific symptoms, overall symptom burden, or health-related quality of life across institutions. Discordance exists between self-reported and actual access to local inpatient and outpatient PC services. Most ILD providers use PC and are comfortable discussing PC. Barriers to PC identified in this survey include the following: perceived lack of local access to PC, lack of systematic tools to assess symptom burden, lack of established optimal timing of PC referral, and unclear need for specialized PC delivery.

Long-Term Safety and Effectiveness of PF-05280014 (a Trastuzumab Biosimilar) Treatment in Patients with HER2-Positive Metastatic Breast Cancer: Updated Results of a Randomized, Double-Blind Study.

BackgroundPF-05280014 was compared with trastuzumab sourced from the European Union (trastuzumab-EU), each plus paclitaxel, as first-line treatment for human epidermal growth factor receptor 2-positive metastatic breast cancer in a phase III study. Equivalence between treatment groups was demonstrated.ObjectiveThe aim of this study was to report long-term safety and overall survival (OS) over 6 years after the first patient was screened.Patients and methodsRandomized patients received intravenous PF-05280014 or trastuzumab-EU, each plus paclitaxel, until objective disease progression. OS, long-term safety, subgroup safety (patients ongoing after day 378), and time-to-treatment discontinuation (TTD) were assessed based on the final statistical analysis plan amended for the ad-hoc analyses.ResultsOf 707 randomized patients (n = 352, PF-05280014; n = 355, trastuzumab-EU), 252 (71.6%) in the PF-05280014 and 251 (70.7%) in the trastuzumab-EU group discontinued treatment due to objective progression. Overall, 451 (63.8%) patients completed the study. Between groups (PF-05280014; trastuzumab-EU), estimated median TTDs were 12.25 and 12.06 months (p = 0.692); 61 (17.3%) and 67 (18.9%) patients died; stratified hazard ratio for OS was 0.929 (95% confidence interval 0.656–1.316; p = 0.339); estimated survival rates were 82.3 and 77.4% at 2 years and 77.2 and 75.3% at 3 years. The incidences of treatment-emergent adverse events (TEAEs) overall (98.6%; 96.6%) and for grades ≥3 (41.0%; 43.1%) were comparable between groups. In patients (n = 265; n = 264) ongoing after day 378, the incidences of any TEAEs, grade ≥3 TEAEs, and serious TEAEs were comparable between the treatment groups.ConclusionLong-term safety and OS were consistent with previous results and demonstrated no clinically meaningful differences between treatment groups.Trial registrationClinicalTrials.gov: NCT01989676 (21 November 2013); and EudraCT: 2013-001352-34 (18 December 2013).Supplementary InformationThe online version contains supplementary material available at 10.1007/s40259-021-00513-7.

Palliative and prognostic approach in cancer patients identified in the multicentre NECesidades PALiativas 2 study in Argentina

BackgroundEarly identification of palliative needs has proven benefits in quality of life, survival and decision-making. The NECesidades PALiativas (NECPAL) Centro Coordinador Organización Mundial de la Salud - Instituto Catalán de Oncología (CCOMS-ICO©) tool combines the physician’s insight with objective disease progression parameters and advanced chronic conditions. Some parameters have been independently associated with mortality risk in different populations. According to the concept of the ‘prognostic approach’ as a companion of the ‘palliative approach’, predictive models that identify individuals at high mortality risk are needed.ObjectiveWe aimed to identify prognostic factors of mortality in cancer in our cultural context.MethodWe assessed cancer patients with palliative needs until death using this validated predictive tool at three hospitals in Buenos Aires City. This multifactorial, quantitative and qualitative non-dichotomous assessment process combines subjective perception (the surprise question: Would you be surprised if this patient dies in the next year?) with other parameters, including the request (and need) for palliative care (PC), the assessment of disease severity, geriatric syndromes, psychosocial factors and comorbidities, as well as the use of healthcare resources.Results2,104 cancer patients were identified, 681 were NECPAL+ (32.3%). During a 2-year follow-up period, 422 NECPAL+ patients died (61.9%). The mean overall survival was 8 months. A multivariate model was constructed with significant indicators in univariate analysis. The best predictors of mortality were: nutritional decline (p < 0.000), functional decline (p < 0.000), palliative performance scale (PPS) ≤ 50 (p < 0.000), persistent symptoms (p < 0.002), functional dependence (p < 0.000), poor treatment response (p < 0.000), primary cancer diagnosis (p = 0.024) and condition (in/outpatients) (p < 0.000). Only three variables remained as survival predictors: low response to treatment (p < 0.001), PPS ≤ 50 (p < 0.000) and condition (in/outpatients) (p < 0.000).ConclusionThis prospective model aimed to improve cancer survival prediction and timely PC referral in Argentinian hospitals.

Clinical Trials of Solid Tumor Drugs Approved in Europe: Evidence-Based-Medicine

The Response Evaluation Criteria in Solid Tumors (RECIST) were introduced to determine response to therapy by evaluation of change from baseline while on the treatment of the solid tumor. These criteria are used mainly in clinical trials where tumor objective response (tumor shrinkage) or disease progression is the primary endpoint. RECIST is widely used by academic institutions, cooperative groups, and industry for oncology clinical trials. Regulatory authorities use RECIST as an appropriate guideline for risk-benefit assessments of oncology drugs. This study aimed to assess the impact on pivotal clinical trial designs due to adopting the RECIST for assessing the risk-benefit ratio for oncology drugs approved in Europe for treatment of solid tumors (2000–2019). The Summary of Product Characteristics for all oncology drugs was reviewed to identify the pivotal clinical trials. Results: There were 78 pivotal clinical trials for 38 oncology drugs approved, by the European Medicines Agency (EMA), for treatment of solid tumors. Open-label randomized controlled trials (RCTs) account for 62.82% of the pivotal clinical trials compared to 37.18% blinded RCTs. A total of 6,721 patients (average=1,120) participated in 78 pivotal clinical trials. Around sixty-three percent (4,211 out of 6,721) of patients participated in blinded RCTs, and 37.34% (2,510 out of 6,721) of patients participated in open-label RCTs. Conclusion: Less restrictive rules for oncology drugs approval were applied by the regulatory agency. Over 19 years, EMA had approved oncology drugs based on open-label trials, especially when an oncology drug was compared to an active comparator, with results of few or no clinical improvement over existing therapy. The approval process of oncology drugs should be supported by clear evidence about the clinical effects of the new oncology drugs compared to the existing effective oncology therapies using clinical trial designs that are methodologically rigorous.

Efficacy and Safety of Bevacizumab Biosimilar FKB238 Versus Originator Bevacizumab: Results from AVANA, a Phase III Trial in Patients with Non-Squamous Non-Small-Cell Lung Cancer (non-sq-NSCLC)

BackgroundBevacizumab is an antiangiogenic recombinant humanized monoclonal antibody that inhibits tumor growth. FKB238, a bevacizumab biosimilar, has analytical pharmacokinetic and safety profiles similar to those of bevacizumab.ObjectiveThis phase III trial (NCT02810457) compared the efficacy and safety of FKB238 with that of bevacizumab in patients with advanced/recurrent non-squamous non-small-cell lung cancer (non-sq-NSCLC).MethodsThis global, multicenter, double-blind, parallel, randomized, comparative clinical trial enrolled and randomized patients with advanced/recurrent non-sq-NSCLC to receive intravenous infusions of either FKB238 15 mg/kg or bevacizumab 15 mg/kg. All patients received intravenous infusions of paclitaxel 200 mg/m2 and carboplatin (area under the curve 6.0) immediately prior to investigational products for 4–6 cycles. FKB238 and bevacizumab were administered on day 1 of each 21-day cycle until objective progressive disease by RECIST version 1.1 or other discontinuation criteria were met. The primary efficacy endpoint was overall response rate (ORR), including complete and partial response and based on blinded independent central review assessment. Other efficacy determinations included progression-free survival (PFS), overall survival (OS), and immunogenicity. Adverse events and severity were reported.ResultsThe ORR for the intent-to-treat (ITT) population (N = 731) was 51.6% in the FKB238 arm (N = 364) and 53.7% in the bevacizumab arm (N = 367). The FKB238:bevacizumab ORR ratio (ITT population) was 0.96 (90% confidence interval [CI] 0.86–1.08), and the difference in ORR (per-protocol set) between FKB238 and bevacizumab was − 0.02 (95% CI − 0.09 to 0.06). Both CIs fell within the prespecified equivalence margins. Estimated median PFS was 7.72 and 7.62 months in the FKB238 and bevacizumab arms, respectively (hazard ratio 0.97; 95% CI 0.82–1.16). Treatment-emergent adverse events (TEAEs) were reported for 94.2% and 95.1% of patients in the FKB238 and bevacizumab arms, respectively. Grade 3 or higher TEAEs were reported for 53.6% and 55.5% of patients in the FKB238 and bevacizumab arms, respectively. Serious TEAEs were reported for 25.1% and 26.0% of patients treated with FKB238 and bevacizumab, respectively.ConclusionsEfficacy equivalence was demonstrated between the two drugs, and safety profiles were similar. There were no meaningful differences in efficacy and safety between FKB238 or bevacizumab in patients with non-sq-NSCLC.Trial registration numberNCT02810457.

Safety and activity of the TGFβ receptor I kinase inhibitor galunisertib plus the anti-PD-L1 antibody durvalumab in metastatic pancreatic cancer

BackgroundWe assessed the safety, efficacy, and pharmacokinetics of the transforming growth factor beta (TGFβ) receptor inhibitor galunisertib co-administered with the anti-programmed death-ligand 1 (PD-L1) antibody durvalumab in recurrent/refractory metastatic pancreatic...

Mycoplasma hyorhinis infection promotes tyrosine kinase inhibitor (TKI) resistance in lung adenocarcinoma patients.

To explore the relationship between Mycoplasma hyorhinis infection and tyrosine kinase inhibitor (TKI) resistance in lung adenocarcinoma patients. Mycoplasma hyorhinis infection can be verified with the monoclonal antibody PD4, which specifically recognizes a distinct protein of M. hyorhinis. Immunohistochemistry (IHC), using PD4 to detect M. hyorhinis, was performed on paraffin-embedded lung adenocarcinoma tissues of patients who had epidermal growth factor (EGFR) mutations and had received oral TKI. The number of patients enrolled in our study was 101. Assessments following TKI treatment were performed until objective disease progression or stable disease at the cutoff date was reached. In all of the patients, the primary endpoint was investigator-assessed progression-free survival (PFS). Immunohistochemistry revealed that 61 of 101 cases (60.4%) of lung adenocarcinoma were positive for M. hyorhinis, which comprised of 31 low-positive cases and 30 high-positive cases; the remaining 40 cases (39.6%) were negative. The median PFS was significantly longer in the negative group [18months (95% CI 14.15-21.85)] than in the low-positive group [10months (95% CI 7.70-12.30); hazard ratio (HR) 4.095, 95% CI 2.254-7.438; p < 0.001] and in the high-positive group [4months (95% CI 2.85-5.15); HR 31.703, 95% CI 14.425-69.678; p < 0.001]. The results of the subgroup analysis were satisfactory. The PFS benefit with negative M. hyorhinis infection was consistent across subgroups. In this retrospective, exploratory analysis, M. hyorhinis infection significantly reduced PFS. With increased levels of M. hyorhinis infection, the progression of the disease was more advanced, likely due to the hydrolysis of TKI by M. hyorhinis. A strong correlation was found between M. hyorhinis infection and TKI resistance in lung adenocarcinoma. This study provides potent evidence that M. hyorhinis hydrolyses TKI and will assist in the research of related mechanisms in the future. It provides an option to improve the efficacy of TKI, including strategies to decrease M. hyorhinis infection, thereby reducing long-term distress in TKI resistance patients with EGFR mutations.