Response- and Progression-Based End Points in Trial and Observational Cohorts of Patients With NSCLC.

Importance: Response Evaluation Criteria in Solid Tumors (RECIST) are commonly used to assess therapeutic response in clinical trials but not in routine care; thus, RECIST-based end points are difficult to include in observational studies. Clinician-anchored approaches for measuring clinical response have been validated but not widely compared with clinical trial data, limiting their use as evidence for clinical decision-making. Objective: To compare response- and progression-based end points in clinical trial and observational cohorts of patients with non-small cell lung cancer (NSCLC). Design, Setting, and Participants: This retrospective cohort study used patient-level data from the IMpower132 trial (conducted April 7, 2016, to May 31, 2017) and a nationwide electronic health record (EHR)-derived deidentified database (data collected January 1, 2011, to March 31, 2022). Patients in the observational cohort were selected according to the inclusion and exclusion criteria of the IMpower132 trial. All patients in the observational cohort had stage IV NSCLC. Exposure: All patients were randomized to or received first-line carboplatin or cisplatin plus pemetrexed. Main Outcomes and Measures: End points included response rates, duration of response, and progression-free survival, compared between the trial and observational cohorts before and after weighting. Response rates for the observational cohort were derived from the EHR. Results: A total of 769 patients met inclusion criteria, 494 in the observational cohort (median [IQR] age, 67 [60-74] years; 228 [46.2%] female; 45 [9.1%] Black or African American; 352 [71.3%] White; 53 [10.7%] American Indian or Alaska Native, Asian, Hawaiian or Pacific Islander, or multiracial) and 275 in the trial cohort (median [IQR] age, 63 [56-68] years; 90 [32.7%] female; 4 [1.5%] Black or African American; 194 [70.5%] White; 65 [23.6%] American Indian or Alaska Native, Asian, Hawaiian or Pacific Islander, or multiracial). All 3 end points were comparable between the study cohorts. Trial patients had a higher number of response assessments compared with patients in the weighted observational cohort. The EHR-derived response rate was numerically higher than the objective response rate after weighting (100.3 of 249.3 [40.2%] vs 105 of 275 [38.2%]) due to higher rates of observed partial response than RECIST-based partial response. Among patients with at least 1 response assessment, the EHR-derived response rate remained higher than the objective response rate (100.3 of 193.4 [51.9%] vs 105 of 256 [41.0%]) due to a higher proportion of patients in the observational cohort with no response assessment. Conclusions and Relevance: In this study, response- and progression-based end points were similar between clinical trial and weighted observational cohorts, which increases confidence in the reliability of observational end points and can inform their interpretation in relation to trial end points. Additionally, the difference observed in response rates (including vs excluding patients with no response assessment) highlights the importance of future research adopting this 2-way approach when evaluating the relationship of EHR-derived and objective response rates.

Response Evaluation Criteria in Gastrointestinal and Abdominal Cancers: Which to Use and How to Measure.

As the management of gastrointestinal malignancy has evolved, tumor response assessment has expanded from size-based assessments to those that include tumor enhancement, in addition to functional data such as those derived from PET and diffusion-weighted imaging. Accurate interpretation of tumor response therefore requires knowledge of imaging modalities used in gastrointestinal malignancy, anticancer therapies, and tumor biology. Targeted therapies such as immunotherapy pose additional considerations due to unique imaging response patterns and drug toxicity; as a consequence, immunotherapy response criteria have been developed. Some gastrointestinal malignancies require assessment with tumor-specific criteria when assessing response, often to guide clinical management (such as watchful waiting in rectal cancer or suitability for surgery in pancreatic cancer). Moreover, anatomic measurements can underestimate therapeutic response when applied to molecular-targeted therapies or locoregional therapies in hypervascular malignancies such as hepatocellular carcinoma. In these cases, responding tumors may exhibit morphologic changes including cystic degeneration, necrosis, and hemorrhage, often without significant reduction in size. Awareness of pitfalls when interpreting gastrointestinal tumor response is required to correctly interpret response assessment imaging and guide appropriate oncologic management. Data-driven image analyses such as radiomics have been investigated in a variety of gastrointestinal tumors, such as identifying those more likely to respond to therapy or recur, with the aim of delivering precision medicine. Multimedia-enhanced radiology reports can facilitate communication of gastrointestinal tumor response by automatically embedding response categories, key data, and representative images. ©RSNA, 2024 Test Your Knowledge questions for this article are available in the supplemental material.

First-in-human study of GFH018, a small molecule inhibitor of transforming growth factor-ß receptor I inhibitor, in patients with advanced solid tumors.

BACKGROUND: Transforming growth factor-ß (TGF-ß) is a cytokine with multiple functions, including cell growth regulation, extracellular matrix production, angiogenesis homeostasis adjustment and et al. TGF-ß pathway activation promotes tumor metastasis/progression and mediates epithelial-mesenchymal transmission suppressing immunosurveillance in advanced tumors. GFH018, a small molecule inhibitor blocking TGF-ß signal transduction, inhibits the progression and/or metastasis of advanced cancers. This first-in-human study evaluated the safety, tolerability, pharmacokinetics (PK), and efficacy of GFH018 monotherapy in patients with advanced solid tumors. METHODS: This phase I, open-label, multicenter study used a modified 3+3 dose escalation and expansion design. Adult patients with advanced solid tumors failing the standard of care were enrolled. Starting at 5 mg, eight dose levels up to 85 mg were evaluated. Patients received GFH018 BID (14d-on/14d-off) starting on the 4th day after a single dose on cycle 1, day 1. Subsequent cycles were defined as 28 days. The study also explored the safety of 85 mg BID 7d-on/7d-off. Adverse events were graded using NCI criteria for adverse events (NCI-CTCAE v5.0). PK was analyzed using a noncompartmental method. Efficacy was evaluated using RECIST 1.1. Blood samples were collected for biomarker analysis. RESULTS: Fifty patients were enrolled and received at least one dose of GFH018. No dose-limiting toxicity occurred, and the maximum tolerated dose was not reached. Forty-three patients (86.0%) had at least one treatment-related adverse event (TRAE), and three patients (6.0%) had ≥ G3 TRAEs. The most common TRAEs (any grade/grade ≥3) were AST increased (18%/0%), proteinuria (14%/2%), anemia (14%/2%), and ALT increased (12%/0%). No significant cardiotoxicity or bleeding was observed. GFH018 PK was linear and dose-independent, with a mean half-life of 2.25-8.60 h from 5 - 85 mg. Nine patients (18.0%) achieved stable disease, and one patient with thymic carcinoma achieved tumor shrinkage, with the maximum target lesion decreased by 18.4%. Serum TGF-ß1 levels were not associated with clinical responses. The comprehensive recommended dose for Phase II was defined as 85 mg BID 14d-on/14d-off. CONCLUSIONS: GFH018 monotherapy presented a favorable safety profile without cardiac toxicity or bleeding. Modest efficacy warrants further studies, including combination strategies. TRIAL REGISTRATION: ClinicalTrial. gov ( https://www. CLINICALTRIALS: gov/ ), NCT05051241. Registered on 2021-09-02.

Tumor Size Is Not Everything: Advancing Radiomics as a Precision Medicine Biomarker in Oncology Drug Development and Clinical Care. A Report of a Multidisciplinary Workshop Coordinated by the RECIST Working Group.

Radiomics, the science of extracting quantifiable data from routine medical images, is a powerful tool that has many potential applications in oncology. The Response Evaluation Criteria in Solid Tumors Working Group (RWG) held a workshop in May 2022, which brought together various stakeholders to discuss the potential role of radiomics in oncology drug development and clinical trials, particularly with respect to response assessment. This article summarizes the results of that workshop, reviewing radiomics for the practicing oncologist and highlighting the work that needs to be done to move forward the incorporation of radiomics into clinical trials.

Immune checkpoint inhibitors: Assessment of the performance and the agreement of iRECIST, irRC, and irRECIST.

INTRODUCTION: Immunotherapy has become more widely accepted and used by medical oncologists. Radiologists face challenges in assessing tumor response and becoming more involved in the management of treatment. We aimed to assess the agreement between immune-related response criteria (irRC), immune-related RECIST (irRECIST), and immune RECIST (iRECIST) to correlate the response measured by them with overall survival (OS), and to determine the confirmation rate of progressive disease (PD). METHODS: A total of 43 patients (28 men, 15 women; average age = 54.6 ± 15.7 years) treated with immunotherapy were included in this study. Pairwise agreements between iRECIST, irRC, and irRECIST were calculated using Cohen's kappa statistics. The correlation of the criteria-based response and OS was evaluated using the Kaplan-Meier method and log-rank test. A confirmation rate with 95% confidence intervals (CI) was calculated in patients with PD. RESULTS: The kappa values between iRECIST and irRC, iRECIST and irRECIST, and irRC and irRECIST were 0.961 (almost perfect; P < 0.001), 0.961 (almost perfect; P < 0.001), and 0.922 (almost perfect; P < 0.001), respectively. The Kaplan-Meier method and log-rank test showed for each criterion a statistically significant correlation with OS (P < 0.05). The confirmation rates of PD for irRC, irRECIST, and iRECIST were 95% (19/20; 95% CI = 76.4-99.1%), 90% (18/20; 95% CI = 69.9-97.2%), and 90.5% (19/21; 95% CI = 71.1-97.4%), respectively. CONCLUSION: There was an almost perfect and statistically significant agreement between iRECIST, irRC, and irRECIST. The measurements performed with them significantly correlated with the OS; their confirmation rates were similar. iRECIST and irRECIST might be favored over irRC because of their relative ease of use.

Distinguishing recurrence from radiation-induced lung injury at the time of RECIST progressive disease on post-SABR CT scans using radiomics.

Stereotactic ablative radiotherapy (SABR) is a highly effective treatment for patients with early-stage lung cancer who are inoperable. However, SABR causes benign radiation-induced lung injury (RILI) which appears as lesion growth on follow-up CT scans. This triggers the standard definition of progressive disease, yet cancer recurrence is not usually present, and distinguishing RILI from recurrence when a lesion appears to grow in size is critical but challenging. In this study, we developed a tool to do this using scans with apparent lesion growth after SABR from 68 patients. We performed bootstrapped experiments using radiomics and explored the use of multiple regions of interest (ROIs). The best model had an area under the receiver operating characteristic curve of 0.66 and used a sphere with a diameter equal to the lesion's longest axial measurement as the ROI. We also investigated the effect of using inter-feature and volume correlation filters and found that the former was detrimental to performance and that the latter had no effect. We also found that the radiomics features ranked as highly important by the model were significantly correlated with outcomes. These findings represent a key step in developing a tool that can help determine who would benefit from follow-up invasive interventions when a SABR-treated lesion increases in size, which could help provide better treatment for patients.

Efficacy and safety of temozolomide-based regimens in advanced pancreatic neuroendocrine tumors: a systematic review and meta-analysis.

BACKGROUND: Recent advances in the management of pancreatic neuroendocrine tumors (pNETs) highlight the potential benefits of temozolomide, an alkylating agent, for these patients. In this meta-analysis, we aimed to assess the outcome of temozolomide, alone or in combination with other anticancer medications in patients with advanced pNET. METHODS: Online databases of PubMed, Web of Science, Embase, the Cochrane Library, and ClinicalTrials.gov were searched systematically for clinical trials that reported the efficacy and safety of temozolomide in patients with advanced pNET. Random-effect model was utilized to estimate pooled rates of outcomes based on Response Evaluation Criteria in Solid Tumors criteria, biochemical response, and adverse events (AEs). RESULTS: A total of 14 studies, providing details of 441 individuals with advanced pNET, were included. The quantitative analyses showed a pooled objective response rate (ORR) of 41.2% (95% confidence interval, CI, of 32.4%-50.6%), disease control rate (DCR) of 85.3% (95% CI of 74.9%-91.9%), and a more than 50% decrease from baseline chromogranin A levels of 44.9% (95% CI of 31.6%-49.0%). Regarding safety, the results showed that the pooled rates of nonserious AEs and serious AEs were 93.8% (95% CI of 88.3%-96.8%) and 23.7% (95% CI of 12.0%-41.5%), respectively. The main severe AEs encompassed hematological toxicities. CONCLUSIONS: In conclusion, our meta-analysis suggests that treatment with temozolomide, either as a monotherapy or in combination with other anticancer treatments might be an effective and relatively safe option for patients with advanced locally unresectable and metastatic pNET. However, additional clinical trials are required to further strengthen these findings. This study has been registered in PROSPERO (CRD42023409280).

Correlation between tumor size change and outcome in a rare cancer immunotherapy basket trial.

BACKGROUND: RECIST criteria for progressive disease, partial response, and complete response, reflecting +20%, -30%, and -100% tumor size changes, respectively, are critical outcome variables in oncology clinical trials. Herein, we evaluated post-immunotherapy tumor size change correlation with outcomes. METHODS: We used a unique clinical trial data resource, a multicenter basket trial in patients with rare solid tumors treated with nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) between 2017 and 2023 (National Cancer Institute/Southwest Oncology Group-sponsored DART trial [NCT02834013]) (open at 1083 sites at its peak). Outcome associations were evaluated by survival analysis techniques including Martingale residuals. RESULTS: In 638 evaluable patients, we found strong linear relationships between percent change in tumor measurement up to a 40%-50% increase and progression-free (PFS) and overall survival (OS) (both Cox regression P < .001; landmark analyses based on day 65). Pearson R correlation between survival estimates and tumor change category were -0.94, -0.89, and -0.89 (PFS) and -0.84, -0.90, and -0.90 (OS) for median, 6-month (PFS), and 1-year (OS) and for 1-year (PFS) and 2-year (OS) estimates. CONCLUSIONS: Percent change in tumor measurement per RECISTv1.1 (the sum of longest dimensions of target lesions) has a linear association with PFS and OS up to a 40% to 50% increase in tumor measurement in this cohort of patients with rare cancers who received combination immune checkpoint blockade. Quantitative first scan tumor measurement changes include important information to evaluate the potential efficacy of a therapy beyond the proportion of patients who achieve an objective response.

Poor Concordance Between Cancer Antigen-125 and RECIST Assessment for Progression in Patients With Platinum-Sensitive Relapsed Ovarian Cancer on Maintenance Therapy With a Poly(ADP-ribose) Polymerase Inhibitor.

PURPOSE: Cancer antigen-125 (CA-125) is recommended by treatment guidelines and widely used to diagnose ovarian cancer recurrence. The value of CA-125 as a surrogate for disease progression (PD) and its concordance with radiologic progression are unclear, particularly for women with platinum-sensitive relapsed ovarian cancer (PSROC) who have responded to chemotherapy and treated with maintenance poly(ADP-ribose) polymerase inhibitor (PARPi). METHODS: In this pooled analysis of four randomized trials of maintenance PARPi or placebo (Study 19, SOLO2, ARIEL3, and NOVA), we extracted data on CA-125 PD as defined by Gynecologic Cancer InterGroup criteria and RECIST v1.1. We evaluated the concordance between CA-125 and RECIST PD and reported on the negative predictive value (NPV) and positive predictive value (PPV). RESULTS: Of 1,262 participants (n = 818 PARPi, n = 444 placebo), 403 (32%) had CA-125 PD, and of these, 366 had concordant RECIST PD (PPV, 91% [95% CI, 88 to 93]). However, of 859 (68%) without CA-125 PD, 382 also did not have RECIST PD (NPV, 44% [95% CI, 41 to 48]). Within the treatment arms, PPV remained high (PARPi, 91% [95% CI, 86 to 94]; placebo, 91% [95% CI, 86 to 95]) but NPV was lower on placebo (PARPi, 53% [95% CI, 49 to 57]; placebo, 25% [95% CI, 20 to 31]). Of 477 with RECIST-only PD, most (95%) had a normal CA-125 at the start of maintenance therapy and the majority (n = 304, 64%) had CA-125 that remained within normal range. Solid organ recurrence without peritoneal disease was more common in those with RECIST-only PD than in those with CA-125 and RECIST PD (36% v 24%; P < .001). CONCLUSION: In patients with PSROC treated with maintenance PARPi, almost half with RECIST PD did not have CA-125 PD, challenging current guidelines. Periodic computed tomography imaging should be considered as part of surveillance, particularly in those with a normal CA-125 at the start of maintenance therapy and on treatment.

A perspective: the integration of ctDNA into Response Evaluation Criteria in Solid Tumours 1.1 for phase II immunotherapy clinical trials.

A consensus guideline, iRECIST, was developed by the Response Evaluation Criteria in Solid Tumours (RECIST) working group for the use of the modified RECIST version 1.1 in cancer immunotherapy trials. iRECIST was designed to separate pseudoprogression from real progression. However, this is not the only ambiguous situation. In clinical immunotherapy trials, stable disease may reflect three tumor responses, including real stable disease, progressive disease and responsive disease. The prediction of a "true complete/partial response" is also important. Much data has accumulated showing that ctDNA can guide decisions at this point; thus, integrating ctDNA into the RECIST 1.1 criteria may help to distinguish a true tumor response type earlier in patients treated with immunotherapy; however, prospectively designed validation studies are needed.

Evaluating Oncologists' Practice Patterns and Decision-Making in Locally Advanced or Metastatic Urothelial Carcinoma: The US Physician PARADIGM Study.

BACKGROUND: The treatment landscape for locally advanced/metastatic urothelial carcinoma (la/mUC) has evolved. This study examined US prescribing patterns and clinical decision-making for first-line (1L) and first-line maintenance (1LM) treatment. MATERIALS AND METHODS: US-based oncologists (N = 150) completed an online survey on patient demographics, practice patterns, and important factors considered in 1L/1LM selection. Multivariable logistic regression was used to assess factors associated with more vs less frequent 1L/1LM prescribing. RESULTS: Physician reports estimated that 23% of patients with la/mUC had not received any systemic therapy in the previous 6 months; however, 46% received 1L, 32% received second-line, and 22% received subsequent-line systemic treatments. Of patients who were receiving 1L treatment, 72% were estimated to be receiving 1L platinum-based chemotherapy. Around 69% of patients eligible for 1LM received the treatment. Physicians categorized as frequent prescribers reported overall survival (OS), disease control rate (DCR), and rate of grade 3/4 adverse events (AEs) as factors associated with 1L treatment selection (all P < .05). OS, rate of grade 3/4 immune-mediated AEs, and inclusion in institutional guidelines were reported as attributes used in 1LM treatment selection (all P < .05). Multivariable analysis revealed OS, DCR, and rate of grade 3/4 AEs as important factors in oncologists' 1L treatment selection; academic practice setting and use of Response Evaluation Criteria in Solid Tumors version 1.1 were associated with 1LM use (all P < .05). CONCLUSION: OS and AEs were found to be relevant factors associated with offering 1L and 1LM treatment. Variability exists in physicians' decision-making in the real-world setting for la/mUC.

RECIST-Induced Reliable Learning: Geometry-Driven Label Propagation for Universal Lesion Segmentation.

Automatic universal lesion segmentation (ULS) from Computed Tomography (CT) images can ease the burden of radiologists and provide a more accurate assessment than the current Response Evaluation Criteria In Solid Tumors (RECIST) guideline measurement. However, this task is underdeveloped due to the absence of large-scale pixel-wise labeled data. This paper presents a weakly-supervised learning framework to utilize the large-scale existing lesion databases in hospital Picture Archiving and Communication Systems (PACS) for ULS. Unlike previous methods to construct pseudo surrogate masks for fully supervised training through shallow interactive segmentation techniques, we propose to unearth the implicit information from RECIST annotations and thus design a unified RECIST-induced reliable learning (RiRL) framework. Particularly, we introduce a novel label generation procedure and an on-the-fly soft label propagation strategy to avoid noisy training and poor generalization problems. The former, named RECIST-induced geometric labeling, uses clinical characteristics of RECIST to preliminarily and reliably propagate the label. With the labeling process, a trimap divides the lesion slices into three regions, including certain foreground, background, and unclear regions, which consequently enables a strong and reliable supervision signal on a wide region. A topological knowledge-driven graph is built to conduct the on-the-fly label propagation for the optimal segmentation boundary to further optimize the segmentation boundary. Experimental results on a public benchmark dataset demonstrate that the proposed method surpasses the SOTA RECIST-based ULS methods by a large margin. Our approach surpasses SOTA approaches over 2.0%, 1.5%, 1.4%, and 1.6% Dice with ResNet101, ResNet50, HRNet, and ResNest50 backbones.

Reclassification of therapeutic response of unresectable hepatocellular carcinoma to anti-angiogenic therapy and immunotherapy using alpha RECIST.

OBJECTIVES: To assess the therapeutic response of HCC to antiangiogenic therapy plus immunotherapy by integrating RECIST 1.1 and alpha-fetoprotein (AFP) response at the 6th week to predict overall survival (OS). METHODS: This retrospective study included 150 and 214 patients with HCC who received combination therapy in training and validation cohorts. The medical images and AFP levels obtained at baseline and 6th week were collected. AFP response stratification: partial response (PR): AFP% ≥ 75% decline; stable disease (SD): AFP% < 75% decline and ≤ 10% elevation; progressive disease (PD): AFP% > 10% elevation. The alpha-RECIST was: PR: RECIST 1.1-PR or AFP-PR; PD: AFP-PD or RECIST 1.1-PD and does not satisfy AFP-PR; SD: neither PR nor PD. OS was compared using Kaplan-Meier curves. The predictive ability of various criteria was evaluated using the concordance index and time-dependent area under the receiver-operating characteristic curve. RESULTS: RECIST 1.1 achieved significant OS stratification (p = 0.020) for AFP < 20 ng/mL. For AFP ≥ 20 ng/mL, alpha-RECIST showed better performance than RECIST 1.1, mRECIST, and AFP response according to C-index (0.73 vs 0.66 vs 0.68 vs 0.69). The National Cancer Center (NCC) strategy utilized RECIST 1.1 for AFP < 20 ng/mL and alpha-RECIST for AFP ≥ 20 ng/mL and showed better performance than RECIST 1.1, mRECIST and AFP response according to C-index (0.73 vs 0.67 vs 0.69 vs 0.64). The performances of alpha-RECIST and NCC Strategy were confirmed in the validation cohort (C-index = 0.77 and 0.74). CONCLUSIONS: The alpha-RECIST and NCC Strategy achieved better survival stratification in patients with HCC under combination therapy in the AFP ≥ 20 ng/mL group and the whole cohort compared to the RECIST 1.1, mRECIST, and AFP response. CLINICAL TRANSLATIONAL RELEVANCE: The alpha-RECIST and National Cancer Center strategy are optimal methods for determining therapeutic response to a combination of anti-angiogenic therapy plus immunotherapy and facilitating accurate prognostic stratification for HCC in the AFP ≥ 20 ng/mL group and the whole cohort, which may help oncologists for early identification of responders and progression at 6 weeks and clinical decision-making. KEY POINTS: • RECIST 1.1 is indicated for patients with baseline alpha-fetoprotein (AFP) < 20 ng/mL. • For patients with baseline AFP ≥ 20 ng/mL, integrating RECIST 1.1 and AFP response (alpha-RECIST) may aid in the early identification of survival benefits and progression definition prior to the administration of additional efficacious drugs. • The National Cancer Center strategy is an optimal stratified strategy for determining therapeutic response to a combination of anti-angiogenic therapy and immunotherapy for HCC based on baseline AFP levels.

What is the predictive value of RECIST criteria following stereotactic lung radiation?

PURPOSE: Response EvaluationCriteriain Solid Tumors (RECIST) is commonly used to assess response to anti-cancer therapies. However, its application after lung stereotactic ablative radiotherapy (SABR) is complicated by radiation-induced lung changes. This study assesses the frequency of progressive disease (PD) by RECIST following lung SABR and correlates this with actual treatment outcomes as determined by longitudinal follow-up. METHODS AND MATERIALS: We reviewed patients treated with lung SABR for primary lung tumors or oligometastases between 2010 and 2015. Patients were treated with SABR doses of 54-60 Gy in 3-8 fractions. All follow-up scans were assessed and the treated lesion was serially measured over time, with the maximum diameter on axial CT slices used for RECIST calculations. Lesions demonstrating PD by RECIST criteria were identified and subsequently followed for long-term outcomes. The final 'gold-standard' assessment of response was based on size changes after PD and, as available, positron emission tomography scan and/or biopsy. RESULTS: Eighty-eight lesions met inclusion criteria. Seventy-five were lung primaries and thirteen were lung metastases. Median follow-up was 52 months (interquartile range: 33-68). Two-thirds (66 %, 58/88) of treated lesions met RECIST criteria for PD; however, local recurrence was only confirmed in 16 % (9/58) of cases. Most lesions that triggered PD by RECIST (47/58, 81 %) were ultimately found not to represent recurrence, while a minority (2/58, 3 %) had an uncertain response. The positive predictive value [PPV] of a RECIST defined PD event was 0.16. If PD was triggered within 12-months post-treatment, PPV was 0.08, compared to 0.21 for lesions triggering PD after 12-months. CONCLUSION: Using RECIST criteria, two-thirds of patients treated with lung SABR met criteria for PD. However, only a minority had recurrence, leading to a poor PPV of RECIST. This highlights the limitations of RECIST in this setting and provides context for physicians when interpreting post-lung SABR imaging.

Modified response evaluation criteria in solid tumors: A better response evaluation criteria for patients with non-squamous non-small cell lung cancer after bevacizumab treatment.

AIM: Cavitation of lesions is common in non-squamous non-small cell lung cancer (non-squamous-NSCLC) patients treated with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFRIs). However, traditional response evaluation criteria in solid tumors (RECIST) do not take cavitation into consideration and may no longer be accurate for potentially reflecting the real clinical efficacy of anti-vessel growth therapy. Here, we aimed to optimize the traditional RECIST version 1.1 by adding cavitation into the evaluation criteria. METHODS: We performed a post-hoc radiologic review of 517 patients in a phase III clinical trial of bevacizumab biosimilar (SIBP04) combined with chemotherapy for the treatment of non-squamous NSCLC. Tumor responses were assessed by RECIST1.1 and mRECIST criteria (modified RECIST, a novel alternate method where the longest diameter of the cavity was subtracted from the overall longest diameter of that lesion to measure target lesions), respectively, and correlated with clinical outcomes. RESULTS: Cavitations of pulmonary lesions were seen in nine (2%) patients at baseline, and 97 (19%) during treatment. The use of mRECIST resulted in an alteration of the response category. For patients with post-therapy cavitation, the objective response rate was 56% using RECIST1.1 and 67% by mRECIST. In addition, the survival rates between partial response, stable disease, and progressive disease when the mRECIST was applied were significantly different (p < 0.05), while RECIST1.1 failed to show survival differences (p = 0.218). CONCLUSION: For patients with post-therapy cavitation, mRECIST exhibited higher predictability of survival than RECIST1.1. Response assessment might be improved by incorporating cavitation into assessment, potentially altering outcomes of key clinical efficacy parameters.

Discordance between GCIG CA-125 progression and RECIST progression in the CALYPSO trial of patients with platinum-sensitive recurrent ovarian cancer.

BACKGROUND: CA-125 alone is widely used to diagnose progressive disease (PD) in platinum-sensitive recurrent ovarian cancer (PSROC) on chemotherapy. However, there are increasing concerns regarding its accuracy. We assessed concordance between progression defined by CA-125 and RECIST using data from the CALYPSO trial. METHODS: We computed concordance rates for PD by CA-125 and RECIST to determine the positive (PPV) and negative predictive values (NPV). RESULTS: Of 769 (79%) evaluable participants, 387 had CA-125 PD, where only 276 had concordant RECIST PD (PPV 71%, 95% CI 67-76%). For 382 without CA-125 PD, 255 had RECIST PD but 127 did not (NPV 33%, 95% CI 29-38). There were significant differences in NPV according to baseline CA-125 (≤100 vs >100: 42% vs 25%, P < 0.001); non-measurable vs measurable disease (51% vs 26%, P < 0.001); and platinum-free-interval (>12 vs 6-12 months: 41% vs 14%, P < 0.001). We observed falling CA-125 levels in 78% of patients with RECIST PD and CA-125 non-PD. CONCLUSION: Approximately 2 in 3 women with PSROC have RECIST PD but not CA-125 PD by GCIG criteria. Monitoring CA-125 levels alone is not reliable for detecting PD. Further research is required to investigate the survival impact of local therapy in radiological detected early asymptomatic PD.

Liquid Biopsy Response Evaluation Criteria in Solid Tumors (LB-RECIST).

Current evaluation of treatment response in solid tumors depends on dynamic changes in tumor diameters as measured by imaging. However, these changes can only be detected when there are enough macroscopic changes in tumor volume, which limits the usability of radiological response criteria in evaluating earlier stages of disease response and necessitates much time to lapse for gross changes to be notable. One promising approach is to incorporate dynamic changes in circulating tumor DNA (ctDNA), which occur early in the course of therapy and can predict tumor responses weeks before gross size changes manifest. However, several issues need to be addressed before recommending the implementation of ctDNA response criteria in daily clinical practice such as clinical, biological, and regulatory challenges and, most importantly, the need to standardize/harmonize detection methods and ways to define ctDNA response and/or progression for precision oncology. Herein, we review the use of liquid biopsy (LB) to evaluate response in solid tumors and propose a plan toward standardization of LB-RECIST.

BETA prime: a first-in-man phase 1 study of AdAPT-001, an armed oncolytic adenovirus for solid tumors.

AdAPT-001 is an oncolytic adenovirus (OAV) with a transforming growth factor beta (TGF-ß) trap, which neutralizes the immunosuppressive and profibrotic cytokine, TGF-ß. The aim or purpose of this phase 1 study was to assess the safety and tolerability and, secondarily, the efficacy of AdAPT-001 after single intratumoral injection (IT) (Part 1) and multidose IT injection (Part 2) in patients with superficially accessible, advanced refractory solid tumors. Part 1 enrolled 9 patients with a 3 + 3 single dose-escalation safety run-in involving 2.5 × 1011, 5.0 × 1011, 1.0 × 1012 viral particles (vps). No dose-limiting toxicities or treatment-related serious adverse events (SAEs) were seen. In Part 2, a dose-expansion phase, 19 patients received AdAPT-001 at 1.0 × 1012 vps until disease progression according to Response Evaluation Criteria in Solid Tumors or RECIST 1.1. The overall responses to treatment included confirmed partial responses (3), durable stable disease ≥ 6 months (5), and progressive disease (13). AdAPT-001 is well tolerated. Evidence of an anti-tumor effect was seen in both injected and uninjected lesions. The recommended Phase 2 dose was 1.0 × 1012 vp administered by intratumoral injection once every 2 weeks. Combination of AdAPT-001 with a checkpoint inhibition is enrolling.

A first-in-human, open-label, dose-escalation and dose-expansion phase I study to evaluate the safety, tolerability, pharmacokinetics/pharmacodynamics, and antitumor activity of QL1604, a humanized anti-PD-1 mAb, in patients with advanced or metastatic solid tumors.

Background: QL1604 is a humanized immunoglobulin G4 monoclonal antibody against programmed cell death protein 1. This first-in-human, open-label phase I study aimed to investigate the safety and tolerability and to identify the recommended doses of QL1604 for future studies. Pharmacokinetics/pharmacodynamics (PK/PD) and preliminary antitumor activity were also assessed. Methods: Patients with advanced or metastatic solid tumors who failed or had no standard therapies available were recruited. In the dose-escalation phase, patients were treated with QL1604 at 0.3 mg/kg, 1 mg/kg, 3 mg/kg, and 10 mg/kg intravenously once every 2 weeks (Q2W) in an accelerated titration with a traditional 3 + 3 design, followed by a dose-expansion phase at 3 mg/kg Q2W, 3 mg/kg once every 3 weeks (Q3W), 10 mg/kg Q2W and a fixed dose of 200 mg Q3W. Dose-limiting toxicities (DLTs) were assessed during the first 28 days after the first dose of study drug. Adverse events (AEs) were graded per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0, and antitumor activity of QL1604 was evaluated by investigators on the basis of Response Evaluation Criteria in Solid Tumors version 1.1. Results: A total of 35 patients with advanced or metastatic solid tumors were enrolled. DLTs were reported in one patient at the dose level of 3 mg/kg Q2W (grade 3 immune-mediated myositis and myasthenia gravis), and maximum tolerated dose was not reached. The most frequent treatment-related AEs (≥10%) were fatigue (37.1%), anemia (22.9%), increased blood thyroid-stimulating hormone (17.1%), increased aspartate aminotransferase (AST) (17.1%), increased alanine aminotransferase (ALT) (14.3%), decreased white blood cell (WBC) count (11.4%), rash (14.3%), and pruritus (14.3%). AEs leading to discontinuation of QL1604 occurred in three of the 35 patients (8.6%). Partial responses (PRs) occurred in seven patients, resulting in an objective response rate of 20.0% (7/35). Single dose of QL1604 exhibited a dose-dependent increase in the exposure ranging from 0.3 mg/kg to 10 mg/kg. Mean receptor occupancy (RO) for QL1604 at the dose of 3 mg/kg (Q2W and Q3W) and 200 mg (Q3W) was greater than 80% during cycle 1 after one infusion. Conclusion: QL1604 monotherapy exhibited favorable safety, PK, and signal of antitumor activity in patients with advanced or metastatic solid tumors, and the results supported further clinical studies of QL1604. On the basis of the safety, PK, and RO data, the recommended dosage for further clinical trials is 3 mg/kg or a fixed dose of 200 mg given every 3 weeks. Clinical Trial Registration: https://classic.clinicaltrials.gov/ct2/show/NCT05649761?term=QL1604&draw=2&rank=1, identifier NCT05649761.