Progression-free Survival Outcomes Research Articles

COMBI-r: A Prospective, Non-Interventional Study of Dabrafenib Plus Trametinib in Unselected Patients with Unresectable or Metastatic BRAF V600-Mutant Melanoma.

Combined BRAF/MEK-inhibition constitutes a relevant treatment option for BRAF-mutated advanced melanoma. The prospective, non-interventional COMBI-r study assessed the effectiveness and tolerability of the BRAF-inhibitor dabrafenib combined with the MEK-inhibitor trametinib in patients with advanced melanoma under routine clinical conditions. Progression-free survival (PFS) was the primary objective, and secondary objectives included overall survival (OS), disease control rate, duration of therapy, and the frequency and severity of adverse events. This study enrolled 472 patients at 55 German sites. The median PFS was 8.3 months (95%CI 7.1-9.3) and the median OS was 18.3 months (14.9-21.3), both tending to be longer in pre-treated patients. In the 147 patients with CNS metastases, PFS was similar in those requiring corticosteroids (probably representing symptomatic patients, 5.6 months (3.9-7.2)) compared with those not requiring corticosteroids (5.9 months (4.8-6.9)); however, OS was shorter in patients with brain metastases who received corticosteroids (7.8 (6.3-11.6)) compared to those who did not (11.9 months (9.6-19.5)). The integrated subjective assessment of tumor growth dynamics proved helpful to predict outcome: investigators' upfront categorization correlated well with time-to-event outcomes. Taken together, COMBI-r mirrored PFS outcomes from other prospective, observational studies and confirmed efficacy and safety findings from the pivotal phase III COMBI-d/-v and COMBI-mb trials.

Surveillance as a safe and effective option for treatment of stage I seminoma.

Retrospective, single institution study, with 55 patients diagnosed with clinical stage I seminoma between 2007 and 2020. Selected patients were analysed regarding three management approaches - surveillance, adjuvant radiotherapy and adjuvant carboplatin AUC7. Overall survival and progression-free survival outcomes were analysed. Predictors of treatment choice were determined, and predictors of recurrence were analysed in patients on active surveillance. The median follow-up time was 91 months (13-165). Overall survival at 10 years was 98.2%. Stage I seminoma patients had a 1-, 3- and 10-year progression free survival of 98%, 94% and 89%, respectively. Three-year progression free survival was 92.0% for those on active surveillance (IC95%, 91.5-92.5%), 95.2% for carboplatin (IC95%, 94.8-95.6%) and 100% for those on adjuvant radiotherapy (p > 0.05). All relapses on active surveillance protocols occurred during the first 24 months. Overall, 43% of patients who underwent adjuvant treatment reported adverse effects of therapy, with higher incidence on radiotherapy group (63%). Stage I seminoma have excellent prognosis, high cure rates, and low treatment-associated morbidity. Active surveillance is a safe modality when applied to selected patients. Adjuvant radiotherapy and adjuvant chemotherapy with carboplatin show similar results, with fewer adverse effects on chemotherapy arm.

Key Prognostic Factors Create a Composite Risk Score to Stratify Patients into High- and Low-Treatment Benefit Groups: A Multicenter, Retrospective Data Analysis of 84 Metastatic Colorectal Cancer Patients Treated with Regorafenib as Part of the CORRECT and CONSIGN Trials

Introduction: In further-line mCRC treatment, median progression-free survival (PFS) is rather short, and many patients do not benefit from any antitumor treatment and should therefore be treated according to best-supportive care. A risk score based on standard laboratory values using markers of tumor inflammation aims to define a patient cohort with high treatment benefit and might offer insights into tumor biology. As regorafenib has been dropped off the German market due to an unfavorable risk-benefit ratio, patient selection is key for any further-line treatment option. Methods: We used Cox regression analysis to determine laboratory markers that are independent prognostic factors of OS and PFS outcome. The influence of these variables was weighted using an estimator, which was calculated using Cox regression analysis. The estimators were implemented as multiplication factors, resulting in a risk score. A cut-off value for the resulting risk values was then determined via Cox regression analysis resulting in a low- and high-risk subgroup. Results: Using data of 82 patients, a risk score identifying long-term survival in patients with last-line mCRC treatment could be calculated. The following parameters were associated with significantly longer survival in multivariate analysis: NLR ≤5 (p = <0.001), AP ≤200 U/L (p = 0.001), CRP ≤3.2 mg/dL (p = <0.001). The following estimator values were used to calculate a risk score: NLR: 0.132 (p = 0.046), AP: 0.004 (p = 0.014), and CRP: 0.032 (p = 0.039). Implementing the estimators as multiplication factors yielded the following risk score: 0.132*NLR + 0.004*AP + 0.032*CRP = Risk value. Cox regression resulted in low- and high-risk subgroups with risk values below and above 1.4, respectively. In the group with a low-risk score (<1.4), patients had a median OS of 10.5 months after initiating regorafenib. Patients with a high-risk score (>1.4) survived only 3.3 months after starting therapy with regorafenib (n = 43, p < 0.001, HR = 3.76). Conclusions: The presented composite risk score stratifies patients into two prognostic subgroups characterized by standard laboratory values. Patients with signs of systemic inflammation characterized by elevated NLR, AP, and CRP have a high composite risk score and a significant shorter overall survival. Although this score needs to be prospectively validated in larger cohorts, it may be used to stratify patients suitable for further-line treatment studies.

Bilateral Laser Interstitial Thermal Therapy for Butterfly Gliomas Compared With Needle Biopsy: A Preliminary Survival Study.

Bilateral/butterfly glioblastoma (bGBM) has a poor prognosis. Resection of these tumors is limited due to severe comorbidities that arise from surgical procedures. Laser interstitial thermal therapy (LITT) offers a minimally invasive cytoreductive therapy for deep-seated tumors such as bGBM. The objective of this study was to evaluate the safety of bilateral LITT in patients with bGBM. Medical records of all consecutive patients diagnosed with bGBM by a single surgeon at a single institution from January 2014 to August 2022 were reviewed. Clinical, safety, and radiographic volumetric data were obtained. In addition, an exploratory analysis of survival was performed. A total of 25 patients were included; 14 underwent biopsy only, and 11 underwent biopsy + LITT (7 underwent bilateral and 4 underwent unilateral LITT). No (0%) intraoperative or postoperative complications were recorded in the treatment group. Tumor volume negatively correlated with extent of treatment (r 2 = 0.44, P = .027). The median progression-free survival was 2.8 months in the biopsy-only group and 5.5 months in the biopsy + LITT group ( P = .026). The median overall survival was 4.3 months in the biopsy-only group and 10.3 months in the biopsy + LITT group ( P = .035). Bilateral LITT for bGBM can be safely performed and shows early improvement of the progression-free survival and long-term survival outcomes of these patients.

CDKN2A mutations have equivalent prognostic significance to homozygous deletion in IDH-mutant astrocytoma.

Homozygous deletion of CDKN2A/B is currently considered a molecular signature for grade 4 in IDH-mutant astrocytomas, irrespective of tumor histomorphology. The 2021 WHO Classification of CNS Tumors does not currently include grading recommendations for histologically lower-grade (grade 2-3) IDH-mutant astrocytoma with CDKN2A mutation or other CDKN2A alterations, and little is currently known about the prognostic implications of these alternative CDKN2A inactivating mechanisms. To address this, we evaluated a cohort of institutional and publicly available IDH-mutant astrocytomas, 15 with pathogenic mutations in CDKN2A, 47 with homozygous CDKN2A deletion, and 401 with retained/wildtype CDKN2A. The IDH-mutant astrocytomas with mutant and deleted CDKN2A had significantly higher overall copy number variation compared to those with retained/wildtype CDKN2A, consistent with more aggressive behavior. Astrocytoma patients with CDKN2A mutation had significantly worse progression-free (p = 0.0025) and overall survival (p < 0.0001) compared to grade-matched patients with wildtype CDKN2A, but statistically equivalent progression-free survival and overall survival outcomes to patients with CDKN2A deletion. No significant survival difference was identified between CDKN2A mutant cases with or without loss of the second allele. These findings suggest that CDKN2A mutation has a detrimental effect on survival in otherwise lower-grade IDH-mutant astrocytomas, similar to homozygous CDKN2A deletion, and should be considered for future grading schemes.

Balancing Efficacy and Tolerability of First-Line Systemic Therapies for Advanced Hepatocellular Carcinoma: A Network Meta-Analysis

Background: Atezolizumab + bevacizumab represent the current standard of care for first-line treatment of advanced hepatocellular carcinoma (HCC). However, direct comparison with other combination treatments including immune checkpoint inhibitors (ICI) + tyrosine kinase inhibitors (TKIs) are lacking. Objectives: This network meta-analysis (NMA) aims to indirectly compare the efficacy and the safety of first-line systemic therapies for unresectable advanced HCC. Method: A literature search of MEDLINE, Embase, and SCOPUS databases was conducted up to October 31, 2022. Phase 3 randomized controlled trials (RCTs) testing TKIs, including sorafenib and lenvatinib, or ICIs reporting overall survival (OS) and progression-free survival (PFS) were included. Individual survival data were extracted from OS and PFS curves to calculate restricted mean survival time. A Bayesian NMA was performed to compare treatments in terms of efficacy (15- and 30-month OS, 6-month PFS) and safety, represented by grade ≥3 (severe) adverse events (SAEs). The incremental safety-effectiveness ratio as measure of net health benefit was calculated as the difference in SAE probability divided by survival difference between the 2 most effective treatments. Results: Nine RCTs enrolling 6,600 patients were included. Atezolizumab plus bevacizumab showed the highest probability (88%) of achieving the 30-month OS landmark. Lenvatinib showed a probability of 86% of achieving best PFS outcomes. ICI monotherapies ranked as most tolerable. Atezolizumab plus bevacizumab showed the best net health benefit for OS, compared to durvalumab plus tremelimumab. When evaluating the net health benefit for PFS, at a willingness-to-risk threshold of 10% of SAEs for life-month gained, atezolizumab plus bevacizumab was favoured in 78% of cases, while at threshold of 30% of SAEs for life-month gained, lenvatinib was favoured in 76% of cases. Conclusions: Atezolizumab plus bevacizumab is the best treatment in terms of net benefit and therefore it should be recommended as standard of care. Compared to atezolizumab plus bevacizumab, lenvatinib monotherapy had the best net benefit for PFS when physicians and patients are available to accept a higher risk of toxicity.

The REWRITE Study – REal-WoRld effectIveness of TrifluridinE/tipiracil in Patients with Previously Treated Metastatic Colorectal Cancer

AimsIn the pivotal RECOURSE trial, trifluridine/tipiracil improved survival outcomes in refractory metastatic colorectal cancer (mCRC), while demonstrating an acceptable toxicity profile. Routine clinical practice evidence is important to support the ongoing value of recently approved medicines. Our objective was to assess the utilisation patterns and real-world effectiveness of trifluridine/tipiracil in previously treated mCRC patients. Materials and methodsThis was a retrospective observational study including consecutive patients who started trifluridine/tipiracil between 1 April 2018 and 30 September 2019 in the medical oncology departments of three major public hospitals in Portugal. The primary outcome measure was overall survival. Associations between overall survival and patient and tumour characteristics were assessed using multivariate Cox regression analyses. ResultsIn total, 111 patients were included in the study, with a mean age of 64 years. From these, 45.9% received two prior lines of treatment, 47.8% had three or more previous lines of treatment and 83.6% had Eastern Cooperative Oncology Group (ECOG) performance status 0–1 at baseline. The median duration of trifluridine/tipiracil treatment was 3.7 cycles (95% confidence interval 3.4–4.1). Most patients (80.4%) remained on their planned dose throughout the trifluridine/tipiracil treatment period, fulfilling 100% relative dose intensity. The median overall survival in the total study cohort was 7.9 months (95% confidence interval 6.4–9.8) and the median progression-free survival was 3.4 months (95% confidence interval 3.2–3.9). The median overall survival was significantly higher in patients with a normal serum lactate dehydrogenase (LDH) level (median overall survival 11.2 months for [135, 205] IU/l LDH [95% confidence interval 8.2–NR] and 13.6 months for [205, 251] IU/l LDH [95% confidence interval 8.2–NR]) and in better fitted (ECOG = 0–1) patients (median overall survival 8.0 months; 95% confidence interval 6.7–10.0). The median time to worsening performance status was 6.2 months (95% confidence interval 5.0–8.0). Treatment discontinuation due to adverse events was low (3.1%). ConclusionOur study confirms the effectiveness of trifluridine/tipiracil in real-life mCRC patients. Overall survival and progression-free survival outcomes are consistent with the efficacy profile reported in the earlier randomised RECOURSE clinical trial. Like other real-world studies, we found no additional safety concerns in the use of trifluridine/tipiracil.

Fusion-based tensor radiomics using reproducible features: Application to survival prediction in head and neck cancer

BackgroundNumerous features are commonly generated in radiomics applications as applied to medical imaging, and identification of robust radiomics features (RFs) can be an important step to derivation of reliable, reproducible solutions. In this work, we utilize a tensor radiomics (TR) framework, where numerous fusions are explored, to generate different flavours of RFs, and we aimed to identify RFs that are robust to fusion techniques in head and neck cancer. Overall, we aimed to predict progression-free survival (PFS) using Hybrid Machine Learning Systems (HMLS) and reproducible RFs. MethodsThe study was performed on 408 patients with head and neck cancer from The Cancer Imaging Archive. After image preprocessing, 15 fusion techniques were employed to combine Positron Emission Tomography (PET) and Computed Tomography (CT) images. Subsequently, 215 RFs were extracted through a standardized radiomics software, with 17 ‘flavours’ generated using PET-only, CT-only, and 15 fused PET&CT images. The variability of RFs across flavours was studied using the Intraclass Correlation Coefficient (ICC). Furthermore, the features were categorized into seven reliability groups, 106 reproducible RFs with ICC>0.75 were selected, highly correlated flavours were removed, Principal Component Analysis was used to convert 17 flavours to 1 attribute, the polynomial function was utilized to increase RFs, and Analysis of variance (ANOVA) was used to select the relevant attributes. Finally, 3 classifiers including Random Forest (RFC), Logistic regression (LR), and Multi-layer perceptron were applied to the preselected relevant attributes to predict binary PFS. In 5-fold cross-validation, 80% of 4 divisions were utilized to train the model, and the remaining 20% was utilized to evaluate the model. Further, the remaining fold was used for external nested testing. ResultsReliability analysis indicated that most morphological features belong to the high-reliability category. By contrast, local intensity and statistical features extracted from images belong to the low-reliability category. In the tensor framework, the highest 5-fold cross-validation accuracy of 76.7%±3.3% with an external nested testing of 70.6%±6.7% resulted from the reproducible TR+polynomial function+ANOVA+LR algorithm while the accuracy of 70.0%±4.2% with the external nested testing of 67.7%±4.9% was achieved through the PCA fusion+RFC (non-tensor paradigm). ConclusionsThis study demonstrated that using reproducible RFs as utilized within a tensor fusion radiomics framework, linked with ANOVA and LR, added value to prediction of progression-free survival outcome in head and neck cancer patients.

Neutrophil-to-eosinophil ratio as a biomarker for clinical outcomes in advanced stage melanoma patients treated with anti-PD-1 therapy.

Neutrophil-to-lymphocyte ratios (NLR) and eosinophil counts are associated with improved survival in melanoma patients treated with immune checkpoint inhibitors, but no study has investigated neutrophil-to-eosinophil ratios (NER) as a predictive indicator in this population. In this retrospective study evaluating anti-PD-1 treated patients with advanced melanoma, progression-free survival (PFS), overall survival (OS), objective response rates (ORR), and risk of high-grade (grade ≥3) immune-related adverse events (irAEs) were compared between groups defined by median pretreatment NLR and NER as well as median NLR and NER at 1-month post-treatment. Lower baseline NLR and NER were associated with improved OS [HR: 0.504, 95% CI: 0.328-0.773, p = .002 and HR: 0.442, 95% CI: 0.288-0.681, p < .001, respectively] on univariate testing. After accounting for multiple covariates, our multivariate analysis found that lower pretreatment NER was associated with better ORR (by irRECIST) (OR: 2.199, 95% CI: 1.071-4.582, p = .033) and improved OS (HR: 0.480, 95% CI: 0.296-0.777, p = .003). Baseline NLR, 1-month NLR, and 1-month NER were not associated with ORR, PFS, or OS outcomes; but 1-month NER correlated with lower risk of grade ≥3 irAEs (OR: 0.392, 95% CI: 0.165-0.895, p = .029). Our findings suggest baseline NER merits additional investigation as a novel prognostic marker for advanced melanoma patients receiving anti-PD-1-based regimens.

A prospective phase 2 study of expeditious EGFR genotyping and immediate therapeutic initiation through extracellular vesicles (EV)-based bronchoalveolar lavage fluid (BALF) liquid biopsy in advanced NSCLC patients.

In our previous study, epidermal growth factor receptor (EGFR) genotyping using extracellular vesicles (EV)-derived DNA isolated from bronchoalveolar lavage fluid (BALF) was proven to be highly concordant with conventional tissue-based genotyping and its turn-around-time (TAT) was only 1-2 days. On this background, we prospectively validated the performance of EV-based BALF liquid biopsy for EGFR genotyping in the real practice of advanced non-small cell lung cancer (NSCLC) patients. After screening 120 newly diagnosed stage III-IV NSCLC patients, 51 cases were detected as EGFR-mutated by EV-based BALF EGFR genotyping and 40 patients were enrolled for gefitinib treatment. BALF EV were isolated by ultracentrifuge method and EGFR genotyping was performed with PCR-based PNA-clamping assisted fluorescence melting curve analysis. The objective response rate, progression-free survival (PFS), TAT, time to treatment initiation (TTI), and concordance rate were analyzed with clinical parameters. There was only one false positive case among the 120 screened patients and the overall concordance rate between tissue biopsy and EV-based BALF liquid biopsy was 99.2% including the subtype of EGFR mutations. TAT for EV-based BALF EGFR genotyping was 1.9±1.1 days, while tissue-based TAT was 12.1±7.2 days (P<0.001). EGFR genotyping was determined even before obtaining histopathologic report in most cases. TTI in BALF EGFR genotyping was faster than tissue genotyping (7.8±6.5 vs. 13.8±12.9 days). Therapeutic outcomes of response rate and PFS were almost similar to tissue-based results. We demonstrated, for the first time, that EV-based BALF liquid biopsy should be an excellent platform for expeditious EGFR genotyping and rapid therapeutic intervention even before obtaining the result of histopathology in advanced NSCLC patients.

Ramucirumab plus erlotinib versus placebo plus erlotinib in previously untreated EGFR-mutated metastatic non-small-cell lung cancer (RELAY): exploratory analysis of next-generation sequencing results

Ramucirumab plus erlotinib (RAM+ ERL) demonstrated superior progression-free survival (PFS) over placebo+ ERL (PBO+ ERL) in the phase III RELAY study of patients with epidermal growth factor receptor (EGFR)-mutated metastatic non-small-cell lung cancer (EGFR+ mNSCLC; NCT02411448). Next-generation sequencing (NGS) was used to identify clinically relevant alterations in circulating tumor DNA (ctDNA) and explore their impact on treatment outcomes. Eligible patients with EGFR+ mNSCLC were randomized 1 : 1 to ERL (150 mg/day) plus RAM (10 mg/kg)/PBO every 2 weeks. Liquid biopsies were to be prospectively collected at baseline, cycle 4 (C4), and postdiscontinuation follow-up. EGFR and co-occurring/treatment-emergent (TE) genomic alterations in ctDNA were analyzed using Guardant360 NGS platform. In those with valid baseline samples, detectable activating EGFR alterations in ctDNA (aEGFR+) were associated with shorter PFS [aEGFR+: 12.7 months (n= 255) versus aEGFR-: 22.0 months (n= 131); hazard ratio (HR)= 1.87, 95% confidence interval (CI) 1.42-2.51]. Irrespective of detectable/undetectable baseline aEGFR, RAM+ ERL was associated with longer PFS versus PBO+ ERL [aEGFR+: median PFS (mPFS)= 15.2 versus 11.1 months, HR= 0.63, 95% CI 0.46-0.85; aEGFR-: mPFS= 22.1 versus 19.2 months, HR= 0.80, 95% CI 0.49-1.30]. Baseline alterations co-occurring with aEGFR were identified in 69 genes, most commonly TP53 (43%), EGFR (other than aEGFR; 25%), and PIK3CA (10%). PFS was longer in RAM+ ERL, irrespective of baseline co-occurring alterations. Clearance of baseline aEGFR by C4 was associated with longer PFS (mPFS= 14.1 versus 7.0 months, HR= 0.481, 95% CI 0.33-0.71). RAM+ ERL improved PFS outcomes, irrespective of aEGFR mutation clearance. TE gene alterations were most commonly in EGFR [T790M (29%), other (19%)] and TP53 (16%). Baseline aEGFR alterations in ctDNA were associated with shorter mPFS. RAM+ ERL was associated with improved PFS outcomes, irrespective of detectable/undetectable aEGFR, co-occurring baseline alterations, or aEGFR+ clearance by C4. aEGFR+ clearance by C4 was associated with improved PFS outcomes. Monitoring co-occurring alterations and aEGFR+ clearance may provide insights into mechanisms of EGFR tyrosine kinase inhibitor resistance and the patients who may benefit from intensified treatment schedules.

Melanoma in children: A systematic review and individual patient meta-analysis.

The current evidence on paediatric melanoma is heterogeneous, especially regarding the prognosis of different histological subtypes. We sought to systematically review the evidence on paediatric melanoma, highlighting the major sources of heterogeneity and focusing on available data on single patients. A systematic search was performed from 1948 to 25 January 2021. Only studies reporting at least one case of cutaneous melanoma in patients aged ≤18 years were included. Unknown primary and uncertain malignant melanomas were excluded. Three couples of authors independently performed title/abstract screening and two different authors reviewed all the relevant full texts. The selected articles were manually cross-checked for overlapping data for qualitative synthesis. Subsequently data on single patients were extracted to perform a patient-level meta-analysis. PROSPERO registration number: CRD42021233248. The main outcomes were melanoma-specific survival (MSS) and progression-free survival (PFS) outcomes. Separate analyses were done of cases with complete information on histologic subtype, focusing on superficial spreading (SSM), nodular (NM) and spitzoid melanomas, as well as of those classified as de-novo (DNM) and acquired or congenital nevus-associated melanomas (NAM). The qualitative synthesis covered 266 studies; however, data on single patients were available from 213 studies including 1002 patients. Among histologic subtypes, NM had a lower MSS than both SSM and spitzoid melanoma, and a lower PFS than SSM. Spitzoid melanoma had a significantly higher progression risk than SSM and trended toward lower mortality. Focusing on nevus-associated status, DNM demonstrated better MSS after progression than congenital NAM, and no differences were highlighted in PFS. Our findings describe the existence of different biological patterns in paediatric melanoma. Specifically, spitzoid melanomas demonstrated intermediate behaviour between SSM and NM and showed a high risk of nodal progression but low mortality. This raises the question of whether spitzoid lesions are being over-diagnosed as melanoma in childhood.

Prognostic value of liver metastases in colorectal cancer treated by systemic therapy: An ARCAD pooled analysis.

3554 Background: Approximately 30% of patients (pts) diagnosed with colorectal cancer (CRC) develop liver metastases (LM). Liver is the most common organ of metastasis of CRC. The ARCAD database contains individual patient data of randomized trials that included CRC pts with initially unresectable metastases treated with systemic therapy. The aim of this study was to assess the response and survival outcomes in non-LM (NLM) vs LM across different lines of treatment. Methods: We analyzed survival outcomes of mCRC pts with either single site (SS) or multiple sites (MS) according to LM status in the following treatment groups: A: chemotherapy (CT) alone, B: CT + VEGF-antibodies, C: CT + EGFR-antibodies in KRAS wild-type tumors, within first-line (1L) and second line (2L) of therapy and D: pts enrolled on third line (≥3L) trials treated with trifluridine/tipiracil or regorafenib and placebo. The primary and secondary endpoints were overall survival (OS) and progression-free survival (PFS) which were assessed using Kaplan-Meier estimates and adjusted Cox models on ECOG PS, age, and gender. Results: We included 26 trials with 17924 pts. 14066 pts had LM. Pts with LM had a higher rate of colon vs rectum as primary tumor (72 vs 62%; P &lt; .001) and less SS (31 vs 47%; P &lt; .001) than those with NLM. OS and PFS results in subgroups are reported in the table. In groups A and B, we found better OS and PFS outcomes in NLM pts as either SS or MS in 1L and 2L. In group C from 1L, we found better survival outcomes in pts with SS LM. In pts with MS, NLM superiority was observed in OS but not in PFS. However, these results were influenced by primary tumor sidedness. In group D, better OS and PFS was observed in pts without LM than those with LM whether in pts with SS or MS. Response rates were higher in LM than in NLM in most 1L and 2L subgroups. Conclusions: LM is a poor prognostic factor for mCRC increasing from the 1L to ≥3L. Survival with CT alone and CT + anti-VEGF according to LM and NLM differs significantly in 1L and 2L but not with CT + anti-EGFR. This data justifies using LM as a stratification factor at least in ≥3L trials. [Table: see text]

Correlation between biomarkers and treatment outcomes in diverse cancers: A meta-analysis of phase I and II immunotherapy clinical trials.

e14638 Background: Many immuno-oncology (IO) trials are conducted without biomarker selection. We performed a meta-analysis of phase I/II clinical trials evaluating immune checkpoint inhibitors (ICIs) to determine the association between biomarkers and clinical outcomes, if any. Methods: We searched PubMed for phase I/II clinical trials of drugs approved by the Food and Drug Administration (labeled, off-label, or combined with investigational ICIs or other treatment modalities) from 2018 to 2020. We compared the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) between biomarker-positive and biomarker-negative groups, using data from correlative studies. Results: Overall, 174 clinical studies that included 19,178 patients were identified and 131 studies investigated &gt;30 correlative biomarkers, that included PD-L1 expression (≥1%, 111 studies), tumor mutational burden (20 studies), and microsatellite instability/mismatch repair deficiency (10 studies). Overall, 123, 46, and 30 cohorts (drugs, tumor types, or biomarkers) with 11,692, 3,065, and 2,256 patient outcomes for ORR, PFS, and OS, respectively, were analyzed in correlation with biomarkers. Meta-analyses demonstrated that ICIs in patients with biomarker-positive tumors were associated with higher ORR (odds ratio 2.15 [95% CI, 1.79-2.58], p&lt;0.0001); and longer PFS (hazard ratio [HR] 0.55 [95% CI, 0.45-0.67], p&lt;0.0001), and OS (HR 0.65 [95% CI, 0.53-0.80], p&lt;0.0001) compared with those with biomarker-negative tumors. Significance for ORR and PFS was retained in multivariate analysis (p&lt;0.001) (OS, not included owing to the small number of trials reporting OS). Conclusions: Our data suggest that IO biomarkers should be used in patient selection for ICIs. Prospective studies are warranted.

Combination therapy with immune checkpoint inhibitors in recurrent or metastatic squamous cell carcinoma of the head and neck: A meta-analysis.

To evaluate the efficacy and safety of immune checkpoint inhibitor (ICI) combination therapy in the first-line treatment for recurrent or metastatic squamous cell carcinoma of the head and neck (R/M-SCCHN). We conducted a meta-analysis between ICI combination therapy and standard of care (SOC) treatment (chemotherapy with or without cetuximab) in R/M-SCCHN based on randomized controlled trials (RCTs). The outcomes were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs). Five RCTs involving 2576 patients were included in the analysis. Compared with SOC, PD-1 inhibitor plus chemotherapy significantly improved OS (hazard ratio [HR], 0.73, 95% CI 0.62-0.87, p=0.0004), PFS (HR, 0.65, 95% CI 0.43-0.99, p=0.04) and ORR (risk ratio [RR], 1.10; 95% CI 1.01-1.19, p=0.02) of patients, while double-agent immunotherapy could not improve either the outcome of OS, PFS, or ORR (all p>0.05). In safety analyses, combination immunotherapy showed similar risks of grade 3 or higher treatment-related AEs (RR, 0.79, 95% CI 0.56-1.11, P=0.17) and treatment-related deaths (RR, 1.16, 95% CI 0.65-2.07, P=0.63) compared to SOC. Compared with SOC, PD-1 inhibitor plus chemotherapy enhanced OS, PFS, and ORR in the first-line treatment for patients with R/M-SCCHN, but double-agent immunotherapy showed no more benefit for these patients.

A single-institution analysis of a rare variant of pancreatic neoplasm-osteoclastic giant cell tumor.

e16315 Background: Pancreatic osteoclastic giant cell tumor (OGCT) is a rare variant (&lt;1% cases) of pancreatic neoplasm. Due to its rarity, prospective studies on management are limited. The prognosis and molecular characteristics may differ from pancreatic adenocarcinoma. Methods: We analyzed demographics, clinical features, treatment modalities, and outcomes of overall survival (OS) and progression-free survival (PFS) in patients with pancreatic OGCT at our institution from 2005-2022. Results: We identified 8 OGCT patients with a median age of 67, of whom 7 had locoregional disease (resectable- 5, borderline resectable- 1, locally advanced-1), and 1 had denovo metastatic disease at diagnosis. The borderline resectable and locally advanced patients eventually developed metastatic disease. The majority of patients were male (n=5), Caucasian (n=7), former smokers (n=5), had no significant alcohol use (n=8) and had no pre-existing pancreatitis (n=8). 4 of the 5 resectable patients had surgery, and 2 received adjuvant chemotherapy. The median OS was 54 months for locoregional disease (n=5) vs.16 months for metastatic disease (denovo metastatic and progression to metastatic disease, n=3). The median OS was 54 months for surgical resection (n=4) vs. 25 months for those without surgical resection (n=4) based on quartile computations from the Kaplan-Meier survival curve. Conclusions: Our patients had a longer OS than the previously reported OS of less than 12 months for all stages of pancreatic OGCT. There was no progression in resectable patients, indicating an indolent disease with an overall good prognosis. Patients with locoregional disease or those who underwent surgical resection had longer OS, but due to the small sample size and censored patient survival times (i.e., patients still alive), the statistical significance of this trend could not be calculated. Studies are required to understand tumor biology and determine the optimal multidisciplinary treatment. [Table: see text]

Analysis of overall survival (OS) and progression-free survival (PFS) in the phase 1b clinical trial of anti–PD-1 ab (toripalimab) plus intrahepatic injection of orienX010 in stage IV melanoma with liver metastases.

9564 Background: Advanced melanoma with liver metastasis has a lower response rate and survival even in immunotherapy era which might because of its immunosuppressive tumor microenvironment. CPI combined with TVEC had showed a remarkable in cutaneous melanoma. The initial results of the phase 1b trial, systemic toripalimab (anti-programmed cell death-1 antibody) combined with Intratumoral injection of liver with OrienX010 - a HSV-1-derived oncolytic virotherapy with expression of GM-CSF in liver metastasis patients without extra-hepatic injectable lesions had shown its efficacy. Here we present the PFS and overall survival (OS) outcomes. Methods: Eligible pts included those over 18 with injectable liver metastasis confirmed by biopsy with or without extra-hepatic metastasis; the ocular melanoma and brain metastasis were excluded. Pts received intravenous toripalimab Q2W combined with ultrasound guided intratumoral injection of OrienX010 Q2W (8×107 pfu/ml, 10ml per injection) until intolerance or disease progression per iRECIST criteria. Liver biopsy would be performed at baseline and first tumor evaluation (8-12weeks). The primary endpoint was toxicity; secondary endpoints included ORR, disease control rate (DCR), PFS and OS. NCT04206358. Results: From Jul 2019 to Feb 2023, 30 pts enrolled. 60.0% pts primary from mucosal,; 73.3% got extra-hepatic metastasis; median size of injected lesions: 24mm(10-94mm); median number of liver metastasis: 7(1-10); median number of injection: 10 (3-36). Among these pts, 29 pts could be evaluated for efficacy. The median PFS was 7.0months (95%CI: 4.7-9.3 months) and the median OS was not reached. The 3-year OS rates 51.5%. The global ORR by investigator was 20.7% (6/29), DCR 48.3% (14/29); the response rate was 31.0%(9/29) for injected lesions, 30.0%(6/20) for non-injected lesions in liver, and 27.8% (5/18) for extra-hepatic metastases. For pts（21.7%( 2 PR and 3 SD)）with no melanoma cells residual by immunohistochemistry in biopsies the median PFS was 14.0 months (95%CI: 3.7-24.4 months), and it was much longer than that of other pts which was 4.1 months (95%CI: 1.4-6.8 months). The median OS of the pts with no melanoma cells was 19.7 months (95%CI: 7.5-31.9 months). Most adverse events (AE) were grade 1-2 and manageable. The grade 3-4 treatment-related AE included elevated transaminase (3 [10.0%]), nausea (1 [3.3%]), pulmonary embolism (1 [3.3%]) and vomiting (1 [3.3%]). No treatment-related deaths occurred. Conclusions: Systemic toripalimab combined with intrahepatic OrienX010 injection has shown remarkable long PFS, OS and ORR in melanoma pts with liver metastases with manageable toxicity. Clinical trial information: Clinical trial information: NCT04206358 .

A phase II trial of JDQ443 in KRAS G12C-mutated NSCLC with PD-L1 expression &lt;1% or PD-L1 expression ≥1% and an STK11 co-mutation.

TPS9158 Background: Kirsten rat sarcoma viral oncogene homolog ( KRAS) is the most frequently mutated oncogene in non-small cell lung cancer (NSCLC). KRAS G12C, the most frequent KRAS variant, is found in ~13% of patients (pts) with NSCLC. KRAS is a GTPase that regulates cell signaling pathways necessary for proliferation, differentiation, and survival. KRAS mutation reduces the intrinsic GTPase activity of the enzyme, allowing for the accumulation of active, GTP-bound KRAS and hyperactivation of downstream signaling, driving tumorigenesis. JDQ443 is a potent, selective KRASG12C inhibitor that irreversibly traps KRASG12C in its inactive, GDP bound state and blocks downstream signaling. In preliminary data from the Phase Ib part of the KontRASt-01 study (NCT04699188), JDQ443 showed promising antitumor activity and an acceptable safety profile in previously treated pts with KRAS G12C-mutated advanced NSCLC. Pts with KRAS G12C-mutated NSCLC currently receive the same first-line (1L) treatment as those without driver mutations, consisting of immunotherapy alone or combined with chemotherapy; however, ~30% of pts with NSCLC present with programmed death-ligand 1 (PD-L1) expression &lt;1%, and ~10–20% of pts harbor an STK11 mutation, both indicators of poor response to immunotherapy. Therefore, alternative 1L treatment options are needed for these pts. Of note, PD-L1 expression and STK11 mutation do not affect responsiveness to KRASG12C inhibitors, raising interest in the evaluation of these targeted therapies as 1L alternatives to immunotherapy for pts with KRAS G12C-mutated NSCLC. Methods: KontRASt-06 (NCT05445843) is an open-label, Phase II, single-arm, multicenter study evaluating JDQ443 monotherapy (200 mg JDQ443 twice daily in 21-day cycles) as a 1L treatment for 2 cohorts of adult pts with locally advanced or metastatic, KRAS G12C-mutated NSCLC. Cohort A (n=90) includes pts whose tumors have PD-L1 expression &lt;1%, regardless of STK11 mutation status, while Cohort B (n=30) includes pts whose tumors have PD-L1 expression ≥1% and an STK11 co-mutation. Local testing for PD-L1 status and KRAS and STK11 mutations is accepted; KRAS and STK11 mutations may be assessed in blood samples. A tissue sample is required for retrospective biomarker status confirmation and exploratory study. The study is currently enrolling pts into both cohorts. The primary endpoint is the overall response rate (ORR) per RECIST version 1.1, assessed by a blinded independent review committee, in Cohort A. Key secondary endpoints are ORR in Cohort B and duration of response in both cohorts. Other secondary endpoints include progression-free survival, overall survival, safety, pharmacokinetics, and pt-reported outcomes. A comprehensive biomarker strategy aims to investigate predictors of treatment response and resistance in the study population. © 2023 American Association for Cancer Research®. Reused with permission. Clinical trial information: NCT05445843 .

UNMET NEED IN RELAPSED/REFRACTORY (R/R) MANTLE CELL LYMPHOMA (MCL) POST‐BRUTON TYROSINE KINASE INHIBITOR (BTKI): A SYSTEMATIC LITERATURE REVIEW AND META‐ANALYSIS

Background: Most patients with MCL, a rare B-cell non-Hodgkin lymphoma, will relapse or become refractory to treatment. While the introduction of BTKis has been transformative, options for patients who fail to respond or whose disease progresses on BTKis remain limited and largely palliative in nature. We sought to characterize and quantify the unmet clinical need of patients with R/R MCL in the post-BTKi setting. Methods: MEDLINE, Embase, and CENTRAL were systematically searched to October 2022—supplemented with hand searches of select conferences—to identify studies reporting overall survival (OS), progression-free survival (PFS), and/or response outcomes of patients receiving non-CAR-T treatments or brexucabtagene autoleucel (brexu-cel) in the post-BTKi setting. Random effects bivariate meta-analyses of OS/PFS were conducted based on studies with published Kaplan-Meier (KM) curves from which individual patient data could be estimated. Response outcomes, based on the best response achieved, were meta-analyzed using a generalized linear mixed model. Outcomes were evaluated separately for patients treated with non-CAR-T and brexu-cel. Results: Twenty-six studies (23 observational; 3 trials), reporting the outcomes of 1845 patients treated from 2005 to 2022, were included, where patients were initially enrolled for treatment with a BTKi (12 studies) or for treatment post-BTKi (14 studies). The non-CAR-T interventions varied, with most studies reporting outcomes from cohorts of patients receiving a variety of interventions. Across the included studies, most patients were male (65-94%) and older, with the median age varying from 63 to 77 years. OS and PFS KM curves were published in 10 and 3 studies, respectively, for non-CAR-T outcomes. The pooled median OS/PFS for these patients was 9.1 and 7.6 months, respectively (Table 1). The pooled objective response rate (ORR) and percentage of patients achieving a complete response (CR) were 45% and 23%, respectively. The median OS/PFS of patients who received brexu-cel was 32.1 and 14.9 months, based on 5 and 6 studies with KM curves, respectively, with ORR/CR rates of 89% and 74%. Analyses were not sensitive to different survival distributions or fixed/random effects models. Conclusions: Treatment options in the post-BTKi setting are heterogeneous and a significant unmet clinical need persists. Though longer follow-up is needed for survival outcomes, treatment with brexu-cel is emerging as a promising option in this difficult-to-treat setting. The research was funded by: This study was funded by Kite, a Gilead company. Keywords: Aggressive B-cell non-Hodgkin lymphoma, Cellular therapies Conflicts of interests pertinent to the abstract M. Dreyling Consultant or advisory role Astra Zeneca, Beigene, BMS/Celgene, Gilead/Kite, Janssen, Lilly/Loxo, Novartis, Roche Research funding: Abbvie, Bayer, BMS/Celgene, Gilead/Kite, Janssen, Roche Educational grants: Janssen, Roche Other remuneration: Astra Zeneca, Gilead/Kite, Janssen, Lilly, Novartis, Roche B. Shah Consultant or advisory role Pepromene Bio; Takeda Honoraria: Kite/Gilead; BMS; Novartis; Amgen; Pfizer; Beigene; Adaptive; Century Therapeutics; Autolus Research funding: Kite; Servier; Jazz Pharma Educational grants: Kite/Gilead; Takeda Other remuneration: Chair, NCCN Adult ALL subcommittee J. Wu Employment or leadership position: Kite, a Gilead company Stock ownership: Gilead; Amgen; Abbott; AbbVie; Avid; Curis; Viracta T. Itani Employment or leadership position: Kite, a Gilead company Stock ownership: Gilead Sciences M. J. Zoratti Research funding: RainCity Analytics has received funds from for-profit healthcare companies for research S. Kanters Research funding: RainCity Analytics has received funds from for-profit healthcare companies for research S. W. Wade Consultant or advisory role Kite Pharma; Amgen; Allergan/Abbvie; Johnson & Johnson W. Peng Employment or leadership position: Kite, a Gilead company Stock ownership: Gilead J. Castaigne Employment or leadership position: Kite, a Gilead company Stock ownership: Gilead I. Kloos Employment or leadership position: Kite, a Gilead company Stock ownership: Gilead Sciences M. Wang Consultant or advisory role AbbVie; Acerta Pharma; ADC Therapeutics America; Amphista Therapeutics Limited; AstraZeneca; Be Biopharma; BeiGene; BioInvent; Deciphera; DTRM Biopharma (Cayman) Limited; Genentech; InnoCare; Janssen; Kite Pharma; Leukemia & Lymphoma Society; Lilly; Merck; Miltenyi Biomedicine; Milken Institute; Oncternal; Parexel; Pepromene Bio; Pharmacyclics; VelosBio Honoraria: AbbVie; Acerta Pharma; AstraZeneca; Bantam Pharmaceutical; BeiGene; BioInvent; Bristol Myers Squibb; CAHON; Dava Oncology; Eastern Virginia Medical School; Genmab; i3Health; IDEOlogy Health; Janssen; Kite Pharma; Leukemia & Lymphoma Society; Medscape; Meeting Minds Experts; MD Education ; MJH Life Sciences; Merck; Moffit Cancer Center; Nurix; Oncology Specialty Group; OncLive; Pharmacyclics; Physicians Education Resources (PER); Practice Point Communications (PPC); Studio ER Congressi Research funding: Acerta Pharma; AstraZeneca; BeiGene; BioInvent; Celgene; Genmab; Genentech; Innocare; Janssen; Juno Therapeutics; Kite Pharma; Lilly; Loxo Oncology; Molecular Templates; Oncternal; Pharmacyclics; VelosBio; Vincerx

Circulating tumour DNA (ctDNA) as a predictor of clinical outcome in non-small cell lung cancer undergoing targeted therapies: A systematic review and meta-analysis.

e21124 Background: Liquid biopsy (LB) analysis using circulating-tumour DNA (ctDNA)/cell-free DNA (cfDNA) is an emerging alternative to tissue profiling in non-small cell lung cancer (NSCLC). LB is used to guide treatment decisions, detect resistance mechanisms, and predicts responses, and therefore outcomes. This systematic review and meta-analysis evaluated the impact of LB quantification on clinical outcomes in molecularly altered advanced NSCLC undergoing targeted therapies. Methods: We searched Embase, MEDLINE, PubMed and Cochrane Database, between 01/01/2000 and 01/08/2022. The primary outcome was progression-free survival (PFS) and overall survival (OS). Secondary outcomes included objective response rate (ORR), sensitivity and specificity of the test. Age stratification was performed based on the mean age of the individual study population. The quality of studies was assessed using the Newcastle-Ottawa Scale (NOS). Results: Twenty-seven studies reporting 2424 patients were included. Eleven studies (n = 1359) reported an association of baseline ctDNA levels, while 16 studies (n = 1649) reported an association of dynamic ctDNA changes to treatment, with clinical outcomes of PFS and/or OS. Baseline ctDNA-negative patients had higher PFS (pooled hazard ratio [pHR] = 2.97; (95%CI: 1.92-4.85; I2= 97.4%), and OS (pHR = 3.49; (95%CI: 1.73-6.95; I2= 84.2%), than ctDNA-positive patients. Egger’s test suggested publication bias (p &lt; 0.001). Early reduction/clearance of ctDNA levels after treatment improved PFS (pHR = 3.78; 95%CI: 1.91-7.38; I2= 98.4%) and OS (pHR = 2.20; 95%CI: 1.49-3.28; I2= 90.6%), compared to those with no reduction/persistence of ctDNA levels. The PFS was comparable for patients stratified by age (age ≤60 years [pHR = 2.92; 95%CI: 1.43-5.93; I2= 98.3 %] vs. age &gt; 60 years [pHR = 3.94; 95%CI: 1.54-10.07; I2= 83.6 %]). The sensitivity analysis based on study quality (NOS) demonstrated improved PFS only for good quality studies (pHR = 3.67; 95%CI: 1.79-7.54; I2= 91.6 %), but not for poor or fair quality studies. Conclusions: This large systematic review, despite heterogeneity, found that baseline negative ctDNA levels, and early reduction in ctDNA following treatment are strong prognostic markers for PFS and OS in patients undergoing targeted therapies for advanced NSCLC. Future randomised clinical trials should incorporate serial ctDNA monitoring to further establish the clinical utility in advanced NSCLC management. Systematic review registration: PROSPERO registration No. CRD42022347791 Keywords: non-small cell lung cancer; NSCLC; liquid biopsy; circulating tumour DNA; ctDNA; progression-free survival; targeted therapies.