Early Tumor Shrinkage Research Articles

Tumor Shrinkage as a Prognostic Factor of Metastatic Renal Cell Carcinoma in the Era of Molecular Targeted Therapy

We evaluated the impact of tumor shrinkage (TS) induced by molecular targeted therapy as the first-line systemic therapy on the survival of patients with metastatic renal cell carcinoma (mRCC). A total of 67 patients with mRCC who received first-line molecular targeted therapy were included in this study. Sixty patients were evaluable by response evaluation criteria in solid tumors. Patients underwent the first evaluation at 8-12 weeks after the start of the therapy. Twenty patients had TS ≧30%, 32 from 30% to -20%, and 8 ≦-20%. The median overall survival periods of patients who achieved TS ≧30%, from 30% to -20%, and ≦-20% at first evaluation were 41.0, 35.0, and 11.5 months, respectively. Univariate and multivariate analyses showed that TS of≧0%, in addition to negative C-reactive protein and the absence of bone metastasis were good predictors of overall survival. The patients who achieved 0% or more at the initial evaluation had longer survival than those who had no tumor reduction (40.0 months vs 12.0 months, p<0. 001). These findings suggest that early TS affects overall survival in real practice. We should consider alternative therapies for patients who have not achieved tumor reduction at the initial evaluation.

The impact of early tumor shrinkage on conversion surgery and the survival in patients with unresectable locally advanced pancreatic cancer.

Owing to recent advances in induction chemo(radio)therapy, patients with unresectable locally advanced pancreatic ductal adenocarcinoma (UR-LA PDAC) are sometimes indicated for conversion surgery (CS). However, the predictors for proceeding to CS are unclear. We investigated the predictive factors for CS, especially at the early stage of induction therapy, and evaluated the impact of CS on the survival. We analyzed 49 UR-LA PDAC patients retrospectively and investigated the predictive factors for proceeding to CS, including early tumor shrinkage (ETS). ETS in this study was defined as shrinkage of tumors by ≥ 15% at 8-12weeks after the induction of treatment. CS was performed in 21 patients (43%). In a multivariate logistic regression analysis, ETS was an independent predictive factor for successfully proceeding to CS (P = 0.046). The median overall survival (OS) was not reached in the CS group but was 17.2months in the non-CS group (P < 0.0001). A multivariate analysis by the Cox proportional hazard model identified CS as the only significant independent determinant of the OS (hazard ratio: 0.26, 95% confidence interval: 0.07-0.94, P = 0.004). ETS by induction therapy is a significant predictor of proceeding to CS among patients with UR-LA PDAC. CS was the only independent prognostic factor for this population.

Analysis of early tumor shrinkage and depth of response in patients with advanced biliary tract cancer treated with gemcitabine plus cisplatin or gemcitabine plus S-1: An exploratory analysis of JCOG1113.

301 Background: JCOG1113 is a randomized phase III trial to confirm the non-inferiority of gemcitabine (GEM) plus S-1 (GS) compared with GEM plus cisplatin (GC) regarding overall survival (OS) in patients with advanced biliary tract cancer (BTC). Although the non-inferiority of GS to GC was demonstrated, the difference in the nature of tumor shrinkage effects between GC and GS is not clear. Early tumor shrinkage (ETS) and depth of response (DpR) are considered as on-treatment markers that reflect the anti-tumor effect to chemotherapy and have been reported to be associated with survival in metastatic colorectal cancer. However, there are few studies assessing ETS or DpR in advanced BTC. Therefore, we evaluated the association between ETS, DpR, and clinical outcomes in JCOG1113. Methods: We conducted an exploratory analysis of JCOG1113, which included chemotherapy-naïve patients with recurrent or unresectable BTC. ETS was defined as tumor reduction in the sum of the longest diameters of the target lesions at week 6 when compared with that at baseline. DpR was defined as the maximum tumor shrinkage observed until 12 weeks from enrollment. Survival curves were estimated using the Kaplan–Meier method. Progression-free survival (PFS) and OS for ETS and DpR were estimated from week 6 and 12 (landmarks) after enrollment, respectively. Multivariable analyses for PFS and OS, adjusted for baseline factors, were performed using a stratified Cox regression model. Results: Of the 354 registered patients in JCOG1113, 277 patients in the ETS group and 230 patients in the DpR group were included in this study. Seventy-seven patients (27.8%) achieved ETS ≥ 20% (ETS high group) and 52 patients (22.6%) achieved DpR ≥ 40% (DpR high group). The proportion of ETS high group (GC, 25.4%; GS, 30.4%) and DpR high group (GC, 21.2%; GS, 24.1%) was similar between the arms. The patient characteristics of ETS high group were not different between GC and GS. The hazard ratio (HR) of the ETS high group compared with the ETS low group for PFS and OS was 0.76 (95% confidence interval [CI] 0.58–1.00) and 0.80 (95% CI 0.60–1.07), respectively. The impact of ETS was higher in GC (HR 0.64, 95% CI 0.43–0.95) than GS (HR 0.88, 95% CI 0.60–1.28) in PFS. The HR of DpR high group compared with DpR low group for PFS and OS was 0.75 (95% CI 0.55–1.03) and 0.79 (95% CI 0.57–1.09), respectively. The impact of DpR was higher in GC (HR 0.63, 95% CI 0.40–0.998) than GS (HR 0.88, 95% CI 0.57–1.37) in PFS. ETS and DpR were significantly associated with both PFS and OS in the multivariable analyses. Conclusions: ETS and DpR may be useful as on-treatment markers associated with PFS and OS in patients with advanced BTC, especially in those treated with GC. Clinical trial information: UMIN000010667.

Safety analysis of the randomized phase II study of FOLFOXIRI plus cetuximab versus FOLFOXIRI plus bevacizumab as the first-line treatment in metastatic colorectal cancer with RAS wild-type tumors: The DEEPER trial (JACCRO CC-13).

86 Background: Triplet regimens, FOLFOXIRI, combined with bevacizumab (bev) or panitumumab have been shown to be superior in terms of early tumor shrinkage (ETS) and depth of response (DpR) compared to doublet regimen plus bev or triplet regimen in patients with RAS wild-type metastatic colorectal cancer (mCRC), in the TRIBE trial ( N Engl J Med 2014) or VOLFI trial ( J Clin Oncol 2019), respectively. There have been few studies which directly compared cetuximab (cet) with bev when combined with triplet regimen. Therefore, we investigated the efficacy and safety of bev vs. cet in combination with FOLFOXIRI in previously untreated mCRC patients with RAS wild-type tumors. Methods: This trial was a randomized phase II trial to evaluate modified (m)-FOLFOXIRI (irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, 5-FU 2400 mg/m2) plus cet vs. bev as first-line treatment in terms of the DpR during the entire course as the primary endpoint in 360 patients with RAS wild-type mCRC (ClinicalTrials.gov Identifier: NCT02515734). The experimental arm with cet was considered to be active if the difference of median DpR was over 12.5% compared with the bev arm, under the conditions of significance level of 0.05 and power of 0.85. Secondary endpoints included the ETS at week 8, progression-free survival, overall survival, secondary resection rate, and toxicity. Results: A total of 359 patients were enrolled between July 2015 and June 2019. For the safety analysis set (median age 65y, 64% male, PS0/1:91%/9%, left/right primary:83%/17%), 173 and 175 patients were randomly assigned to the cet and bev arms, respectively, some patients were excluded for the safety analysis due to the violation of inclusion criteria (6 for cet arm and 5 for bev). On the cutoff date of September 2020, median number of cycles administered was 10 (range, 1-51) for the cet arm and 12 (range, 1-51) for the bev arm. The incidence of severe adverse events (AEs) was 25.4% (44/173) for the cet arm and 25.7% (45/175) for the bev arm, respectively. The following AEs of grade 3-4 were observed more frequently in the cet arm compared to the bev arm: oral mucositis (9.2% vs. 2.3%), diarrhea (12.1% vs. 8.0%), dermatitis acneiform (12.1% vs. 0%), and hypomagnesemia (4.0% vs. 0%). The treatment-related death occurred in 2 patients of the cet arm, while no patients in the bev arm. The rate of treatment discontinuation due to AEs of any cause was comparable between the cet and bev arms (7% vs. 9%). Conclusions: This safety analysis indicated that both regimens of m-FOLFOXIRI plus cet or bev were tolerable in RAS wt mCRC patients although some frequent severe AEs were observed. Clinical trial information: UMIN000018217.

Impact of early tumor shrinkage and depth of response on the outcomes of panitumumab-based maintenance in patients with RAS wild-type metastatic colorectal cancer

In patients with metastatic colorectal cancer (mCRC) receiving highly active first-line combination treatments, early tumor shrinkage (ETS) and depth of response (DoR) are associated with survival, but their influence on outcomes during maintenance therapy is unknown. The Valentino study showed inferior PFS in 229 RAS wild-type mCRC patients randomized to panitumumab plus FOLFOX followed by maintenance with panitumumab vs. panitumumab + 5-FU/LV. After blinded independent central review of ETS (≥20% reduction of the sum of target lesions) and DoR in patients enrolled in Valentino, the prognostic and predictive role of such parameters was investigated, along with their combination with PRESSING panel (uncommon genomic alterations associated with anti-EGFRs resistance beyond RAS and BRAF). One hundred and ninety-six patients were included (ETS in 132 [67.3%], median DoR: 44.1%). Both ETS and DoR ≥34% were associated with longer mPFS (p=0.010 and p<0.001) and mOS (p=0.006 and p<0.001). The PFS benefit of 5-FU/LV added to panitumumab maintenance, reported in the study, was independent from ETS and DoR status (interaction tests NS for both PFS and OS). However, outcomes were extremely poor in patients who received single-agent panitumumab and had no-ETS (mPFS and mOS: 7.7 and 18.7 months) or DoR<34% (mPFS and mOS: 6.5 and 18 months). Combining PRESSING panel ('molecular hyperselection') and response dynamics allowed to stratify both PFS (p<0.001 and p<0.001 for ETS and DoR, respectively) and OS (p<0.001 and p=0.017 for ETS and DoR, respectively). ETS and DoR allow on-treatment anticipation of outcomes following an anti-EGFR-based strategy planning de-escalation, and poor radiological response may guide enrolment in crossover strategy trials. As in vivomarkers of drug sensitivity, ETS and DoR may be integrated with several patient- and tumor-related factors to wisely drive decision-making on upfront treatment duration and intensity.

Clinical impact of primary tumour location, early tumour shrinkage, and depth of response in the treatment of metastatic colorectal cancer with first-line chemotherapy plus cetuximab or bevacizumab

The primary tumour location is an important prognostic factor for previously untreated metastatic colorectal cancer (mCRC). However, the predictive efficacies of primary tumour location, early tumour shrinkage (ETS), and depth of response (DpR) on mCRC treatment has not been fully evaluated. This study aimed to investigate the predictive efficacies of these traits in mCRC patients treated with first-line 5-fluorouracil-based chemotherapy plus biologic agents, namely, cetuximab and bevacizumab. This was a retrospective analysis of the medical records of 110 patients with pathology-documented unresectable mCRC. Patients with left-sided mCRC receiving any first-line regimen showed better overall survival (OS) than those with right-sided mCRC [33.3 vs 16.3 months; hazard ratio (HR) 0.44; 95% confidence interval (CI) 0.27–0.74; p < 0.001]. In patients with left-sided tumours, treatment with chemotherapy plus cetuximab yielded longer OS than chemotherapy plus bevacizumab (50.6 vs 27.8 months, HR 0.55; 95% CI 0.32–0.97; p = 0.0378). mCRC patients with ETS and high DpR showed better OS than those lacking ETS and with low DpR (33.5 vs 19.6 months, HR 0.50, 95% CI 0.32–0.79, p = 0.023 and 38.3 vs 19.0 months, HR 0.43, 95% CI 0.28–0.68, p < 0.001, respectively). Moreover, ETS and/or high DpR achieved in patients with right-sided mCRC receiving chemotherapy plus cetuximab were associated with significantly better OS than in those lacking ETS and with low DpR (34.3 vs 10.4 months, HR 0.19, 95% CI 0.04–0.94, p = 0.025 and 34.3 vs 10.4 months, HR 0.19, 95% CI 0.04–0.94, p = 0.0257, respectively). Taken together, our study demonstrates that primary tumour location is not only a well-known prognostic factor but also a relevant predictive factor in patients with mCRC receiving chemotherapy plus cetuximab. Additionally, both ETS and DpR could predict treatment outcomes and also potentially guide cetuximab treatment even in right-sided mCRCs.

Relationship of early tumor shrinkage and depth of response with the prognosis and treatment effect of trastuzumab combined with chemotherapy as first-line treatment in advanced gastric cancer patients with epidermal growth factor receptor 2 positive

Objective: To explore the relationship of early tumor shrinkage (ETS) and depth of response (DpR) with the prognosis and treatment effect of trastuzumab combined with chemotherapy as first-line treatment in advanced gastric cancer with epidermal growth factor receptor 2 (HER-2) positive. Methods: We retrospectively analyzed the clinical and pathological data of 23 patients with metastatic gastric adenocarcinoma diagnosed by imaging in The Second Affiliated Hospital of Zhejiang University School of Medicine from January 1st, 2008 to December 31th, 2017. Kaplan-Meier method and the log-rank test were used for the survival analysis. Cox regression was used to analyze the factors associated with prognosis. Results: The objective response rate (ORR) of the 23 patients was 43.5% and the disease control rate (DCR) was 82.6%. Univariate analysis showed the median progress-free survival (mPFS) of ETS≥20% and ETS<20% were 13.0 months and 4.5 months, respectively, with statistical significance (P<0.001). The median overall survival (mOS) of ETS≥20% and ETS<20% were 26.8 months and 10.1 months, respectively, with statistical significance (P<0.001). The median progress-free survival (mPFS) of DpR≥15% and DpR<15% were 13.0 months and 4.5 months, respectively, with statistical significance (P=0.001). The median overall survival (mOS) of DpR≥15% and DpR<15% were 26.8 months and 9.5 months, respectively, with statistical significance (P<0.001). Multivariable Cox regression analysis revealed ETS was an independent factor of PFS (P=0.030), tumor site and Eastern Cooperative Oncology Group (ECOG) score were independent factors of OS (P<0.05). Conclusion: ETS and DpR might be used to predict the treatment efficacy and prognosis of trastuzumab combined with chemotherapy as the first-line treatment of HER-2 positive gastric cancer.

A phase II study of FOLFOXIRI plus bevacizumab as initial chemotherapy for patients with untreated metastatic colorectal cancer: TRICC1414 (BeTRI)

PurposeFOLFOXIRI plus bevacizumab is regarded as a first-line therapeutic option for selected patients with metastatic colorectal cancer (mCRC). Our aim was to assess the efficacy and safety of induction treatment with FOLFOXIRI plus bevacizumab in patients with untreated mCRC harboring UGT1A1 wild (*1/*1), or single-hetero (*1/*6 or *1/*28) genotypes.MethodsTwelve cycles of FOLFOXIRI plus bevacizumab were administered to patients with untreated mCRC. The primary endpoint was the overall response rate (ORR) assessed by central independent reviewers. Secondary endpoints included time to treatment failure (TTF), progression-free survival (PFS), overall survival (OS), relative dose intensity (RDI), R0 resection rate, and safety. The exploratory objectives were early tumor shrinkage (ETS) and depth of response (DoR).ResultsOf the 47 patients enrolled, 46 and 44 patients were eligible for the safety and efficacy analysis, respectively. The primary endpoint was met. The ORR was 63.6% (95% CI 47.8–77.6). At a median follow-up of 25.4 months, median TTF, PFS, and OS was 8.1, 15.5, and 34.4 months, respectively. The median RDI of 5-fluorouracil, irinotecan, oxaliplatin, and bevacizumab was 72, 69, 62, and 71%, respectively. R0 resection rate was 22.7%. Grade 3 or higher adverse events (≥ 10%) included neutropenia (65.2%), febrile neutropenia (26.1%), leukopenia (23.9%), anorexia (10.9%), nausea (10.9%), and diarrhoea (10.9%). No treatment-related deaths were observed. ETS and DoR were 70.5 and 45.4%, respectively.ConclusionsFOLFOXIRI plus bevacizumab induction treatment of Japanese patients was shown to be beneficial and manageable, although caution is required since the treatment causes febrile neutropenia.

Depth of Response and Early Tumor Shrinkage for Predicting Clinical Outcomes in HER2-Positive Metastatic Breast Cancer Treated with Trastuzumab.

BackgroundTo evaluate whether the depth of response (DepRe) and early tumor shrinkage (ETS) are predictive factors of clinical outcomes in HER2-positive metastatic breast cancer (mBC) patients treated with trastuzumab.MethodsWe performed a retrospective study of 100 HER2-positive mBC patients who received trastuzumab combined with chemotherapy as first-line treatment. ETS and DepRe were calculated. We employed Youden’s index to determine the optimal cutoff value of ETS and DepRe for predicting progression-free survival (PFS) and overall survival (OS). We used Kaplan–Meier analysis, Log-rank tests, and Cox proportional hazards regression models to evaluate the impacts of ETS and DepRe on clinical outcomes.ResultsThe optimal cutoff values were 30% for ETS and 40% for DepRe; ETS and DepRe were observed in 51.0% (51/100) and in 56.0% (56/100) of patients, respectively. Both ETS≥30% and DepRe≥40% were significant tumor-size metrics for predicting PFS (ETS: median 1.43 vs 0.69 years, hazard ratio [HR] = 0.384; 95% confidence interval [CI]: 0.245 to 0.601; P=0.000030; DepRe: median 1.43 vs 0.59 years, HR = 0.390; 95% CI: 0.250 to 0.609; P=0.0000034), but only DepRe≥40% was a significant predictor for OS (median 4.02 vs 3.07 years, HR = 0.484; 95% CI: 0.255 to 0.919; P = 0.027). Multivariate analyses also identified DepRe as an independent prognostic factor for PFS (HR = 0.52; 95% CI: 0.29 to 0.93; P = 0.028) and OS (HR=0.37; 95% CI:0.15 to 0.90; P = 0.029).ConclusionETS≥30% and DepRe≥40% were significant predictors of better clinical outcomes in mBC patients treated with first-line trastuzumab-based chemotherapy. Further validation in prospective trials with larger patient populations is needed.

P-78 Early tumour shrinkage, depth of response and survival outcomes for RAS wild-type metastatic colorectal cancer patients classified by baseline tumour load: Retrospective pooled analysis of panitumumab PRIME/PEAK studies

Early and deep tumour responses are important metastatic colorectal cancer (mCRC) treatment objectives. It is not known whether achieving early/deep responses is more important in high- vs low-volume disease. We evaluated whether baseline tumour load (BTL) predicts ETS and DpR, and assessed outcomes by BTL, early tumour shrinkage (ETS) and depth of response (DpR), using RAS wild-type data from two randomised mCRC studies.

P-164 The role of response as a predictor of improved outcome in advanced pancreatic cancer patients treated with first-line gemcitabine plus nab-paclitaxel

Gemcitabine plus nab-paclitaxel (GemNab) is one of the first-line standard treatments (tx) of advanced pancreatic cancer (APC). To date, no predictive factors, both clinical and molecular, of benefit from this regimen exist. Two retrospective studies showed that early tumor shrinkage (ETS) can predict an improved outcome in APC pts receiving a first-line tx with FOLFIRINOX or GemNab. However, data regarding GemNab, limited to a small population of only 57 pts, seem to not confirm the association of ETS with a better outcome.

P-270 Early tumor shrinkage as a predictor of favorable outcomes in patients with unresectable metastatic colorectal cancer treated with first-line chemotherapy plus bevacizumab

Obtaining early tumor shrinkage, defined as ≥ 20% shrinkage in tumor size per RECIST criteria at the first radiological assessment (8 weeks of treatment), has been shown to be prognostic for improved survival of patients with mCRC treated with cetuximab with or without chemotherapy. The aim of our study was to evaluate the impact of this parameter in patients treated with first-line of chemotherapy combining fluoropyrimidine, irinotecan, and bevacizumab. All pts who received first-line chemotherapy combining fluoropyrimidine, irinotecan, and bevacizumab for unresectable mCRC, between March 2012 and May 2015, were included in an exploratory analysis of survival based on the presence or not of ETS. The univariate analysis of the PFS and OS was based on the Kaplan-Meier method and the Log-Rank test. Multivariate analysis was performed using a Cox model including ETS, sex and Köhne prognostic score. Fifty-two patients were enrolled; median age was 59 years (range 32-75), performance status 0-1 was 84.6%. 69.2% had multi-organ involvement. The median follow-up was 40 months. Fifty-one patients were evaluable for response: ORR 39.2%, SD 43.1 for a clinical benefit of 82.3%. 33% qualified for early response. Median PFS and OS for the whole group was 11 months (95% CI: 7.8-14.2) and 20.8 months (95% CI: 16.5-25.1), respectively. ETS was associated with prolonged PFS and OS (22.5 vs 10.3 months, p = 0.001; 52 vs 20 months, p< 0.0001). Early response to chemotherapy may predict favorable outcomes in patients with metastatic CRC treated with first-line bevacizumab plus chemotherapy, but large prospective analysis and validation are mandatory.

Impact of Size and Location of Metastases on Early Tumor Shrinkage and Depth of Response in Patients With Metastatic Colorectal Cancer: Subgroup Findings of the Randomized, Open-Label Phase 3 Trial FIRE-3/AIO KRK-0306

BackgroundThe Response Evaluation Criteria in Solid Tumors (RECIST) are used to define degrees of response to chemotherapy. For accelerated response evaluation, early tumor shrinkage (ETS) of ≥ 20% has been suggested as a predictor for outcome in metastatic colorectal cancer (mCRC). Together with depth of response (DpR), new alternative metrics have been provided, yielding promising outcome parameters. In this analysis, we aimed to further characterize ETS and DpR. Patients and MethodsThis analysis was based on FIRE-3, a randomized phase 3 trial comparing first-line FOLFIRI plus either cetuximab or bevacizumab in KRAS exon 2 wild-type mCRC. ETS and DpR were determined on the basis of RECIST 1.1 in a blinded radiologic review. ETS was evaluated as a categorized (≥ 20% shrinkage) and continuous parameter. The impact of baseline location and size of metastases on ETS and DpR were evaluated by univariate and multivariate analyses. ResultsOf 592 patients, 395 (66.7%) had data available for radiologic review. Median continuous ETS for lung, liver, and suspected lymph node metastases was 20%, 23%, and 30%, respectively. The median DpR was −32%, −44%, and −50%, respectively (all P < .01). In multivariate analysis, lung metastases were significantly associated with inferior DpR (P = .021), whereas hepatic metastases led to higher DpR (P = .024). Large metastases were associated with favorable ETS, whereas small metastases were correlated with higher DpR (P < .001). ConclusionETS and DpR depend on the location and size of metastases in mCRC. These associations may establish the basis for further research to optimize the predictive accuracy of both parameters. This may help basing treatment decisions on ETS and DpR.

Early tumor shrinkage identifies long-term disease control and survival in patients with lung cancer treated with atezolizumab

BackgroundPreliminary evidence indicates that early tumor shrinkage (ETS) following immune checkpoint inhibitor (ICI) initiation may be associated with survival outcomes in patients with advanced melanoma. ETS has not been explored...

The role of response as predictor of improved outcome in advanced pancreatic cancer (APC) patients (pts) treated with first-line Gemcitabine plus Nab-paclitaxel (GemNab).

e16758 Background: GemNab is one of the first-line standard treatment (tx) of APC. To date, no predictive factors, both clinical and molecular, of benefit from this regimen exist. Two retrospective studies showed that early tumor shrinkage (ETS) can predict an improved outcome in APC pts receiving a first-line tx with FOLFIRINOX or GemNab. However, data regarding GemNab, limited to a small population of only 57 pts, seem to not confirm the association of ETS with a better outcome. Hence, we retrospectively analysed an homogeneous population of APC treated with first-line GemNab at our Institution, investigating the impact of several clinical factors, including response and ETS. Methods: APC pts receiving a first-line tx with GemNab were included in the analysis. The association of RECIST response and ETS with PFS and OS was evaluated. The following variables were collected: gender; age ( &gt; vs ≤ 55 years and ≥ vs &lt; 70 years ); baseline ECOG PS; Ca 19.9 baseline level (≥ vs &lt; 200); anamnesis of diabetes; site of primary tumor (head/uncinate process vs body/tail); locally A vs metastatic (m) PC; synchronous vs metachronous; number of m sites (1 vs &gt; 1); m sites (liver, peritoneum, lung, nodes); number of tx lines (1 vs &gt; 1). Univariate and multivariate analyses for PFS and OS were performed. Results: A total of 184 APC pts receiving first-line GemNab at our Institution from February 2014 to May 2019 were included in the analysis. RR and ETS were assessed in 174 and 168 pts, respectively. RR was 30%, disease control rate (DCR) 63% and ETS was 24%. Responders had a significant better PFS (12.5 vs 5.7 months, p &lt; 0.0001) and OS (25.1 vs 12.1 months, p &lt; 0.0001). ETS was significantly associated with improved PFS (12.3 vs 6.2 months, p &lt; 0.0001) and OS (24.0 vs 12.8 months, p &lt; 0.0001). At the multivariate analysis a significant association with survival parameters was confirmed for RECIST response, but not for ETS. At the multivariate analysis, also metachronous disease and number of tx lines &gt; 1 were independently associated with better OS. Conclusions: Despite its retrospective nature, this is one of the largest series of APC pts treated with first-line GemNab investigating the role of RECIST response and ETS in predicting outcome. On the basis of our results, RECIST response may be considered a positive prognostic factor, whereas ETS does not. In conclusion, achieving tumor shrinkage, not necessarily early, significantly delays PC progression and prolongs survival in pts treated with first-line GemNab.

Early Tumor Shrinkage as a Predictive Factor for Outcomes in Hepatocellular Carcinoma Patients Treated with Lenvatinib: A Multicenter Analysis.

We investigated the association between early tumor shrinkage (ETS) and treatment outcome in patients with hepatocellular carcinoma treated with lenvatinib (LEN). A retrospective analysis was performed in 104 patients. ETS was defined as tumor shrinkage at the first evaluation in the sum of target lesions’ longest diameters from baseline according to the Response Evaluation Criteria in Solid Tumors (RECIST). The median overall survival (OS) was not reached, whereas the median progression-free survival (PFS) was 5.0 months. The receiver operating characteristic curve analysis in differentiating long-term responders (PFS ≥ 5.0 months) from short-term responders (PFS < 5.0 months) revealed an ETS cut-off value of 10%. ETS ≥ 10% was significantly correlated with better PFS and OS compared with ETS < 10%. Additionally, ETS ≥ 10% showed a better discrimination ability on prognosis compared with modified RECIST-based objective response at the first evaluation. Multivariate analysis confirmed ETS ≥ 10% as an independent predictor of better OS, as well as a Child–Pugh score of 5 and macrovascular invasion. In conclusion, ETS ≥ 10% was strongly associated with outcome in patients treated with LEN. This biomarker could allow earlier assessment of the treatment response and guide treatment decision-making for HCC.

Factors That Influence Conversion to Resectability and Survival After Resection of Metastases in RAS WT Metastatic Colorectal Cancer (mCRC): Analysis of FIRE-3- AIOKRK0306

BackgroundTumor assessments after first-line therapy of RAS wild-type mCRC with cetuximab (cet) versus bevacizumab (bev) in combination with FOLFIRI were evaluated for factors influencing resectability, conversion to resectability, and survival after best response.MethodsConversion to resectability was defined as conversion of initially unresectable to resectable disease at best response as determined by retrospective assessment. Univariate and multivariate logistic models were fitted with resectability at best response as response variable. A Cox model comparing the survival from best response was used to measure the influence of treatment, resectability at best response, and resection. Interaction of resection and treatment arm on survival was tested by likelihood ratio test.ResultsOverall, 270 patients were evaluable (127 cet-arm, 143 bev-arm). Lung metastases (odds ratio [OR] 0.35, 95% confidence response [CI] 0.19–0.63), BRAF mutation (OR 0.33, 95% CI 0.12–0.82), and elevated alkaline phosphatase (OR 0.42, 95% CI 0.18–0.9) before randomization were associated with less chance of successful conversion and were integrated into a nomogram. Early tumor shrinkage (OR 1.86, 95% CI 1.06–3.3; p 0.034) and depth of response (OR 1.02, 95% CI 1.01–1.03; p < 0.001) were associated with successful conversion therapy. Resection of metastases improved post-best-response survival (hazard ratio 0.53, 95% CI 0.29–0.97; p = 0.039), predominantely in cet-treated patients (interaction test, p = 0.02).ConclusionsConversion to resectability is significantly associated with baseline characteristics that can be used in a nomogram to predict conversion. Moreover, early efficacy parameters (ETS and DpR) are associated with successful conversion therapy. In FIRE-3, resection of metastases was associated with improved post-best response survival, this effect originated predominantly from the cetuximab-based study arm.

Analysis of early tumor shrinkage (ETS) and depth of response (DpR) in metastatic colorectal cancer (mCRC) patients (pts) treated with second-line FOLFIRI plus panitumumab (Pani) or bevacizumab (Bev): Results from a randomized phase II WJOG6210G trial.

201 Background: The WJOG 6210G trial demonstrated a similar efficacy between Pani and Bev arms at 2nd-line setting in pts with KRAS exon2 wild-type mCRC (Shitara K, et al, Cancer Sci 2016). The exploratory analyses of clinical trials evaluating 1st-line chemotherapy for mCRC have shown significant associations of ETS and DpR with prognosis; however, there is few data in 2nd-line treatment. We investigated whether ETS and DpR are associated with clinical outcomes in mCRC pts treated with 2nd-line treatment using the data of WJOG 6210G trial. Methods: ETS was defined as tumor reduction of 20% at week 8 compared to baseline in the sum of longest diameters of target lesions according to the RECIST criteria. DpR was defined as the percentage of maximum tumor shrinkage of target lesions. Fisher’s exact test and t-test were used to compare ETS and DpR between Pani and Bev arms. A Cox regression model was used to evaluate associations between ETS and progression-free survival (PFS), and overall survival (OS). The association of DpR with PFS and OS was analyzed using Spearman’s rank correlation coefficient. Results: Eighty-seven pts were evaluable for ETS and DpR (Pani, n = 41; Bev, n = 46) among 121 pts enrolled in the WJOG6210G. Pts in the Pani arm had a higher ETS rate (39.0 % vs. 8.7 %, p &lt; 0.001) and greater DpR [median: 23.7 % (range: -49.0 to 100) vs. 0 % (range: -40.7 to 61.5), p &lt; 0.001] than pts in the Bev arm. Pts with ETS achieved longer PFS [median: 10.5 vs. 5.4 m, HR: 0.40 (95% CI: 0.20-0.80), p = 0.009] and OS [median: 22.3 vs. 14.5 m, HR: 0.49 (95% CI: 0.23-0.98), p = 0.044] than pts without ETS in the Pani arm. Similarly, the Bev arm pts with ETS had longer PFS [median: 17.1 vs. 5.6 m, HR: 0.078 (95% CI: 0.004-0.38), p = 0.0002] and OS [median: 30.9 vs. 13.2 m, HR: 0.35 (95% CI: 0.083-0.99), p = 0.048]. There were moderately linear correlations of DpR with PFS and OS in both Pani (PFS: r = 0.75, p &lt; 0.001; OS: r = 0.60, p &lt; 0.001) and Bev arms (PFS: r = 0.68, p &lt; 0.001; OS: r = 0.44, p = 0.002). Conclusions: ETS and DpR were significantly associated with PFS and OS in mCRC pts treated with 2nd-line FOLFIRI in combination with Pani or Bev. Clinical trial information: UMIN000031621.

A phase II study of FOLFOXIRI plus bevacizumab (Bmab) as initial chemotherapy for patients (pts) with untreated metastatic colorectal cancer (mCRC): TRICC1414 (Be TRI).

134 Background: FOLFOXIRI-Bmab has been recognized as one of the standard first-line treatments for mCRC. We conducted a single arm, multicenter, phase II study to assess the efficacy and safety of FOLFOXIRI-Bmab in pts with untreated mCRC harboring UGT1A1(*6 and *28) wild or single hetero genotype. Methods: Pts received FOLFOXIRI-Bmab (irinotecan 165 mg/m2, oxaliplatin 85 mg/m2, l-leucovorin 200mg/m2, fluorouracil 3200 mg/m2 and Bmab 5mg/kg repeated biweekly) up to a maximum of 12 cycles, followed by the sequential therapy which consisted of the remaining drugs if any of the individual drugs were discontinued at the investigator’s discretion. Protocol therapy was continued until progressive disease, an unacceptable adverse event, tumor resection or consent withdrawal. The primary endpoint was ORR evaluated by central reviewers. Secondary endpoints include TTF, PFS, OS, R0 resection rate, relative dose intensity (RDI) and safety. The exploratory objectives were early tumor shrinkage (ETS), depth of response (DoR). Results: 47 pts were enrolled from 16 centers between April 2015 and May 2017, of whom 1 was excluded for not meeting the inclusion criteria. The full analysis set consisted of 44 pts because 2 had no target lesions that were considered measurable lesion by central reviewers. 46 pts had the following characteristics: median age 58 (29-68), 57% male, 76% PS0, 22% right-sided tumors and 52% UGT1A1 wild. RAS status was 37% wild, 52% mutant, 11% unknown. Primary endpoint was met. The ORR was 63.6% (95% CI, 47.8-77.6). ETS and DoR was 70.5%, 43.9%, respectively. R0 resection rate was 23%. Median PFS was 15.5mo (95% CI, 11.5-23.4). Median TTF was 8.1mo (95% CI, 5.3-10.1). Median OS was 34.4mo (95% CI, 26.4-not reached). The mean RDI of fluorouracil, irinotecan and oxaliplatin were 71%, 67%, and 64%, respectively. Grade 3 or higher adverse events (≥10%) were neutropenia (65.2%), febrile neutropenia (FN) (26.1%), anorexia (10.9%), nausea (10.9%), and diarrhea (10.9%). No treatment-related deaths were observed. Conclusions: Our results of FOLFOXIRI-Bmab in Japanese pts showed to be beneficial and manageable although caution to FN is required. Clinical trial information: NCT02497157.

Avelumab and cetuximab in combination with FOLFOX in patients with previously untreated metastatic colorectal cancer (MCRC): Final results of the phase II AVETUX trial (AIO-KRK-0216).

96 Background: Single agent PD-1/L1 inhibition is efficacious in MCRC patients (pts) with high microsatellite instability (MSI-H). For the vast majority of MCRC pts with MS stable (MSS) phenotype the role of immunotherapy remains undetermined. Methods: The single arm phase II AVETUX trial combined mFOLFOX6 and cetuximab with avelumab (10mg/kg day 1 from cycle 2 onwards) in RAS/BRAF wildtype (local lab) MCRC pts. Primary endpoint was 12 month progression-free survival rate. Secondary endpoints included overall response rate (ORR), tolerability, overall survival and translational research evaluating tissue including PD-L1 expression (tumour/immune cells) and serial ctDNA. Efficacy analyses were done by intention to treat (ITT). Results: Overall 43 pts were enrolled. Median age was 61 (range 29-82), 14 pts (33%) were female and 39 (91%) left sided. 30 pts (70%) had liver mets and 17 (40%) liver mets only. 2 pts were MSI-H, one MSI-low and 40 MSS. Besides immediate and otherwise unexplained fever in 4 pts treatment was well tolerated and avelumab was not associated with unexpected adverse events to standard FOLFOX/cetuximab. Central tissue review found 4 pts to be ineligible due to low frequent KRAS or BRAF mutation (15-31%). Thus, ITT included 39 pts. The ORR was 79.5%, including 6 complete (CR) and 25 partial responses (PR). Further 5 stable diseases were noted, thus disease control rate was 92.3%; 2 pts had progression and 1 was not evaluable. Early tumor shrinkage (ETS) rate (≥20% after 8 weeks) was 79.5% (1 CR, 27 PR and 3 SD with ≥20% - &lt; 30%). In MSI-H pts 1 PR and 1 SD and in the 3 low RAS mut pts 2 PR were noted. Panel sequencing was feasible with 153 mutations detected, showing an immediate ctDNA drop within 4 weeks of treatment, mirroring the high rate of early tumor response. Notably, the 4 pts with fever had a high T cell infiltration in the tumor. Final data including the primary endpoint and translational data will be presented at the meeting. Conclusions: The AVETUX regimen was feasible producing a high rate of responses in MSS pts mainly occurring within the first 8 weeks. The noted ORR/ETS of 79.5% warrants further evaluation in a randomized trial. Clinical trial information: NCT03174405.