Depth Of Response Research Articles

P-90 Prognostic impact of depth of response (DpR) and early tumour shrinkage (ETS) in patients (pts) with BRAFV600E mutated (mut) metastatic colorectal cancer (mCRC) receiving targeted therapy (TT) as second-line treatment

P-90 Prognostic impact of depth of response (DpR) and early tumour shrinkage (ETS) in patients (pts) with BRAFV600E mutated (mut) metastatic colorectal cancer (mCRC) receiving targeted therapy (TT) as second-line treatment

Response characteristics of tislelizumab combined with chemotherapy in first-line treatment of locally advanced or metastatic non-squamous non-small cell lung cancer

Objective: To investigate the response characteristics of patients with locally advanced/metastatic non-squamous non-small cell lung cancer (nsq-NSCLC) treated with tislelizumab in combination with chemotherapy in the first line. Methods: Patients with nsq-NSCLC who achieved complete or partial remission after treatment with tislelizumab in combination with chemotherapy or chemotherapy alone in the RATIONALE 304 study, as assessed by an independent review board, were selected to analyze the response characteristics and safety profile of the responders. Time to response (TTR) was defined as the time from randomization to the achievement of first objective response. Depth of response (DpR) was defined as the maximum percentage of tumor shrinkage compared with the sum of the baseline target lesion length diameters. Results: As of January 23, 2020, 128 patients treated with tislelizumab in combination with chemotherapy achieved objective tumor response (responders), representing 57.4%(128/223) of the intention-to-treat population, with a TTR of 5.1 to 33.3 weeks and a median TTR of 7.9 weeks. Of the responders (128), 50.8%(65) achieved first remission at the first efficacy assessment (week 6), 31.3%(40) at the second efficacy assessment (week 12), and 18.0%(23) at the third and subsequent tumor assessments. The percentages of responders who achieved a depth of tumor response of 30% to <50%, 50% to <70% and 70% to 100% were 45.3%(58/128), 28.1%(36/128) and 26.6%(34/128), respectively, with median progression-free survival (PFS) of 9.0 months (95% CI: 7.7 to 9.9 months), 11.5 months (95% CI: 7.7 months to not reached) and not reached (95% CI: 11.8 months to not estimable), respectively. Tislelizumab plus chemotherapy were generally well tolerated in responders with similar safety profile to the overall safety population. Conclusion: Among responders to tislelizumab in combination with chemotherapy for nsq-NSCLC, 82.0%(105/128) achieves response within the first two tumor assessments (12 weeks) and 18.0%(23/128) achieves response at later (18 to 33 weeks) assessments, and there is a trend toward prolonged PFS in responders with deeper tumor response.

ORIENT-32: Updated characterization of response to sintilimab plus bevacizumab biosimilar (IBI305) vs sorafenib for unresectable hepatocellular carcinoma.

570 Background: ORIENT-32 trial (NCT03794440) assessed sintilimab (anti-PD-1 antibody) plus a bevacizumab biosimilar (anti-VEGF antibody) versus sorafenib (Sor) as first-line treatment for unresectable HCC and demonstrated a significant improvement in both overall survival and progression-free survival. Here we report the updated results of objective response rate (ORR), time to response (TTR), duration of response (DoR) and depth of response (DpR). Methods: 571 eligible patients (pts) with unresectable HCC were enrolled and randomized (2:1) to receive sintilimab (200 mg IV Q3W) plus IBI305 (15 mg/kg IV Q3W) or Sor (400 mg orally, BID) until disease progression or unacceptable toxicity. Tumors were evaluated using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1)and HCC-modified RECIST (mRECIST). ORR, TTR, DoR, and DpR were analyzed. The DpR was defined as the minimum percentage of (1) sum of longest diameter (SLD) change and (2) longest diameter (LD) change described as mean (standard deviation, SD). Results: At the data cutoff on Dec 30th, 2021, the median follow-up time was 26.7 months. The ORR in sintilimab plus IBI305 and Sor group was 21.0% (77/367) vs 4.7 (8/169) per RECIST 1.1 and 25.1% (92/367) vs 7.7% (13/169) per mRECIST. The median TTR in sintilimab plus IBI305 group was 2.8 (2.4–3.3) months per RECIST 1.1 and 2.6 (1.6–2.9) months per mRECIST. The median DoR in sintilimab plus IBI305gourp was 20.3 (12.3-NE) months per RECIST 1.1. The minimum percentage of SLD change was larger in the sintilimab plus IBI305 arm than in the Sor arm: (−13.4% (35.8) vs 3.2%(26.5) per RECIST 1.1). Similarly, the LD change in the largest liver lesion also favored sintilimab plus IBI305 arm (−27.6% (31.6) vs −11.5% (20.9)), including larger tumors (≥7 cm; −21.2% (30.4) vs −9.9% (23.7)) all per RECIST 1.1. Conclusions: Sintilimab plus IBI305 showed a significant improvement in ORR, TTR, DOR and DpR vs Sor in unresectable HCC. Clinical trial information: NCT03794440 .

Modified (m)-FOLFOXIRI plus cetuximab versus m-FOLFOXIRI plus bevacizumab as initial treatment of patients with unresectable RAS and BRAF wild-type metastatic colorectal cancer: Survival analysis of the phase II randomized DEEPER trial by JACCRO.

120 Background: Triplet regimen, FOLFOXIRI, plus bevacizumab is considered as one of standard first-line treatments in metastatic colorectal cancer (mCRC). On the contrary, FOLFOXIRI plus anti-EGFR antibody has been shown to be a promising regimen with greater depth of response (DpR) in patients with RAS wild-type mCRC from the VOLFI and MACBETH trials (J Clin Oncol 2019, JAMA Oncol 2018). We therefore performed a randomized phase II study, DEEPER trial (JACCRO CC-13) [NCT02515734], to investigate the efficacy and safety of cetuximab (cet) vs. bevacizumab (bev) in combination with modified (m)-FOLFOXIRI in previously untreated mCRC patients with RAS wild-type tumors. We have reported a significantly better DpR of m-FOLFOXIRI plus cet compared to bev as the primary endpoint (Tsuji A, et al. ASCO 2021). 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 initial treatment in terms of DpR during the entire course as the primary endpoint in 360 patients with RAS wild-type mCRC. The aim of the trial was to show that median DpR of cet arm was more than 12.5% higher than bev arm, with a power of 85% at a significance level of 0.05, in per protocol set (PPS) consisted of patients evaluable for the DpR. Secondary endpoints included progression-free survival, overall survival, overall response rate, early tumor shrinkage rate, secondary resection rate, and toxicity. A total of 359 patients were enrolled between July 2015 and June 2019. For the PPS (median age 65y, 64% male, PS0/1: 91%/9%, left/right primary: 84%/16%), 159 and 162 patients were randomly assigned to the cet and bev arms, respectively. Clinical outcomes will be analyzed according to primary tumor sidedness which is included in the stratification factor. Additionally, we will collect data of BRAF status, and analyze the clinical outcomes in mCRC patients with RAS/ BRAF wild-type tumors and/or left-sided tumors. Pre-planned survival analysis will be performed to compare the two treatment arms at the time of 3 years after last patients’ enrollment using a log-rank test. All statistical tests are two-sided, and P values ≤ 0.05 are deemed significant. Statistical analyses will be performed using SAS version 9.4. Clinical trial information: NCT02515734 .

Characterization of Patients With Metastatic Renal Cell Carcinoma Experiencing Complete Response to First-line Therapies: Results From the International Metastatic Renal Cell Carcinoma Database Consortium.

Clinical trials have demonstrated higher complete response rates in the immuno-oncology-based combination arms than in the tyrosine kinase inhibitor arms in patients with metastatic renal cell carcinoma. We aimed to characterize real-world patients who experienced complete response to the contemporary first-line therapies. Using the International Metastatic Renal Cell Carcinoma Database Consortium, response-evaluable patients who received frontline immuno-oncology-based combination therapy or tyrosine kinase inhibitor monotherapy were analyzed. Baseline characteristics of patients and post-landmark overall survival were compared based on best overall response, as per RECIST 1.1. A total of 52 (4.6%) of 1,126 and 223 (3.0%) of 7,557 patients experienced complete response to immuno-oncology-based and tyrosine kinase inhibitor therapies, respectively (P = .005). An adjusted odds ratio for complete response achieved by immuno-oncology-based combination therapy (vs tyrosine kinase inhibitor monotherapy) was 1.56 (95% CI 1.11-2.17; P = .009). Among patients who experienced complete response, the immuno-oncology-based cohort had a higher proportion of non-clear cell histology (15.9% and 4.7%; P = .016), sarcomatoid dedifferentiation (29.8% and 13.5%; P = .014), and multiple sites of metastases (80.4% and 50.0%; P < .001) than the tyrosine kinase inhibitor cohort. Complete response was independently associated with post-landmark overall survival benefit in both the immuno-oncology-based and tyrosine kinase inhibitor cohorts, giving respective adjusted hazard ratios of 0.17 (95% CI 0.04-0.72; P = .016) and 0.28 (95% CI 0.21-0.38; P < .001). The complete response rate was not as high in the real-world population as in the clinical trial population. Among those who experienced complete response, several adverse clinicopathological features were more frequently observed in the immuno-oncology-based cohort than in the tyrosine kinase inhibitor cohort. Complete response was an indicator of favorable overall survival.

Prognostic value of the International Metabolic Prognostic Index for lymphoma patients receiving chimeric antigen receptor T-cell therapy.

Chimeric antigen receptor T-cell therapy (CART) prolongs survival for patients with relapsed/refractory B-cell non-Hodgkin's lymphoma. The recently introduced International Metabolic Prognostic Index (IMPI) was shown to improve prognostication in the first-line treatment of large B-cell lymphoma. Here, we investigate the prognostic value of the IMPI for progression-free (PFS) and overall survival (OS) in the setting of CD19 CART. Consecutively treated patients with baseline 18F-FDG PET/CT imaging and follow-up imaging at 30days after CART were included. IMPI is composed of age, stage, and metabolic tumor volume (MTV) at baseline and was compared with the International Prognostic Index (IPI). Both indices were grouped into quartiles, as previously described for IPI. In addition, the continuous IMPI was subdivided into tertiaries for better separation of risk groups. Overall response rate (ORR), depth of response (DoR), and PFS were determined based on Lugano criteria. Proportional Cox regression analysis studied association of IMPI and IPI with PFS and OS. Thirty-nine patients were included. The IPI was 1 in 23%, 2 in 21%, 3 in 26%, 4 in 21%, and 5 in 10% of the patients. IMPIlow risk, IMPIintermediate risk, and IMPIhigh risk patients had 30-day ORR of 69%, 62%, and 62% and 30-day DoR of - 67%, - 66%, and - 54% with a PFS of 187days, 97days, and 87days, respectively. ORR and DoR showed no correlation with lower IMPI (r = 0.065, p = 0.697). Dividing patients into three risk groups showed a significant trend for PFS stratification (p = 0.030), while IPI did not (p = 0.133). Neither IPI nor IMPI yielded a significant association with OS after CART (both p > 0.05). In the context of CART, the IMPI yielded prognostic value regarding PFS estimation. In contrast with IMPI in the first-line DLBCL setting, we did not observe a significant association of IMPI at baseline with OS after CART.

Depth of response of induction therapy and consecutive maintenance treatment in patients with RAS wild-type metastatic colorectal cancer: An analysis of the PanaMa trial (AIO KRK 0212)

BackgroundIn patients with RAS wild-type metastatic colorectal cancer, depth of response (DpR) has gained importance as a novel end-point in clinical trials. We investigated the overall DpR, as well as the prognostic and predictive impact of DpR to induction therapy (six cycles of 5-fluorouracil, leucovorin [FU/FA], oxaliplatin [FOLFOX] and panitumumab [Pmab]) on consecutive maintenance therapy (FU/FA plus Pmab or FU/FA alone) in patients treated within the PanaMa trial. MethodsCentral radiological assessment was performed according to RECIST 1.1. DpR was defined as percentage change in tumour diameter within defined time intervals (induction therapy, maintenance therapy, total course of therapy). For prognostic and predictive analyses, median DpR (</≥) served as threshold. ResultsOut of 248 patients receiving maintenance therapy, 211 were evaluable for DpR analyses (FU/FA + Pmab, n = 106; FU/FA alone, n = 105). The overall DpR in all patients was 56.5%. DpR of induction therapy (42.5%) accounted for the largest proportion (75.2%) of the overall DpR. While greater DpR to induction therapy was significantly associated with prolonged PFS (HR 0.70, 95% CI 0.52–0.93, p = 0.013) and OS (HR 0.38, 95% CI 0.28–0.51, p < 0.001), there was no significant correlation of DpR and maintenance treatment arm. ConclusionsIn the PanaMa trial, the overall DpR was similar to DpR achieved by other epidermal growth factor receptor-based regimens. DpR to induction therapy accounted for three quarters of the total tumour shrinkage potentially suggesting that FOLFOX plus Pmab can be de-escalated following induction without substantially compromising efficacy. DpR to induction therapy was prognostic but not predictive for efficacy of consecutive maintenance therapy. Clinical trial informationNCT01991873.

MM-188 Depth of Response of Isatuximab plus Carfilzomib and Dexamethasone in Relapsed Multiple Myeloma: IKEMA Updated Analysis

Achieving minimal residual disease negativity (MRD-) in MM is associated with improved survival. Isatuximab (Isa) plus carfilzomib (K) and dexamethasone (d) is approved for relapsed MM patients after ≥1 prior therapy, based on IKEMA interim analysis (NCT03275285). Report updated, longer-term depth of response (DoR) results from IKEMA, including MRD-status. IKEMA, a randomized, open-label, multicenter Phase 3 study, investigates Isa-Kd (n=179) versus Kd (n=123) in relapsed MM patients with 1-3 prior lines of therapy. IV Isa 10 mg/kg was given QW for 4 weeks, followed by Q2W. Both arms received an approved schedule of K (IV) and d (oral/IV). This prespecified analysis evaluated PFS (primary endpoint) at 159 events; secondary endpoints were ≥CR (+stringent CR), MRD-, and ≥CR+MRD-rates, as determined by IRC based on central laboratory data and review of local radiology. MRD status was assessed by NGS (sensitivity threshold ≥10-5) in bone marrow aspirates from patients achieving ≥VGPR. HYDRASHIFT Isa immunofixation (IFE) test, removing Isa interference in IFE, was used to update ≥CR rate. Secondary endpoints were compared between treatment arms using Cochran-Mantel-Haenszel test. One-sided descriptive P-values were provided. All randomized patients not reaching MRD- or without MRD assessment were considered MRD+. At cutoff (14-Jan-2022), with a median follow-up of 44 months, deeper responses were observed in Isa-Kd versus Kd, ≥CR rates 44.1% versus 28.5% (OR: 2.09; 95%CI=1.26-3.48; descriptive P=0.0021). For Isa-Kd versus Kd patients, MRD- (10-5) occurred in 33.5% versus 15.4% (OR: 2.78; 95%CI=1.55-4.99; descriptive P=0.0002), with 26.3% versus 12.2% reaching ≥CR+MRD- (10-5; OR: 2.57; 95%CI=1.35-4.88; P=0.0015); MRD- at 10-6 sensitivity occurred in 10.6% versus 3.3%. MRD- versus MRD+ patients (10-5) had longer mPFS (months); Isa-Kd: not calculable ([NC]; 95%CI=NC-NC) versus 21.7 (95%CI=16.4-27.1); Kd: NC (95%CI=29.2-NC) versus 16.2 (95%CI=13.4-19.5). These results demonstrate clinically meaningful improvement in DoR with Isa-Kd versus Kd. Impressive ≥CR and ≥CR+MRD- (10-5) rates in Isa-Kd versus Kd are the highest reported for proteasome inhibitor-based regimens in relapsed MM. Achieving MRD- led to better outcomes in both arms; Isa-Kd patients had >2-fold higher likelihood of achieving MRD-. Additionally, Isa improved outcomes of MRD+ patients.

396P Impact of depth of response of induction therapy on consecutive maintenance therapy in patients with RAS wild-type metastatic colorectal cancer: An analysis of the PanaMa trial (AIO KRK 0212)

Depth of response (DpR) is associated with improved progression-free survival (PFS) and overall survival (OS) in patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC). There are limited data on the relevance of DpR to induction therapy for consecutive maintenance treatment. Thus, the impact of DpR to induction with 6 cycles of 5-fluoruracil/leucovorin (FU/FA), oxaliplatin and panitumumab (pmab) on the efficacy of maintenance therapy with pmab-FU/FA vs. FU/FA alone was examined within the randomized PanaMa trial. Computed tomography and magnetic resonance imaging were used for central radiologic assessment. DpR was defined as change of tumor diameter from baseline 1 (pre-induction) to baseline 2 (post-induction). Cox regression models and log-rank tests estimated hazard ratios including 95% confidence intervals of DpR (grouped as DpR 1= <0-30%; DpR 2= >30-50%; DpR 3= >50-100%) on PFS and OS during maintenance therapy. Out of 248 patients in the full analysis set 211 were evaluable for central review and DpR analysis (arm A, n=106; arm B, n=105). Median DpR was similar in both treatment arms (42.7% [arm A] vs. 42.2% [arm B]). Cox regression analysis demonstrated a significant correlation of initial DpR with both consecutive PFS (p=0.023) and OS (p=0.046) in the pmab-arm while in patients receiving FU/FA alone this association was not observed. There was no predictive value of DpR groups on efficacy according to treatment arm.Table: 396PFU/FA+pmab (n=106)FU/FA (n=105)DpR 1<0-30%DpR 2>30-50%DpR 3>50-100%DpR 1<0-30%DpR 2>30-50%DpR 3>50-100%Patients (n)215233205233Median PFS, months (95% CI)8.1 (2.7-13.5)9.9 (6.8-13.1)9.5 (5.5-13.5)5.2 (4.6-5.8)5.8 (4.9-6.7)6.1 (4.2-8.1)HR (95% CI), p (log-rank)-0.57 (0.35-1.02)0.43 (0.24-0.80)-0.69 (0.40-1.18)0.60 (0.33-1.08)p=0.023p=0.213Median OS, months (95% CI)16.4 (12.2-20.6)28.2 (23.9-32.5)27.4 (21.1-33.8)17.1 (14.9-19.4)26.4 (22.4-30.5)28.1 (22.9-33.4)HR (95% CI), p (log-rank)-0.50 (0.26-0.94)0.46 (0.23-0.92)-0.52 (0.26-1.303)0.40 (0.18-0.87)p=0.046p=0.054 Open table in a new tab In RAS WT mCRC treated within in the PanaMa trial, DpR to induction therapy has a prognostic impact on subsequent maintenance treatment. This effect appears pronounced in patients receiving pmab-based maintenance therapy.

388P Early tumor shrinkage (ETS) and depth of response (DpR) analyses in metastatic colorectal cancer (mCRC) treated with first-line mFOLFOX6 plus panitumumab (PAN) or bevacizumab (BEV): Results from the phase III PARADIGM trial

The PARADIGM primary analysis demonstrated that PAN significantly improved OS vs BEV combined with mFOLFOX6 in RAS WT and left-sided mCRC. ETS and DpR are on-treatment prognostic factors related to favorable OS and PFS in mCRC chemotherapy. We report ETS and DpR and the correlation with OS and PFS in patients (pts) with RAS WT mCRC from PARADIGM. Relative change in maximum tumor diameter was analyzed between baseline and 8 wks of treatment. ETS was defined as a ≥30% decrease in tumor size by investigator assessment. OS and PFS were compared in pts with/without ETS stratified by treatment arm and primary tumor location (left-sided, overall, right-sided). DpR was the maximum post-baseline percent decrease in the sum diameter of target lesions. No hypothesis was formally tested; P-values were based on a 2-sided stratified log-rank test and were descriptive. Cutoff date: Jan 14, 2022. A greater proportion of pts had ETS with PAN (left: 64.4%; overall: 58.5%) vs BEV (left: 38.0%; overall: 38.8%). Left-sided PAN pts with ETS showed longer OS (median: 42.6 vs 27.1 mo; HR: 0.56 [95% CI: 0.42–0.75]; P<0.001) and PFS (15.7 vs 9.6 mo; 0.62 [0.48–0.81]; P<0.001) than pts without ETS. Similarly, left-sided BEV pts with ETS had longer OS (median: 41.3 vs 32.4 mo; HR: 0.69 [95% CI: 0.52–0.91]; P=0.01) and PFS (14.5 vs 11.5 mo; 0.81 [0.62–1.06]; P=0.094). Right-sided PAN pts with ETS had longer OS, but not BEV (Table). Left-sided and overall PAN groups had greater median DpR than BEV (left, -59.4 vs -43.6; overall, -57.3 vs -43.6), with no difference between right-sided arms. Although ETS was associated with favorable survival outcomes in both arms, PAN achieved more ETS and greater DpR than BEV in left-sided pts. In right-sided pts, ETS was only predictive with PAN, warranting further biomarker analysis to predict PAN benefit.Table: 388POSPAN + mFOLFOX6BEV + mFOLFOX6ETS ≥30%ETS <30%ETS ≥30%ETS <30%Leftn=201n=111n=111n=181Median (95% CI), mo42.6 (37.5–49.7)27.1 (21.8–36.3)41.3 (31.6–46.5)32.4 (27.9–36.8)HR 95% CI P value0.56 0.42–0.75 <0.0010.69 0.52–0.91 0.010Overalln=234n=166n=156n=246Median (95% CI), mo42.1 (37.5–48.4)23.1 (17.7–31.0)33.8 (29.3–41.3)30.5 (26.9–34.0)HR 95% CI P value0.50 0.39–0.64 <0.0010.78 0.62–0.99 0.036Rightn=30n=54n=42n=61Median (95% CI), mo34.1 (21.0–42.2)15.2 (11.3–20.2)22.3 (17.4–30.9)25.5 (16.9–31.6)HR 95% CI P value0.47 0.28–0.79 0.0050.94 0.60–1.45 0.746 Open table in a new tab

LBA21 FOLFOX/FOLFIRI plus either bevacizumab or panitumumab in patients with initially unresectable colorectal liver metastases (CRLM) and left-sided and RAS/BRAFV600E wild-type tumour: Phase III CAIRO5 study of the Dutch Colorectal Cancer Group

Patients (pts) with initially unresectable CRLM may qualify for curative-intent local therapy after downsizing by induction systemic therapy. CAIRO5 was designed to find the optimal induction regimen. We present results of pts with left-sided and RAS/BRAFV600E wild-type tumour. Pts were randomised between FOLFOX/FOLFIRI (patient preference) plus either bevacizumab (arm A) or panitumumab (arm B) up to 12 cycles. Prior systemic or local therapy for metastases was not allowed. (Un)resectability of CRLM was assessed by a liver expert panel of surgeons and radiologists, at baseline by predefined criteria and every 2 months thereafter by individual opinion. Primary endpoint was progression-free survival (PFS). Pts were stratified by potentially resectable vs permanently unresectable CRLM, serum LDH (normal/abnormal) and choice of irinotecan vs oxaliplatin. 256 events were required to detect a hazard ratio (HR) of 0.70 for PFS with 80% power and 2-sided log-rank test at 5% assuming a median PFS of 11.6 months in arm A. 236 pts (118 in each arm) were included in 43 Dutch sites from November 2014 until closure due to futility in March 2022. 6 ineligible pts were excluded. Median follow up was 44 months. Main characteristics were (arm A/B): median age 59/60, male 61/63%, synchronous CRLM 88/92%, prior adjuvant chemotherapy 4/3%, median number of CRLM 12/12. With 197 events, median PFS in arm A vs B was 10.6 vs 10.3 months (stratified HR 1.12, 95% CI 0.84-1.50, p=0.44). Response rate (RR) was 52% vs 76% (p<0.01). Median depth of response (DOR) was 33% vs 49% (p<0.01). R0/1 resection ± ablation rate was 58% vs 56% (p=0.79). Grade ≥3 toxicity occurred in 52% vs 69% (p=0.01), Clavien Dindo grade ≥3 surgical complications in 21% vs 14% (p=0.30). In first-line treatment of pts with initially unresectable CRLM and left-sided and RAS/BRAFV600E wild-type tumour there is no difference in median PFS between the addition of either bevacizumab or panitumumab to FOLFOX/FOLFIRI. The addition of panitumumab significantly increases RR and DOR but this does not translate in an increased local therapy rate of CRLM.

O7-2 FOLFOXIRI plus cetuximab versus bevacizumab in RAS wild-type mCRC: the subgroup-analysis of DEEPER trial (JACCRO CC-13)

FOLFOXIRI plus bevacizumab (bev) or panitumumab has been shown to be superior in terms of early tumor shrinkage and depth of response (DpR) compared to doublet combinations in patients (pts) with RAS wild-type (wt) metastatic colorectal cancer (mCRC). We performed a randomized phase II study, DEPER trial (JACCRO CC-13), to investigate the efficacy and safety of cetuximab (cet) vs bev plus modified (m)-FOLFOXIRI (irinotecan 150mg/m2, oxaliplatin 85mg/m2, 5-FU 2400mg/m2) in previously untreated mCRC pts with RAS wt tumors.

Modified FOLFOXIRI plus panitumumab (mFOLFOXIRI/PAN) versus mFOLFOX6/PAN as initial treatment of patients with unresectable RAS and BRAF wild-type metastatic colorectal cancer (mCRC): Results of the phase III randomized TRIPLETE study by GONO.

LBA3505 Background: The association of a chemotherapy doublet (FOLFOX/FOLFIRI) with an anti-EGFR monoclonal antibody (cetuximab or panitumumab) is an upfront option for the treatment of RAS and BRAF wt mCRC patients. Phase II studies investigating the combination of the triplet FOLFOXIRI with an anti-EGFR reported promising activity results and an acceptable safety profile when lower doses of 5FU and irinotecan were adopted. The added value of intensifying the upfront chemotherapy when combined with a targeted agent in a molecularly selected population is not established. Methods: TRIPLETE is a prospective, open label, phase III trial in which previously untreated patients with unresectable RAS and BRAF wt mCRC were randomized to receive mFOLFOX6/pan (arm A) or mFOLFOXIRI (irinotecan 150 mg/sqm, oxaliplatin 85 mg/sqm, L-leucovorin 200 mg/sqm, 5-fluoruracil 2400 mg/sqm 48 h infusion)/pan (arm B) up to 12 cycles, followed by 5FU/LV/pan until disease progression. The primary endpoint is overall response rate (ORR) according to RECIST 1.1 criteria. Secondary endpoints include safety profile, R0 resection rate, PFS and OS. Under the assumption of an ORR of 60% in arm A, to detect an increase of at least 15% in arm B, a sample size of 432 cases provided approximately 90% power to a two-sided chi square test for heterogeneity at the 0.05 significance level. Results: From September 2017 to September 2021, 435 pts were enrolled (arm A/B: 217/218) in 67 Italian sites. Main pts’ characteristics were (arm A/B): median age 59/59, ECOG PS 0 80%/84%, left-sided 88%/88%, synchronous metastases 88%/87%, prior adjuvant 2%/6%, resected primary 43%/51%, liver-only 37%/39%. Main grade &gt; 2 adverse events were diarrhoea 7%/23%, stomatitis 7%/7%, neutropenia 20%/32%, febrile neutropenia 3%/6%, fatigue 2%/7%, skin rash 29%/19%. 160 (73%) out of 218 patients in arm B and 165 (76%) out of 217 patients in arm A achieved RECIST response (OR 0.87, 95%CI 0.56-1.34, p=0.526). No interaction effect between treatment arm and disease spread (liver-limited vs not-liver limited) was evident. No differences in early tumor shrinkage (arm A/B 58%/57%, p=0.878) and deepness of response (median arm A/B: 47%/48%, p=0.845) were reported, nor in R0 resection rate (arm A/B 29%/25%, p=0.317). At a median follow up of 26.5 mos, 305 (arm A/B: 157/148) PFS events were collected, with no significant difference between arms (median PFS: 12.7 vs 12.3 months, HR: 0.88, 95%CI 0.70-1.11, p=0.277). Conclusions: The intensification of the upfront chemotherapy backbone in combination with panitumumab in molecularly selected and mostly (88%) left-sided mCRC patients does not provide any benefit in terms of treatment activity at the price of a non-negligible increase in gastrointestinal toxicity. Clinical trial information: NCT03231722.

Association between depth of response (DepOR) and clinical outcomes: Exploratory analysis in patients with previously untreated advanced renal cell carcinoma (aRCC) in CheckMate 9ER.

4501 Background: Among patients (pts) with untreated aRCC in the CheckMate 9ER trial, superior progression-free survival (PFS; hazard ratio [HR], 0.56) and overall survival (OS; HR, 0.70) were maintained, and objective response and complete response (CR) rates were doubled for nivolumab plus cabozantinib (N+C) vs sunitinib (SUN) with extended 25.4 mo minimum (32.9 mo median) follow-up. This exploratory analysis evaluated the relationship between DepOR and clinical outcomes in CheckMate 9ER. Methods: Eligible pts received N (240 mg) every 2 weeks plus C (40 mg) once daily or SUN (50 mg once daily; 4 weeks of each 6-week cycle). In this analysis, DepOR subgroups were based on best overall response (blinded independent central review [BICR] per RECIST v1.1) and best tumor reduction threshold, as follows: CR; partial response subdivided by a tumor reduction of ≥80%–&lt;100% (PR1); ≥60%–&lt;80% (PR2); or ≥30%–&lt;60% (PR3); stable disease (SD); and progressive disease (PD). PFS (per BICR) and OS by DepOR subgroups were analyzed after a 6-mo post-randomization landmark. Treatment-related adverse events (TRAEs) were assessed in DepOR subgroups. Results: Of 323 and 328 pts randomized to N+C or SUN, 236 and 157 pts were progression-free and alive and 293 and 253 pts were alive at the 6-mo landmark and were categorized by DepOR subgroup. Overall, greater proportions of pts receiving N+C had deeper responses vs SUN (CR, PR1, PR2; Table). Deeper responses with N+C were associated with improved 12-mo PFS rate vs SUN for CR (94.9% vs 82.4%), PR1 (81.3% vs 37.5%), and PR2 (72.1% vs 53.2%). In both arms, increasingly deeper response led to better OS outcome; yet OS rates and medians were comparable between arms for CR, PR1, PR2, and PR3 (Table). No meaningful patterns for overall TRAE rates by DepOR subgroup were identified in either arm. Conclusions: In CheckMate 9ER, more pts receiving N+C achieved deeper responses vs SUN. Deeper responses were generally associated with improved PFS and OS. Clinical trial information: NCT03141177. [Table: see text]

Response and Disease Dynamics in Untreated Metastatic Colorectal Cancer With Bevacizumab-Based Sequential vs. Combination Chemotherapy—Analysis of the Phase 3 XELAVIRI Trial

IntroductionEarly tumor shrinkage (ETS), depth of response (DpR), and time to DpR represent exploratory endpoints that may serve as early efficacy parameters and predictors of long-term outcome in metastatic colorectal cancer (mCRC). We analyzed these endpoints in mCRC patients treated with first-line bevacizumab-based sequential (initial fluoropyrimidines) versus combination (initial fluoropyrimidines plus irinotecan) chemotherapy within the phase 3 XELAVIRI trial.MethodsDpR (change from baseline to smallest tumor diameter), ETS (≥20% reduction in tumor diameter at first reassessment), and time to DpR (study randomization to DpR image) were analyzed. We evaluated progression-free survival and overall survival with ETS as stratification parameter according to treatment arm, molecular subgroup, and sex.ResultsIn 370 patients analyzed, a higher rate of ETS (60.9% vs. 43.5%; p = 0.001) and significantly greater DpR (-40.0% vs. -24.7%; p < 0.001) were observed in the initial combination therapy arm. The improvement was pronounced in RAS/BRAF wild-type tumors. ETS correlated with improved survival irrespective of treatment arm (PFS: p < 0.001; OS: p = 0.012) and molecular subgroup (PFS: p < 0.001; OS: p < 0.001). Male patients in contrast to female patients with ETS had survival benefit (PFS: p < 0.001, HR 0.532; OS: p < 0.001, HR 0.574 vs. PFS: p = 0.107; OS: p = 0.965).ConclusionsInitial irinotecan-based combination therapy with bevacizumab improved ETS and DpR in mCRC patients with a particularly high irinotecan sensitivity of RAS/BRAF wild-type tumors. ETS seems to be a suitable prognostic marker for fluoropyrimidine- and bevacizumab-based combinations in mCRC. This finding was rather driven by male patients, potentially indicating that ETS might be less predictive of long-term outcome in an elderly, female population.

Tumor response of FOLFOXIRI plus cetuximab versus bevacizumab in RAS wild-type metastatic colorectal cancer: The subgroup-analysis of DEEPER trial (JACCRO CC-13).

109 Background: Triplet regimen, FOLFOXIRI, combined with bevacizumab (bev) or panitumumab has been shown to be superior in terms of early tumor shrinkage and depth of response (DpR) compared to doublet combinations in patients with RAS wild-type metastatic colorectal cancer (mCRC). We performed a randomized phase II study, DEEPER trial (JACCRO CC-13)[NCT02515734], to investigate the efficacy and safety of cetuximab (cet) vs. bevacizumab (bev) in combination with modified (m)-FOLFOXIRI (irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, 5-FU 2400 mg/m2) in previously untreated mCRC patients with RAS wild-type tumors (Tsuji A, et al. ASCO 2021). Methods: The primary endpoint was DpR during the entire course. Secondary endpoints included overall response rate (ORR), disease control rate, R0 resection rate, progression-free survival, and overall survival. A post-hoc subgroup analysis by PS, tumor sidedness, age, and location of metastases was performed to evaluate the efficacy of triplet plus cet vs. bev regimen. Results: A total of 359 patients were enrolled between July 2015 and June 2019. For the full 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. Median DpR was 57.4% vs. 46.0% ( p = 0.001), and the ORR was 69.1% vs. 71.7% ( p = 0.60), in cet vs. bev, respectively. The subgroup analysis was present in the table. There was no significant difference in terms of ORR and R0 resection rate between groups according to PS, tumor sidedness, age, and liver metastases (LM). In patients with only LM, the R0 resection rate of cet vs. bev was 25.0% vs. 14.8% ( p = 0.21). Conclusions: The m-FOLFOXIRI plus cet showed to be significantly superior to the m-FOLFOXIRI plus bev in terms of DpR in first-line treatment for RAS wild-type mCRC. The better DpR of m-FOLFOXIRI plus cet was evident for RAS wild-type mCRC patients with left-sided tumors, LM or under 70 years old. Clinical trial information: UMIN000018217.[Table: see text]

Assessing prognostic value of early tumor shrinkage and depth of response in first-line therapy for patients with advanced unresectable pancreatic cancer

BackgroundThe prognostic potential of early tumor shrinkage (ETS) and depth of response (DpR) in pancreatic cancer (PC) is unclear. Here, we recruited 90 patients with recurrent and metastatic PC (RMPC) who had received chemotherapy as first-line therapy to assess the prognostic potential of these markers.MethodsETS is characterized as a ≥ 20% depletion in the sum-of-the-longest-diameters (SLD) of measurable tumor lesions at 6–12 weeks than the baseline. DpR is the maximum shrinkage (%) from the baseline to nadir. We evaluated corrections in ETS and DpR with survival.ResultsOf the 63 patients in which ETS assessment was possible, 21 (33.3%) achieved ETS. We found a significant association between the incidence of ETS and an improved rate of progression-free survival (PFS; 6.5 vs. 2.2 months; p < 0.001) and overall survival (OS; 12.1 vs. 6.0 months; p = 0.014). The median value of DpR was − 23.66%. DpR was also related to improved PFS (9.3 vs. 3.1 months; p < 0.001) and OS (18.2 vs. 7.3 months; p < 0.001). Patients who had distant metastasis, not local recurrence, with ETS showed markedly better outcomes. In a multivariate model, both ETS and DpR were independent predictors of OS in the whole population.ConclusionsETS and DpR may predict favorable outcomes for RMPC patients who had received chemotherapy as first-line therapy, independent of the agents used. Further studies on the exploratory analyses of the optimum ETS cut-off value in recurrent PC patients to predict favorable clinical outcomes are required.

Relationships Between Köhne Category/Baseline Tumor Load and Early Tumor Shrinkage, Depth of Response, and Outcomes in Metastatic Colorectal Cancer

BackgroundIn metastatic colorectal cancer (mCRC), there are limited data on associations between early tumor shrinkage (ETS), depth of response (DpR), and patient characteristics. MethodsData from patients with RAS wild-type mCRC who had participated in the PRIME (NCT00364013) and PEAK (NCT00819780) studies were analyzed retrospectively. ETS and DpR were assessed by baseline Köhne category/BRAF status (PRIME) and baseline tumor load (pooled PRIME and PEAK). ResultsAnalysis populations included 436 to 665 patients. Patients’ chances of achieving ETS of 30% or greater were 63.8%, 50.4%, and 41.9% in the low-, medium-, and high-risk Köhne categories, and 21.7% in those with BRAF mutations. Corresponding percentages for the highest DpR classification (71%-100%) were 47.7% (low risk), 23.6% (medium risk), 10.0% (high risk), and 4.2% (BRAF mutant). No clear relationship was observed between baseline tumor load and ETS or DpR. An ETS of 30% or greater and higher DpR values were associated with statistically significant prolongation of median progression-free survival and overall survival. ConclusionPatients with mCRC categorized at baseline by the Köhne criteria as high risk or with BRAF mutations have lower chances of achieving an ETS of 30% or greater or a high DpR. Baseline tumor load was not predictive of ETS or DpR. Favorable ETS or DpR is associated with improved progression-free and overall survival.

Treatment responses and disease dynamics in patients with untreated metastatic colorectal cancer receiving bevacizumab-based sequential versus combination chemotherapy: Analysis of a phase 3 trial (AIO KRK0110, XELAVIRI study).

3571 Background: Early response parameters such as early tumor shrinkage (ETS), depth of response (DpR), and time to DpR represent exploratory endpoints that may serve as early efficacy endpoints and potential predictors of long-term outcome. We analyzed the association of these endpoints with bevacizumab-based sequential (initial fluoropyrimidines) versus combination (initial fluoropyrimidines plus irinotecan) chemotherapy within a randomized phase III trial. Methods: DpR (change from baseline to smallest tumor diameter), ETS (≥20% reduction in tumor diameter at first reassessment), and time to DpR (study randomization to DpR-image) were analyzed in the XELAVIRI-trial. Moreover, progression-free survival (PFS) and overall survival (OS) were evaluated with ETS as stratification parameter (ETS vs. no ETS) according to treatment arm, molecular subgroup, and sex. Results: 370 patients were available for analysis of early treatment response parameters. A higher rate of ETS (60.9% vs. 43.5%; p = 0.001) and significantly greater DpR (-40.0% vs. -24.7%; p &lt; 0.001) were observed in the initial combination compared to the sequential therapy arm, respectively. The improvement of ETS and DpR was pronounced in the subpopulation of RAS/ BRAF wildtype patients. Male in contrast to female patients significantly benefitted from initial combination treatment in terms of median DpR (male: -40.0% vs. -22.2%; p &lt; 0.001; female: -34.0% vs. -24.4%; p = 0.13) and rate of ETS (male: 64.8% vs. 40.2%; p &lt; 0.001; female: 52.5% vs. 49.3%; p = 0.73). Achievement of ETS correlated with improved survival irrespective of treatment arm (PFS: p &lt; 0.001; OS: p = 0.012) and molecular subgroup (PFS: p &lt; 0.001; OS: p &lt; 0.001). Whereas the survival benefit in male patients achieving ETS was statistically significant (PFS: p &lt; 0.001, HR 0.532 (0.409-0.692); OS: p &lt; 0.001, HR 0.574 (0.437-0.756)), there were no significant differences in PFS (p = 0.107) and OS (p = 0.965) of female patients depending on ETS. Conclusions: In the XELAVIRI trial, initial irinotecan-based combination therapy with bevacizumab improves ETS and DpR in mCRC patients. Improvement in early response parameters appears pronounced in patients with RAS/ BRAF wildtype tumors suggesting a high sensitivity to irinotecan-based treatment. ETS was predictive of PFS and OS regardless of treatment arm. This finding was rather driven by male than female patients, potentially indicating that ETS might be less predictive of long-term outcome in an elderly, female population.

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).

3501 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 combinations in patients with RAS wild-type metastatic colorectal cancer (mCRC), in the TRIBE trial ( N Engl J Med 2014) or the 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 150mg/m2, oxaliplatin 85mg/m2, 5-FU 2400mg/m2) plus cet vs. bev as first-line treatment in terms of DpR during the entire course as the primary endpoint in 360 patients with RAS wild-type mCRC. The aim of the trial was to show that median DpR of cet arm was more than 12.5% higher than bev arm, with a power of 85% at a significance level of 0.05. Secondary endpoints included ETS rate at week 8, overall response rate (ORR), progression-free survival (PFS), overall survival (OS), secondary resection rate, and toxicity. Results: A total of 359 patients were enrolled between July 2015 and June 2019. For the full 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. On the cutoff date of September 2020, the median number of cycles administered was 10 (range, 1-51) for the cet arm and 12 (range, 1-51) for the bev arm. Safety data was already reported at the ASCO GI symposium 2021 (J Clin Oncol 39, 2021 suppl 3; abstr 86). The primary endpoint was met (p =.001); 57.4%（-15.0̃100）for the cet arm versus 46.0% （-0.6̃100）for the bev arm. As for primary tumor sidedness, median DpR were 60.3% versus 46.1% (p =.0007) in the left-side and 50.0% versus 41.2% (p =.46) in the right-side. The ETS rate and ORR as the secondary endpoints were 77.8% and 69.1% in the cet arm versus 74.6% and 71.7% in the bev arm, respectively, with no statistical significance. Although the survival data were immature, PFS and OS of both arms were 12.7 months (95%CI 11.5-14.0) and 37.6 months (95%CI 30.8 to 43.0), respectively. Conclusion: The mFOLFOXIRI plus cet has been shown to be significantly superior to the mFOLFOXIRI plus bev in terms of DpR as the primary endpoint in first-line treatment for RAS wild-type mCRC. Clinical trial information: NCT02515734. Clinical trial information: UMIN000018217.