Phase II study of anti-EGFR rechallenge therapy with panitumumab driven by circulating tumor DNA molecular selection in metastatic colorectal cancer: The CHRONOS trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3506-3506
Author(s):  
Andrea Sartore-Bianchi ◽  
Filippo Pietrantonio ◽  
Sara Lonardi ◽  
Benedetta Mussolin ◽  
Francesco Rua ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trial ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Liquid Biopsy ◽  
Objective Response ◽  
Circulating Tumor Dna ◽  
Type I ◽  
Tumor Dna

3506 Background: Despite advances in molecular segmentation of metastatic colorectal cancer (mCRC), beyond RAS status therapeutic actionability remains confined to the limited subgroups of ERBB2 amplified, BRAF mutated and MSI-H patients. Optimization of available treatments is therefore warranted. Rechallenge with anti-EGFR monoclonal antibodies is often empirically used with some benefit as late-line therapy. We previously found that mutant RAS and EGFR ectodomain clones, which emerge in blood during EGFR blockade, decline upon antibody withdrawal leading to regain drug sensitivity. Based on this rationale, we designed CHRONOS, a multicenter phase II trial of anti-EGFR therapy rechallenge guided by monitoring of the mutational status of RAS, BRAF and EGFR in circulating tumor DNA (ctDNA). To our knowledge, this is the first interventional clinical trial of liquid biopsy for driving anti-EGFR rechallenge therapy in mCRC. Methods: Eligible patients were PS ECOG 0-2 RAS/BRAF WT mCRC having first achieved an objective response and then progression in any treatment line with an anti-EGFR antibody containing regimen, displaying RAS, BRAF and EGFR ectodomain WT status in ctDNA at molecular screening after progression to the last anti-EGFR-free regimen. Clonal evolution in ctDNA was analyzed by ddPCR and next generation sequencing. Panitumumab 6 mg/kg was administered IV every two weeks until progression. The primary endpoint was objective response rate (ORR) by RECIST version 1.1 with independent central review. 27 total patients and 6 responses were required to declare the study positive (power = 85%, type I error = 0.05). Results: Between Aug 19, 2019 and Nov 6, 2020 52 patients were screened by liquid biopsy and 36 (69%) were negative in ctDNA for RAS/BRAF/EGFR mutations. Of these, 27 patients were enrolled in 4 centers. Median age was 64 years (range: 42-80). PS ECOG was 0/50%, 1/46%, 2/4%. Previous anti-EGFR was administered in 1st line in 63%, 2nd in 15% and > 2nd in 22%. Median number of previous treatments was 3. The primary endpoint was met, with 8/27 partial responses (PR) observed (2 unconfirmed) (ORR = 30%, 95% CI: 12-47%). Stable disease (SD) was obtained in 11/27 (40%, 95% CI: 24-59%), lasting > 4 months in 8/11. Disease control rate (PR plus SD > 4 months) was therefore obtained in 16/27 (59%, 95% CI: 41-78%). Median progression-free survival was 16 weeks. Median duration of response was 17 weeks (1 ongoing). Maximal grade toxicity was G3, limited to dermatological and occurring in 19% of patients. ctDNA dynamics were studied in all patients. Conclusions: Liquid biopsy-driven rechallenge with anti-EGFR antibodies leads to further objective responses in one third of patients. Genotyping tumor DNA in the blood to direct therapy can be effectively incorporated in the management of advanced CRCs. Clinical trial information: 2016-002597-12.

TiFFANY study: A multicenter phase II basket-type clinical trial to evaluate efficacy and safety of pan-FGFR inhibitor TAS-120 for advanced solid malignancies with FGFR alterations identified by circulating tumor DNA.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS3156-TPS3156
Author(s):  
Tomoko Jogo ◽  
Yoshiaki Nakamura ◽  
Yoshito Komatsu ◽  
Ken Kato ◽  
Eiji Shinozaki ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase Ii ◽  
Objective Response ◽  
Circulating Tumor Dna ◽  
Survival Duration ◽  
Efficacy And Safety ◽  
Multicenter Phase ◽  
Solid Malignancies ◽  
Ctdna Analysis ◽  
Tumor Dna

TPS3156 Background: Approximately 7% of advanced solid malignancies have FGFR gene alterations. However, standard treatment for FGFR-altered malignancies has not been established. Moreover, circulating tumor DNA (ctDNA) analysis has a potential to accurately identify FGFR alterations by assessing spatial and temporal intratumoral heterogeneity, which have shown to be associated with a poor prognosis and resistance to anti-cancer therapy. Methods: We are conducting an investigator-initiated multicenter phase II basket-type trial to investigate efficacy and safety of TAS-120, a highly selective covalent pan-FGFR inhibitor, for the patients with advanced solid malignancies with FGFR alterations identified by ctDNA analysis as a part of the Nationwide Cancer Genome Screening Project (GOZILA study, UMIN000029315). Eligibility criteria include histologically confirmed unresectable advanced or recurrent solid tumors regardless of histology of origin; ECOG PS of 0 or 1; refractory or intolerant to the standard therapies; and clonal FGFR alterations ( FGFR1-3 gain-of-function mutations, FGFR1,2 amplifications and FGFR2,3 fusions) identified by a 73-gene sequencing ctDNA panel (Guardant360). Enrolled patients will receive TAS-120 20 mg once daily, orally, in a 21 day-cycle. The primary endpoint is to clarify objective response rate (ORR) assessed by investigators per RECIST v1.1. The secondary endpoints are to evaluate progression-free survival, duration of response, time to treatment failure, disease control rate, overall survival, ORR by central determination, and incidence of adverse events. Target sample size is determined as 26 to test the null hypothesis of ORR as 5% with one-sided alpha level of 2.5% and power of 80% to detect an expected value of ORR as 25%. Furthermore, tumor tissue and ctDNA will be serially collected and analyzed to investigate the resistance mechanisms and provide clinically meaningful biomarker which may be used for identifying and implementing treatment changes. Clinical trial information: 194624.

Final results and OS of the randomized phase II VOLFI trial (AIO- KRK0109): mFOLFOXIRI + panitumumab versus FOLFOXIRI as first-line treatment in patients with RAS wild- type metastatic colorectal cancer (mCRC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3511-3511 ◽  
Author(s):  
Michael Geissler ◽  
Jorge Riera-Knorrenschild ◽  
Uwe Marc Martens ◽  
Swantje Held ◽  
Jobst Greeve ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Objective Response ◽  
Open Label ◽  
Secondary Resection ◽  
Strong Trend ◽  
Mutational Status ◽  
Secondary Endpoints

3511 Background: This trial evaluated activity and safety of mFOLFOXIRI + panitumumab vs FOLFOXIRI in ECOG 0-1, primarily non-resectable mCRC patients. The final primary endpoint was presented at ASCO and ESMO 2018. Now we report for the first time the final results regarding OS and PFS. Methods: Prospective 2:1 randomized, controlled, open label multi-center, phase II trial comparing mFOLFOXIRI (Ox 85 mg/m2, Iri 150 mg/m2, 5-FU 3000mg/m2 cont. 48h, LV 200 mg/m2) + Panitumumab 6 mg/KG (arm A) with FOLFOXIRI (Ox 85 mg/m2, Iri 165 mg/m2, 5-FU 3200mg/m2 cont. 48h, LV 200 mg/m2; arm B), both arms q2w. Prospective strata were cohort 1: irresectable mCRC (n=65), and cohort 2: chance of secondary resection of metastatic lesions (n=31). Primary endpoint was ORR, secondary endpoints were secondary resection rate (cohort 2), DCR, PFS, OS, toxicity, quality of life (QLQ-C30). Financially supported by an unrestricted grant from Amgen. Results: A total of 96 patients were randomized (63 arm A, 33 arm B). ORR was 87.3% in arm A and 60.6% in arm B (p=0.0041, OR 4.47; 95%-CI 1.614-12.376). Secondary resections of metastases in the ITT population were observed in 33·3% (arm A Pmab) versus 12·1% (arm B) (OR=3.63; 95%-CI 1.13–11.67, p=0·029) and in cohort 2 in 75% (arm A Pmab) versus 36.4% (arm B) (OR=5.25; 95%-CI 1.07–25.8, p=0.05), respectively. Median PFS was similar in the study arms (9.7 mo in both arms, HR 1.071; 95%-CI 0.689-1.665, p=0.76). OS in the ITT population showed a strong trend in favour of the Pmab-containing arm A with a median OS of 35.7 mo compared to 29.8 mo in arm B (HR: 0·67; 95%-CI 0.41-1.11, P=0·12). mOS of cohort 2 was 52.0 mo in arm A versus 41.7 mo in arm B (HR 0.413; 95%-CI 0.15-1.12, p=0.07). Further results regarding to sidedness and BRAF mutational status will be presented. Conclusions: The addition of Pmab to a mFOLFOXIRI regimen in patients with RASwildtype metastatic colorectal cancer significantly improved objective response rate and the rate of secondary resection of metastases. Although PFS was comparable, there was a strong trend towards improved OS in the Pmab arm. Future studies are warranted to confirm this trend towards improved overall survival with this regimen. Clinical trial information: NCT01328171.

scholarly journals Circulating tumor DNA-guided treatment with pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer: a phase 2 trial

2021 ◽  
Author(s):  
Yoshiaki Nakamura ◽  
Wataru Okamoto ◽  
Takeshi Kato ◽  
Taito Esaki ◽  
Ken Kato ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trials ◽  
Metastatic Colorectal Cancer ◽  
Objective Response Rate ◽  
Response Rate ◽  
Objective Response ◽  
Circulating Tumor Dna ◽  
Phase 2 ◽  
Phase 2 Trial ◽  
Tumor Dna

AbstractThe applicability of circulating tumor DNA (ctDNA) genotyping to inform enrollment of patients with cancer in clinical trials has not been established. We conducted a phase 2 trial to evaluate the efficacy of pertuzumab plus trastuzumab for metastatic colorectal cancer (mCRC), with human epidermal growth factor receptor 2 (HER2) amplification prospectively confirmed by tumor tissue or ctDNA analysis (UMIN000027887). HER2 amplification was confirmed in tissue and/or ctDNA in 30 patients with mCRC. The study met the primary endpoint with a confirmed objective response rate of 30% in 27 tissue-positive patients and 28% in 25 ctDNA-positive patients, as compared to an objective response rate of 0% in a matched real-world reference population treated with standard-of-care salvage therapy. Post hoc exploratory analyses revealed that baseline ctDNA genotyping of HER2 copy number and concurrent oncogenic alterations adjusted for tumor fraction stratified patients according to efficacy with similar accuracy to tissue genotyping. Decreased ctDNA fraction 3 weeks after treatment initiation associated with therapeutic response. Pertuzumab plus trastuzumab showed similar efficacy in patients with mCRC with HER2 amplification in tissue or ctDNA, showing that ctDNA genotyping can identify patients who benefit from dual-HER2 blockade as well as monitor treatment response. These findings warrant further use of ctDNA genotyping in clinical trials for HER2-amplified mCRC, which might especially benefit patients in first-line treatment.

Efficacy of an anti-EGFR after ctDNA conversion from mutated RAS status of metastatic colorectal cancer: Results of a pilot study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15574-e15574
Author(s):  
Mohamed Bouchahda ◽  
Raphael Saffroy ◽  
Abdoulaye Karaboué ◽  
Jocelyne Hamelin ◽  
Pasquale Innominato ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Pilot Study ◽  
Metastatic Colorectal Cancer ◽  
Liquid Biopsy ◽  
Circulating Tumor Dna ◽  
Additional Treatment ◽  
Ras Mutation ◽  
Prior Chemotherapy ◽  
Ras Status ◽  
Tumor Dna

e15574 Background: This pilot study aimed at the evaluation of the efficacy of anti-EGFR therapy in patients with initially RAS-mutated metastatic colorectal cancer, whose liquid biopsy found no RAS mutation after prior chemotherapy failure. Methods: Sixteen patients with RAS-mutated metastatic colorectal cancer in the solid tumor were included, after they had received 1 to 3 prior chemotherapy lines without anti-EGFR. Before inclusion, RAS genotyping was performed in circulating tumor DNA (ctDNA) from liquid biopsy, after a median duration of ̃24 months after the initial RAS status determination. No RAS mutation was detected in the circulating tumor DNA from 9 patients (56%), who then received cetuximab-FOLFIRI. The 7 patients who had persistent RAS mutation in the liquid biopsy (44%) were treated according to standard recommendations without anti-EGFR. Results: The median progression free survival was 8.2 months [95%CL, 4.5 – 11.8] in patients without detectable ctDNA RAS mutation, as compared to 3.5 months [2.1 – 4.9] in the ctDNA mutated patients (p < 0.001). The median overall survival was 22.3 months [17.3 - 27.3] in the patients with undetectable ctDNA RAS mutation, whereas it was 4.7 months [2.6 - 6.7] in those with ctDNA RAS mutation (p = 0.013). These results suggested the efficacy of cetuximab-based chemotherapy in patients with initially RAS mutated metastatic colorectal cancer, who later displayed no detectable ctDNA RAS mutation. Conclusions: The introduction of an anti-EGFR could provide an additional treatment option for patients with metastatic colorectal cancer with apparent conversion of initial RAS mutation, based on ctDNA assessment after prior failure on anti-EGFR-free chemotherapy.

scholarly journals A phase Ib study of capecitabine and ziv-aflibercept followed by a phase II single-arm expansion cohort in chemotherapy refractory metastatic colorectal cancer

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
John H. Strickler ◽  
Christel N. Rushing ◽  
Donna Niedzwiecki ◽  
Abigail McLeod ◽  
Ivy Altomare ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trial ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Dose Escalation ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Objective Response ◽  
Phase Ib ◽  
Expansion Cohort

Abstract Background Patients with chemotherapy refractory metastatic colorectal cancer (CRC) have a poor prognosis and limited therapeutic options. In this phase Ib/II clinical trial, we established the maximum tolerated dose (MTD) and recommended phase II dose (RPTD) for the combination of capecitabine and ziv-aflibercept, and then we evaluated the efficacy of the combination in patients with chemotherapy refractory metastatic CRC. Methods All patients were required to have a Karnofsky Performance Status > 70% and adequate organ function. The phase Ib dose escalation cohort included patients with advanced solid tumors who had progressed on all standard therapies. Using a standard 3 + 3 design, we identified the MTD and RPTD for the combination. Fifty patients with metastatic CRC who had progressed on or were intolerant of a fluoropyrimidine, oxaliplatin, irinotecan, and bevacizumab were then enrolled in a single-arm phase II expansion cohort, and were treated at the RPTD. Prior EGFR antibody therapy was required for subjects with RAS wildtype tumors. The primary endpoint for the expansion cohort was progression-free survival (PFS) at two months. Secondary endpoints included objective response rate (ORR) and overall survival (OS). Results A total of 63 patients were enrolled and evaluable for toxicity (13 dose escalation; 50 expansion). The MTD and RPTD were: capecitabine 850 mg/m2, P.O. bid, days 1–14, and ziv-aflibercept 6 mg/kg I.V., day 1, of each 21-day cycle. In the expansion cohort, 72% of patients were progression-free at two months (95% confidence interval [CI], 60–84%). Median PFS and OS were 3.9 months (95% CI, 2.3–4.5) and 7.1 months (95% CI: 5.8–10.0), respectively. Among all patients evaluable for toxicity, the most common treatment related adverse events (all grade [%]; grade ≥ 3 [%]) included palmar-plantar erythrodysesthesia (41%; 6%), hypertension (33%; 22%), and mucositis (19%; 5%). RNA was isolated from archived tumor specimens and gene expression analyses revealed no association between angiogenic biomarkers and clinical outcomes. Conclusion The combination of capecitabine and ziv-aflibercept at the RPTD demonstrated acceptable safety and tolerability. PFS at 2 months in patients with chemotherapy refractory metastatic CRC was significantly greater than that in historical controls, indicating that this combination warrants further study. Trial registration This clinical trial was registered in the www.clinicaltrials.gov system as NCT01661972 on July 31, 2012.

Multicenter phase I/II trial of BBI608 and pembrolizumab combination in patients with metastatic colorectal cancer (SCOOP Study): EPOC1503.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS3623-TPS3623 ◽  
Author(s):  
Yasutoshi Kuboki ◽  
Akihito Kawazoe ◽  
Yoshito Komatsu ◽  
Tomohiro Nishina ◽  
Eiji Shinozaki ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trial ◽  
Phase I ◽  
Metastatic Colorectal Cancer ◽  
Sample Size ◽  
Phase Ii ◽  
Alternative Hypothesis ◽  
Objective Response ◽  
Clinical Trial Information ◽  
Egfr Antibody

TPS3623 Background: Immune checkpoint inhibitor (ICI) was reported to show durable responses in patients with MSI-H (Microsatellite Instability-High) metastatic colorectal cancer (mCRC). On the other hand, for patients with MSS (Microsatellite Stable) mCRC, ICI monotherapy achieved no response. Recently, WNT/β-catenin signaling has been reported to be involved in the elimination of tumor-infiltrating lymphocytes and the resistance of anti-PD-L1 antibodies. CRC is representative cancer with WNT/β-catenin pathway activation. Furthermore, STAT3 has also been reported to be a key driver of this immune evasion. Considering these rationales, the blocking of these signaling pathways with ICI may enhance antitumor immune response. Therefore, we initiated phase I/II study to assess efficacy and safety for the combination of BBI608, which blocks STAT3 and WNT/β-catenin signaling, with pembrolizumab in patients with mCRC. Methods: The eligibility criteria were patients with gastrointestinal cancer not responded to or intolerant of standard chemotherapies (SOC) for phase I part, and MSS mCRC refractory or intolerant to fluoropyrimidine, irinotecan, oxaliplatin, and anti-EGFR antibody (if wild-type RAS) for Cohort B in phase II part. For Cohort A, MSI-H mCRC refractory or intolerant to the SOC, irrespective of anti-EGFR antibody are investigated. Phase I part was designed to determine the recommended phase II dose in a “3+3” cohort-based dose escalation design of BBI608 (240mg BID every day on level 1 and 480mg BID every day on level 2) with pembrolizumab (200mg/body q3w). Primary endpoint of the phase II part is Immune-related objective response rate (irORR) determined by their Response Evaluation Criteria In Solid Tumors (irRECIST). A null hypothesis and alternative hypothesis for cohort B are irORR = 5% and 20%, respectively. Required sample size for Cohort B was 40 with a one-sided alpha of 5% and power of 90%. Required sample size for Cohort A (10 patients) was determined in an exploratory manner. We also investigate biomarker study using paired samples of both tumor biopsy and blood. The enrollment to phase I part began in November 2016. Clinical trial information: NCT02851004. Clinical trial information: NCT02851004.

Sign in / Sign up

Export Citation Format

Share Document