Background

HER2 amplification (HER2+) is a therapeutic target for 2% (unselected)-6% (RAS wild-type) metastatic colorectal cancer (mCRC). In the HERACLES-A Trial of trastuzumab and lapatinib (Lancet Oncology, 2016), HER2+ KRAS wild-type mCRC patients achieved an overall objective response rate (CR+PR = ORR) of 30%. Based on this result and on preclinical trials, we activated HERACLES-B, evaluating a targeted chemotherapy precision approach by combining pertuzumab with T-DM1.

Methods

HERACLES-B is an open-label phase II trial in RAS/BRAF wild-type HER2+ mCRCs (as defined in Valtorta et al, 2015). ORR and Progression-Free Survival (PFS) are the primary and secondary end-points, respectively. With a Fleming/Hern design (H0=ORR 10%; α = 0.05; power=0.85), 7 OR/30 were required to demonstrate an ORR ≥30% (H1). Main inclusion criteria were: PS 0-1, progression after 5FU, oxaliplatin, irinotecan, and anti-EGFR containing regimens. Pertuzumab was dosed at 840 mg iv load, followed by 420 mg iv q3 weeks and T-DM1 at 3.6 mg/Kg q3 weeks. NGS-based molecular analyses of tumor tissue/plasma were performed.

Results

From 8/2016 to 3/2018, 30 patients were enrolled, treated and evaluable for efficacy. Patients received a median of 3 prior regimens. Data lock and centralized radiological revision were completed by 30/7/2019. ORR was 10% [95% CI: 0-28] and stable disease (SD) 70% [95% CI: 50-85]. Median PFS was 4.8 mos. [95% CI: 3.6-5.8]. Higher HER2 IHC score (3+ vs 2+) was associated with objective response/SD ≥4 mos. [p = 0.03]. Drug-related G3 adverse events were observed only in 2 patients (thrombocytopenia); G ≤ 2 events in 84% of cycles (N = 296), mainly nausea and fatigue.

Conclusions

Although HERACLES-B did not reach its primary endpoint, disease control was achieved in 80% of patients with a median PFS of 4.8 mos. that is superimposable to the 4.2 mos. achieved in the positive HERACLES-A trial. While the ORR could have been weakened by the lower trastuzumab dose delivered with T-DM1, the retained favorable PFS might be due the combined ‘broad-brush’ effect of emtansine and the synergy with pertuzumab. Preliminary molecular results will be presented.

Clinical trial identification

EudraCT: 2012-002128-33.

Legal entity responsible for the study

Fondazione del Piemonte per l’Oncologia IRCC di Candiolo.

Funding

Fondazione Piemontese per l’Oncologia - FPO funded by Associazione Italiana per la Ricerca sul Cancro (AIRC). Roche provided pertuzumab and T-DM1 for free.

Disclosure

A. Sartore-Bianchi: Advisory / Consultancy: Amgen; Advisory / Consultancy: Bayer; Advisory / Consultancy: Sanofi. A. Amatu: Advisory / Consultancy: Roche; Advisory / Consultancy: Bayer; Advisory / Consultancy: Amgen. A. Ardizzoni: Advisory / Consultancy: Roche. L. Trusolino: Research grant / Funding (self): Symphogen; Research grant / Funding (self): Merus; Research grant / Funding (self): Servier; Research grant / Funding (self): Pfizer; Speaker Bureau / Expert testimony: Eli Lilly; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Merck KGaA. S. Siena: Advisory / Consultancy: Amgen; Advisory / Consultancy: Bayer; Advisory / Consultancy: BMS; Advisory / Consultancy: CheckMab; Advisory / Consultancy: Celgene; Advisory / Consultancy: Clovis; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: Incyte; Advisory / Consultancy: Merck; Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche-Genentec; Advisory / Consultancy: Seattle Genetics. All other authors have declared no conflicts of interest.

Background

In non-randomized trials, temozolomide (TMZ) has shown activity in about 10% of pts with chemorefractory mCRC bearing MGMT methylation.

Methods

This multicenter, randomized phase II trial investigated PFS superiority of second-line CAPTEM (Arm A) vs FOLFIRI (arm B) in RAS mutated mCRC pts with MGMT methylation centrally confirmed by MSP. Eligible pts had ECOG PS 0-1, measurable disease, and failed prior oxaliplatin-based therapy. Randomization to arm A (capecitabine 750 mg/sqm b.i.d. days 1-14 plus TMZ 75 mg/sqm b.i.d. days 10-14 q28) or B was stratified according to time elapsed from the start of oxaliplatin-based therapy and PD (</≥9 months); prior bevacizumab. A one-sided log-rank test with an overall sample size of 82 pts (41 per arm) achieved 90% power at 5% significance level to detect PFS increase from 2 to 4 mos. Secondary endpoints: safety, QoL, OS, ORR. Exploratory biomarkers: MGMT IHC; methylBEAMing (MB) in tumor and ctDNA.

Results

A total of 86 pts were randomized (43 per arm). After a median follow-up of 30.5 months (IQR 12.2-36.3), 79 disease PFS events occurred. PFS and OS were 3.5 (2.0-5.0) and 9.5 (8.2-25.8) months in arm A vs 3.5 (2.3-6.1) and 10.6 (8.5-20.8) in arm B (HR = 1.86 [0.82-1.72] and HR = 0.97 [0.58-1.61]), respectively. ORR and DCR were 11.6% and 53.5% in both arms. Grade ≥3 treatment-related adverse events had higher incidence in arm B versus A (47.6% vs 16.3%), and quality of life was significantly worse in arm B. In the subgroup with negative MGMT IHC expression, there were no significant differences between the two arms in terms of activity and efficacy endpoints, whereas in pts with positive MGMT IHC expression CAPTEM regimen was associated with significantly inferior outcomes in terms of PFS (2.0 vs 3.5 mos; HR = 2.08 [1.02-4.21]), OS (5.7 vs 10.6 mos; OR = 1.07 [0.39-2.93]) and DCR (15.4 vs 56.5%; OR = 0.23 [0.04-0.99]), interaction test p = 0.125, 0.732, 0.028. Predicting outcomes with MB was more accurate when using ctDNA vs tumor DNA.

Conclusions

TMZ-based treatment should be investigated by a phase III trial, ideally conducted in patients with MGMT methylated/MGMT IHC negative tumors.

Clinical trial identification

NCT02414009.

Legal entity responsible for the study

Fondazione IRCCS Istituto Nazionale Tumori di Milano.

Funding

Fondazione IRCCS Istituto Nazionale Tumori di Milano.

Disclosure

F. Pietrantonio: Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Merck-Serono; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Servier. F. Morano: Honoraria (self): Servier Italia SpA . S. Lonardi: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Merk-Serono; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Servier; Honoraria (self), Advisory / Consultancy: Bristol-Mayers-Squibb. L. Rimassa: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: AbbVie; Honoraria (self), Advisory / Consultancy: Gilead; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Sirtex Medical; Honoraria (self), Advisory / Consultancy: Italfarmaco; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Baxter; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self), Advisory / Consultancy: ArQule; Honoraria (self), Advisory / Consultancy: Xelixis; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Incyte; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Eisai. A. Sartore-Bianchi: Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Merk-Serono; Honoraria (self), Advisory / Consultancy: Roche. M. Di Bartolomeo: Advisory / Consultancy: Lilly; Advisory / Consultancy: Servier; Travel / Accommodation / Expenses: Roche. F.G.M. De Braud: Honoraria (self), Advisory / Consultancy: TizianaLife Sciences; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Honoraria (self), Advisory / Consultancy: Servier; Honoraria (self), Advisory / Consultancy: Pharm Research Associated; Honoraria (self), Advisory / Consultancy: Daiichi Sankyo; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Ignyta; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Octimet Oncology; Honoraria (self), Advisory / Consultancy: Incyte; Honoraria (self), Advisory / Consultancy: Teofarma; Honoraria (self), Advisory / Consultancy: Pierre Fabre; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Honoraria (self), Advisory / Consultancy: EMD Serono; Speaker Bureau / Expert testimony: Eli Lilly; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Gentili; Speaker Bureau / Expert testimony: Fondazione Menarini. All other authors have declared no conflicts of interest.

Background

ERBB2 amp occurs in approximately 4% of pts with mCRC. We conducted a phase II trial to evaluate the efficacy and safety of T and P in pts with ERBB2-amplified mCRC identified by tissue and/or ctDNA analysis.

Methods

We enrolled pts with central tissue and/or ctDNA (Guardant360) confirmed wild-type RAS and ERBB2-amplified mCRC, refractory or intolerant to standard chemotherapy including EGFR blockade. Pts received T and P every 3 weeks. The primary endpoint was confirmed objective response rate (ORR) by investigator assessment, analyzed for two primary populations: tissue-positive and ctDNA-positive. The required sample size for each group was 25 (one-sided α = 2.5%, β = 10%) to test the threshold ORR of 5% against the expected ORR of 30%; 5 confirmed responses were needed to determine statistical significance.

Results

The first response evaluation was done on Jan 7, 2019. Of 19 pts enrolled at 7 sites, 18 were evaluable for response. ERBB2-amp was confirmed in both tissue and ctDNA for 14 pts, in tissue alone for 3, and in ctDNA alone for 1; therefore, 17 and 15 pts were assigned to the tissue-positive and the ctDNA-positive group, respectively. With median follow-up of 5.4 months, there were 6 confirmed responders in the tissue-positive group (ORR = 35%, 95% confidence interval [CI] 14-62%; 1 CR and 5 PR) and 5 in the ctDNA positive group (ORR = 33%, 95% CI 12-62%; 1 CR and 4 PR). Median progression-free survival for both groups was 4.0 months (95% CI = 1.4-5.6 months and 1.3-5.6 months, respectively). Clonal ctDNA mutations in KRAS, BRAF, PIK3CA, or ERBB2 at baseline were observed only in pts with disease progression as best response. The safety profile of T and P was consistent with prior reports. Severe adverse events were reported in 2 pts: Gr 3 decreased ejection fraction and Gr 3 infusion related reaction.

Conclusions

The TRIUMPH study met its primary endpoint, demonstrating that combination of T and P has promising activity, with an acceptable toxicity profile, in treatment-refractory mCRC pts with ERBB2 amp in tissue and/or ctDNA. Clonal oncogenic ctDNA driver mutations may predict for primary resistance.

Clinical trial identification

UMIN000027887.

Legal entity responsible for the study

SCRUM-Japan GI-SCREEN.

Funding

Japan Agency for Medical Research and Development.

Disclosure

Y. Nakamura: Research grant / Funding (institution): Taiho Pharmaceutical; Research grant / Funding (institution): Ono Pharmaceutical. W. Okamoto: Research grant / Funding (self): MSD. T. Kato: Honoraria (self), Research grant / Funding (self): Chugai Pharma; Honoraria (self): Takeda; Honoraria (self): Bayer; Honoraria (self): Lilly; Honoraria (self): Yakult Honsha; Honoraria (self): Sanofi. K. Kato: Advisory / Consultancy, Research grant / Funding (institution): Ono Pharmaceutical; Advisory / Consultancy, Research grant / Funding (institution): BeiGene; Advisory / Consultancy: MSD; Advisory / Consultancy: Oncolys BioPharma; Research grant / Funding (self): Shionogi; Research grant / Funding (self): MSD Oncology. S. Iwasa: Honoraria (self): Taiho Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Lilly Japan; Honoraria (self), Research grant / Funding (institution): Chugai Pharma; Honoraria (self): Ono Pharmaceutical; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): Otsuka; Research grant / Funding (institution): Bayer. T. Esaki: Honoraria (self), Research grant / Funding (institution): Lilly; Honoraria (self): Taiho Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Bristol-Myers Squibb Japan; Honoraria (self): Eisai; Honoraria (self), Research grant / Funding (institution): Daiichi Sankyo; Honoraria (self), Research grant / Funding (institution): Merck Serono; Honoraria (self): Chugai Pharma; Honoraria (self), Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self): Takeda; Honoraria (self), Research grant / Funding (institution): Bayer; Honoraria (self): Sanofi; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Sumitomo Dainippon Pharma; Research grant / Funding (institution): Astellas Pharma; Research grant / Funding (institution): Nihonkayaku; Research grant / Funding (institution): Pfizer. Y. Komatsu: Speaker Bureau / Expert testimony, Research grant / Funding (self): Taiho Pharmaceutical; Speaker Bureau / Expert testimony, Research grant / Funding (self): Lilly; Speaker Bureau / Expert testimony, Research grant / Funding (self): Chugai Pharma; Speaker Bureau / Expert testimony: Merck Serono; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (self): Novartis; Honoraria (self), Speaker Bureau / Expert testimony: Pfizer; Honoraria (institution), Speaker Bureau / Expert testimony, Research grant / Funding (self): Bayer; Speaker Bureau / Expert testimony, Research grant / Funding (self): Ono Pharmaceutical; Speaker Bureau / Expert testimony: Yakult Honsha; Speaker Bureau / Expert testimony, Research grant / Funding (self): Takeda; Speaker Bureau / Expert testimony, Research grant / Funding (self): Sanofi; Speaker Bureau / Expert testimony: Bristol-Myers Squibb Japan; Speaker Bureau / Expert testimony: Daiichi Sankyo; Speaker Bureau / Expert testimony: TOWA; Speaker Bureau / Expert testimony: Nipro Corporation; Research grant / Funding (self): MSD; Research grant / Funding (self): Yakult Pharmaceutical; Research grant / Funding (self): Sumitomo Dainippon Pharma; Research grant / Funding (self): Boehringer Ingelheim; Research grant / Funding (self): Sysmex. T. Masuishi: Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Merck Serono; Honoraria (self): Chugai Pharma; Honoraria (self), Research grant / Funding (institution): Yakult Honsha; Honoraria (self): Takeda; Honoraria (self): Lilly; Honoraria (self): Bayer Yakuhin; Honoraria (self): Sanofi. T. Nishina: Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Chugai Pharma; Honoraria (self): Lilly; Research grant / Funding (institution): Lilly Japan; Honoraria (self), Research grant / Funding (institution): Merck Serono; Honoraria (self): Takeda; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Nihonkayaku; Research grant / Funding (institution): Sumitomo Dainippon Pharma; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Ono Pharmaceutical. J.I. Odegaard: Shareholder / Stockholder / Stock options, Full / Part-time employment: Guardant Health. S. Olsen: Full / Part-time employment: Guardant Health AMEA; Shareholder / Stockholder / Stock options: Guardant Health; Shareholder / Stockholder / Stock options: AstraZeneca. T. Yoshino: Research grant / Funding (institution): Sumitomo Dainippon Pharma Co., Ltd.; Research grant / Funding (institution): Chugai Pharmaceutical Co., Ltd.; Research grant / Funding (institution): Sanofi. K.K.; Research grant / Funding (institution): Daiichi Sankyo Company, Limited; Research grant / Funding (institution): Parexel International Inc.; Research grant / Funding (institution): Ono Pharmaceutical Co., Ltd.; Research grant / Funding (institution): MSD. K. K. All other authors have declared no conflicts of interest.

Background

HER2 (ERBB2) amplification is present in 5-10% of patients (pts) with KRAS and NRAS (RAS) WT mCRC. Tucatinib (Seattle Genetics, Bothell, WA) is a potent, highly selective oral tyrosine kinase inhibitor of the HER2 receptor. In patient-derived xenograft models of HER2+ mCRC, the combination of tucatinib and trastuzumab showed significantly greater antitumor activity compared with tucatinib or trastuzumab alone. Here we present initial results from a trial of tucatinib and trastuzumab in pts with HER2 amplified mCRC.

Methods

MOUNTAINEER is a multicenter open-label single-arm phase II trial. Pts with RAS WT mCRC had HER2 amplification/overexpression by NGS, FISH, or IHC (3+ or 2+ and amplified by FISH). Prior treatment with 5FU, oxaliplatin, irinotecan, and an anti-VEGF antibody was required. Prior anti-HER2 therapy was excluded. Pts received tucatinib 300mg PO bid and standard doses of trastuzumab (IV, Q3 weeks). The primary endpoint was objective response rate (ORR) per RECIST v1.1. Using a 2-Stage Fleming design, this study compared ORR of 20% (null) vs 40% (alt) in 10 or 25 evaluable pts (1-sided α = 0.11; β=.16). At least 8 responses were needed to meet the primary efficacy endpoint.

Results

As of 26 April 2019, 26 pts enrolled, and 22 pts completed ≥1 evaluation of response. 16/26 pts (62%) were male. Median age= 52.5 (range 24-70). The primary tumor site of origin included right colon (N = 4), left colon/rectum (N = 17), transverse colon (N = 3), and overlapping (N = 2). Among 22 evaluable pts, ORR= 55% (CR/PR= 12; SD = 5; PD = 5). Clinical benefit rate (CR+PR+SD≥4 months) = 64%. At a median follow-up of 10.6 months, median PFS= 6.2 months (95% CI 3.5-NE). Median OS = 17.3 months (95% CI 12.3-NE). Median duration of response has not been reached. There were 2 (9%) grade 3 treatment-related adverse events (TRAEs) and no grade 4/5 TRAEs. The most common TRAEs were AST elevation (48%; all G1), ALT elevation (30%; all G1), and diarrhea (26%; G1/G2/G3=4%/17%/4%).

Conclusions

The combination of tucatinib and trastuzumab is well tolerated and has met its primary efficacy endpoint. Based on these results, further expansion of the MOUNTAINEER trial in pts with HER2 amplified mCRC is justified. Updated results will be presented.

Clinical trial identification

NCT03043313.

Legal entity responsible for the study

Academic and Community Cancer Research United.

Funding

Seattle Genetics.

Disclosure

J.H. Strickler: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Amgen; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self): Chugai; Advisory / Consultancy, Research grant / Funding (institution): Genentech/Roche; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Seattle Genetics; Advisory / Consultancy, Research grant / Funding (institution), Shareholder / Stockholder / Stock options, Non-remunerated activity/ies: OncoMed; Advisory / Consultancy: Celgene; Advisory / Consultancy: Proteus Digital Health; Advisory / Consultancy: Chengdu Kanghong Biotechnology Ltd; Research grant / Funding (institution): Exelixis; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Nektar; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Gilead Sciences; Research grant / Funding (institution): Macrogenics; Research grant / Funding (institution): Leap Therapeutics. A. Cercek: Advisory / Consultancy: Bayer; Advisory / Consultancy: Proteus; Research grant / Funding (institution): Seattle Genetics. C. Wu: Research grant / Funding (institution): Vaccinex; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): Lycera; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Symphogen; Research grant / Funding (institution): FLX Bio. J. Hubbard: Research grant / Funding (institution): Seattle Genetics; Honoraria (institution), Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): Treos Bio; Research grant / Funding (institution): Taiho; Research grant / Funding (institution): Senhwa pharmaceuticals. N. Kemeny: Research grant / Funding (institution): Amgen. P.M. Boland: Research grant / Funding (institution): Merck; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Hemispherx; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): Isofol Medical; Research grant / Funding (institution), Travel / Accommodation / Expenses: Ipsen; Research grant / Funding (institution): Athenex; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Clinical Genomics. K. Ng: Advisory / Consultancy, Research grant / Funding (institution): Genentech; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Tarrex Biopharma; Advisory / Consultancy: Bayer; Advisory / Consultancy, Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Gilead Sciences; Research grant / Funding (institution): Trovagene; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Pharmavite; Research grant / Funding (institution): Consano. T. Bekaii-Saab: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Seattle Genetics. All other authors have declared no conflicts of interest.

Background

We previously showed pTMB selects patients (pts) deriving benefit from PD-L1 and CTLA-4 inhibition with durvalumab and tremelimumab (D+T) compared to best supportive care (BSC) in refractory mCRC in CCTG CO.26.

Methods

We investigated somatic variants contributing to pTMB in MSS pts using cell-free DNA (cfDNA) analysis performed with the GuardantOMNI^TMassay (2.1Mb) on 166 pts from CO.26.

Results

Median pTMB was 16.3 mutations/megabase (mts/Mb). Using a minimum p-value approach, pts with pTMB>28 mts/Mb (21% of MSS pts) had the greatest overall survival (OS) benefit for D + T (HR 0.34, 90% CI 0.18-0.63, p-interaction=0.070) and worse OS in the BSC arm (HR 2.59, 90% CI 1.46-4.62). Of 4044 mts detected, 2718 (67.2%) were subclonal (<10% of max detected mutant allele frequency [MAF]). Anti-EGFR exposure associated with more mts per pt (median 28.5 vs 15.5, P < 0.0001), higher proportion of subclonal mts (78.3% vs 53.7%, P < 0.0001) and higher median pTMB compared to RAS mt pts with no prior anti-EGFR (24.9 vs 13.4 mts/Mb, P < 0.0001). After removing subclonal mts from pTMB calculation, median pTMB decreased to 5.8 mts/Mb. This clonal pTMB remained predictive of D+T improving OS (HR 0.19, 90% CI 0.08-0.45, p-interaction=0.039) when pTMB>10.6 mts/Mb (14.1% pts). Similarly, pTMB calculated using only subclonal mts associated with D+T OS benefit (HR 0.32, 90% CI 0.16-0.67, p-interaction=0.057). Though many genes were associated with pTMB and improved efficacy (see Table), only BRCA1 mts predicted treatment effect (p-interaction=0.035). Most DNA repair mts were subclonal and not associated with increased clonal pTMB.Table:

528PD

Conclusions

Both clonal and subclonal mts causing an elevated pTMB associated with benefit from D+T and mts in select DNA repair genes may correlate with benefit. cfDNA provides an opportunity to evaluate tumor evolution potentially missed in archival tissue.

Clinical trial identification

NCT02870920.

Legal entity responsible for the study

Canadian Cancer Trials Group.

Funding

Canadian Cancer Society.

Disclosure

P.Z. Brohawn: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. K. Banks: Shareholder / Stockholder / Stock options, Licensing / Royalties, Full / Part-time employment: Guardant Health. K. Quinn: Shareholder / Stockholder / Stock options, Licensing / Royalties, Full / Part-time employment: Guardant Health. All other authors have declared no conflicts of interest.

Background

Early identification of treatment effect is wanted in several settings, including management of metastatic colorectal cancer (mCRC). A potential universal marker is circulating tumour DNA (ctDNA). Our prospective study explored the association between progression free survival (PFS) and overall survival (OS), and early change of ctDNA after one cycle of chemotherapy in patients with mCRC.

Methods

The study included mCRC patients receiving standard first line combination chemotherapy with 5-FU, oxaliplatin, and bevacizumab. Hypermethylated neuropeptide Y (NPY) ctDNA (meth-ctDNA) served as a marker analyzed by droplet digital PCR. The meth-ctDNA level was analyzed in plasma before treatment start and again before cycle two. The patients were divided into two groups according to the dynamics of meth-ctDNA. Group 1 included patients with zero or values of meth-ctDNA decreasing to a level including zero in the 95% confidence interval. Group 2 included all other patients (stable, increasing, or slightly decreasing values). The two groups were compared as to PFS and OS.

Results

The study included 107 patients with both of the two blood samples analyzed. The PFS in the two groups was significantly different with a median of 9.5 and 7.4 months, respectively (p = 0.002). This translated into a 12- month difference in OS at a median of 25.4 and 13.5 months, respectively (p = 0.0001).

Conclusions

Early therapeutic reconsideration is of utmost importance. The level of meth-ctDNA after one cycle of chemotherapy in the first line setting seems to divide the patients into two groups with minimal and maximal benefit of treatment. The clinical utility should be confirmed in randomized clinical trials.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

L.H. Jensen: Research grant / Funding (institution): MSD; Research grant / Funding (institution): BMS; Research grant / Funding (institution): 2cureX (research). All other authors have declared no conflicts of interest.

Background

In CRC, the transit-amplifying (TA) subtype is enriched for tumours sensitive to anti-EGFR agents. At the same time, the presence of TA gene signature in tumours belonging to other subtypes may suggest potential anti-EGFR benefit. Hence, we evaluated the association between the TA signature (presence - class 1; absence - class 2) and outcomes in CRC patients (pts) treated with anti-EGFR therapy.

Methods

Formalin-fixed, paraffin-embedded samples from a retrospective discovery cohort (D) and an independent clinical trial cohort (CO.20 study, validation (V)) were classified into the two TA classes using our published nCounter assay (NanoString Technologies). A subset of pts with extended RAS/BRAF wild-type (WT) tumours, cell lines, and pts-derived xenografts (PDXs) were also evaluated. Biomarker portability was evaluated in primary/metastatic samples and different platforms (microarrays).

Results

Up to 295 quality samples were included (D-84; V-121; 30 matched pts and control/treated PDXs). Class 1 pts had significantly longer progression-free survival [PFS; D – adjusted (adj) HR 1.95 (1.15-3.31) p < 0.01; V – adj HR 1.59 (1.07-2.37) p < 0.02] and higher disease control rate (DCR) [D – adj p < 0.0001; V adj p < 0.001]. In D cohort (unselected for RAS/BRAF) classes were significantly associated with sidedness (left 71% class 1; right 58% class 2). In 71 WT pts, class 1 was associated with significantly higher DCR (83% vs. 39%, adj p: 0.003); and trend towards longer PFS and response. This association was more pronounced in a clinically relevant cohort of 51 WT and left-sided pts (class 2 vs. class 1 median PFS: 2 vs. 5.62 months; HR: 1.88 (0.99-3.57) p: 0.049; response rate (class 2 vs. class 1, 8% vs. 33%, odds ratio 0.17(0.02-1.41) p: 0.09, adj (for age, gender) p: 0.14)). WT PDXs and cell lines showed similar response (Wilcoxon test; PDXs p-value: 0.04; cell lines p-value: 0.007). The TA classes were further validated using microarray data from metastatic samples (Khambata-Ford; PFS p < 0.0001).

Conclusions

The detection of TA signature in primary or metastatic samples may further refine the selection of WT CRC pts for anti-EGFR therapy and may explain the differential benefit behind sidedness.

Clinical trial identification

NCT00640471.

Legal entity responsible for the study

The authors.

Funding

NIHR Biomedical Research Centre at The Royal Marsden and the ICR; Cancer Research UK, MedTech SuperConnector.

Disclosure

D. Cunningham: Research grant / Funding (institution): Amgen; AstraZeneca; Bayer; Celgene; MedImmune; Merck Serono; Merrimack; Sanofi. N. Starling: Research grant / Funding (institution): AstraZeneca; Verastem. A. Sadanandam: Research grant / Funding (institution): Bristol-Myers Squibb; Licensing / Royalties: PCT/IB2013/060416. All other authors have declared no conflicts of interest.

Background

Genotyping on cfDNA offers potential advantages in clinical practice for pt selection and serial monitoring of treatment (Tx) efficacy. Clinical relevance of sequential RASmut in cfDNA at different time points during 1L of pt with RASwt solid biopsies (SB) was evaluated.

Methods

Prospective, multi-center study in mCRC pt with RASwt according to SB and treated following standard practice. Liquid biopsies (LB) were collected before starting 1L, at 20 (± 2) weeks (w) and at disease progression (PD). Beaming PCR was used for cfDNA analysis; 3 mutant allele fraction (MAF) cutoffs were considered: 1%, 0.1% & 0.02%.

Results

Median progression-free survival (PFS) was 11.7 months (m) (9.9-13.0) (n = 102). There were no differences in the overall response rate (ORR) according to baseline LB at any cut off, being at MAF 0.02%: 78.7% (68.2- 87.1) in RASwt pt (n = 80) vs 61.5% (31.6 - 86.1) in RASmut pt (n = 13) (OR: 2.32; p = 0.180). MAF was not correlated with total cfDNA levels (p = 0.957). The % of mut cfDNA pt varied along time, with the smallest % at 20 w (Table). There were no emergent mutations at 20 w. Ten pt wt according to baseline LB presented mutations at PD. ORR was 76.9% (63.2 - 87.5) in pt always wt (n = 52) vs 76.2% (52.8 - 91.8) in pt with mut cfDNA at any time point (n = 21) (p = 1.0). There were also no differences in PFS between these 2 groups of pt: 13.0 m (10.9 - 15.4) vs 11.4 m (7.1 – 13.7) at MAF 0.02% (p = 0.095).Table:

531PD

Conclusions

RAS mutational status assessed in cfDNA before starting 1L or sequentially during P+CT Tx in pt with RASwt SB was not a significant predictor of PFS and ORR in none of the cutoffs considered, although in RASmut pt clinical results tended to increase as MAF decreased. The highest proportion of mutated pt was observed at PD, which may be linked to the emergence of resistance. Mutated cfDNA by itself did not predict a lack of clinical benefit to CT and P in our study.

Editorial acknowledgement

Marta Muñoz-Tudurí (TFS, S.L.).

Legal entity responsible for the study

Amgen S.A.

Funding

Amgen S.A.

Disclosure

M. Valladares-Ayerbes: Honoraria (self): Amgen, Merck, Roche, Servier, Bayer, Bristol-Myers; Advisory / Consultancy: Merck, Sanofi, Amgen; Speaker Bureau / Expert testimony: Roche, Servier, Bayer; Research grant / Funding (self): Roche; Travel / Accommodation / Expenses: Merck, Servier, Amgen, Roche. J.M. Viéitez: Travel / Accommodation / Expenses, attendance at conferences: Amgen, Roche, Servier; Research grant / Funding (self): Roche, Amgen. J.J. Cruz-Hernández: Honoraria (self): Amgen, AstraZeneca, Bristol-Myers Squibb, Novartis, Pfizer, Roche Farma; Advisory / Consultancy, Advisory Board: Bristol-Myers Squibb, Merck, MSD, Roche Farma, Pfizer, Janssen Cilag; Advisory / Consultancy, Consulting: Roche Farma. M. Llanos: Advisory / Consultancy, collaboration in lectures: Servier, Roche, Ipsen, Merck, Bristol, Sanofi, Eisai; Advisory / Consultancy: Amgen. A. Lloansí Vila: Shareholder / Stockholder / Stock options, employee and stakeholder of Amgen S.A: Amgen. All other authors have declared no conflicts of interest.

Background

The phase III international FOxTROT trial assessed the effectiveness of pre-operative chemotherapy in locally advanced colon cancer. Patients were randomised across 85 centres to pre- and post-operative FOLFOX-based chemotherapy (pre-op) or to post-operative FOLFOX chemotherapy alone (post-op) in a 2:1 ratio.

Methods

Central pathological review was performed on scanned H&E stained slides in 904 out of 1,052 cases (86%) to include reassessment of the core pathology endpoints and an additional assessment of novel prognostic and immunological markers according to trial arm.

Results

The pre-op group showed a lower pT stage (pT0-pT2 rate 18% vs 8%, p < 0.0001), lower pN stage (pN0 rate 64% vs. 52%, p = 0.0002), smaller tumour diameter (40mm vs. 51mm, p < 0.0001), and greater R0 rate (99% vs. 96%, p = 0.02). The pre-op group showed a lower rate of apical node metastases (3% vs. 8%, p = 0.002), extracapsular spread (8% vs. 19%, p < 0.0001), intramural venous invasion (20% vs. 33%, p < 0.0001), extramural venous invasion (35% vs. 44%, p = 0.004) and lymphatic invasion (46% vs. 55%, p = 0.002). The percentage of the patients with high-grade tumour budding was lower in pre-op group (5% vs. 14%, p < 0.0001). Significantly greater numbers of stromal tumour infiltrating lymphocytes (TILs) (14% vs. 9%, p < 0.0001) and eosinophils (6% vs. 3%, p < 0.0001) were observed in the pre-op group, however, intratumoural TILs were equivalent (5% vs. 5%, p = 0.63). Significantly lower numbers of neutrophils (5% vs. 10%, p < 0.0001) and reduced abscess formation (11% vs. 21%, p < 0.0001) was seen in the pre-op group. The average area of all uninvolved lymph nodes was smaller in the preoperative group as was the average tumour area in metastatic nodes.

Conclusions

Pre-op chemotherapy in locally advanced colon cancer is associated with a significant reduction in many high-risk pathological features and potential mechanisms of metastatic spread. There is also a clear effect on tumour immunology. The association with 2 year DFS is currently being performed and will be presented at the meeting.

Legal entity responsible for the study

University of Birmingham.

Funding

Amgen.

Disclosure

All authors have declared no conflicts of interest.

Background

The benefit of immune checkpoint blockade in mCRC is currently limited to mismatch repair (MMR) deficient tumours. Increasing evidence suggests that the vascular endothelial growth factor (VEGF) pathway plays a role in cancer immune evasion. Co-targeting the PD-1/PD-L1 and VEGF axes may result in clinical activity in mCRC.

Methods

133 patients (pts) were randomized 2:1 to receive C/B/P (Arm A) or C/B/A (Arm B), stratifying by ECOG and RAS. Pts had progressed on 5-FU, oxaliplatin, irinotecan, bevacizumab, and anti-EGFR therapy (if RAS wt). Prior anti-PD-1/PD-L1 therapy was not permitted. Doses were C 850 or 1000 mg/m² d1-14, B 7.5 mg/kg d1, and A 1200 mg d1 in 21 day cycles. Primary endpoint was progression free survival (PFS). 110 events were required to detect PFS hazard ratio (HR) of 0.65 at 1-sided α = 0.1 with 80% power. Secondary endpoints were objective response rate (ORR), overall survival (OS), and safety/tolerability. Primary and secondary efficacy analyses were performed using modified intent to treat analysis (mITT).

Results

Analysis includes 46 pts (Arm A) and 82 pts (Arm B) with median age 58 yo, 40% female, 47% ECOG 0. As of 4/12/19, median follow-up was 12.35 months (mo). Proficient MMR or microsatellite stable (MSS) is present in 86.7% vs 85.7%. In mITT analysis, median PFS is 3.3 mo (2.1-6.2) vs 4.4 mo (4.1-6.4) with a HR of 0.725 (0.491-1.07), 1-sided log-rank p-value 0.051. In MSS only pts, HR for PFS is 0.67 (0.44-1.03). ORR is 4.35% (0.5-14.8) vs 8.54% (3.5-16.8), p = 0.5. The 12 mo OS is 43% (29-63) vs 52% (42-65), HR 0.94 (0.56-1.56), p = 0.4. Most common grade > = 3 related adverse events are hypertension (7% vs 9%), hand-foot syndrome (4% vs 6%), and diarrhea (2% vs 7%).

Conclusions

The study reached its prespecified primary endpoint and the addition of A to CB results in a significantly longer PFS. No new or increased safety signals are identified. Further investigation in a larger phase III study may be warranted. This is the first positive study co-targeting PD-1/PD-L1 and VEGF axes in mCRC and correlative analyses may help identify predictors of benefit.

Clinical trial identification

NCT0287319.

Legal entity responsible for the study

ACCRU.

Funding

Genentech Roche.

Disclosure

H.J. Lenz: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Genentech Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb. P.M. Boland: Research grant / Funding (institution): Merck; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Hemispherx; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): Isofol Medical; Research grant / Funding (institution), Travel / Accommodation / Expenses: Ipsen; Research grant / Funding (institution): Athenex; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Clinical Genomics. A.B. Nixon: Research grant / Funding (self): Seattle Genetics; Research grant / Funding (self): MedPacto; Research grant / Funding (self): Genentech Roche; Advisory / Consultancy, Research grant / Funding (self): Tracon Pharma; Research grant / Funding (self): Acceleron Pharma; Research grant / Funding (self): Leadiant Biosciences; Research grant / Funding (self): Sanofi-Aventis; Advisory / Consultancy: Eli Lilly. H. Hurwitz: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genentech Roche. M.G. Fakih: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Amgen; Advisory / Consultancy: Array; Advisory / Consultancy: Bayer; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Novartis. All other authors have declared no conflicts of interest.