ESMO Supporter 2018

Displaying One Session

Hall A2 - Room 18 Proffered Paper session
Date
22.10.2018
Time
09:15 - 11:00
Location
Hall A2 - Room 18
Chairs
  • Dirk Arnold (Hamburg, DE)
  • Alfredo Falcone (Pisa, IT)
Proffered paper session - Gastrointestinal tumours, colorectal Proffered Paper session

LBA18_PR - Durable Clinical Benefit With Nivolumab (NIVO) Plus Low-Dose Ipilimumab (IPI) as First-Line Therapy in Microsatellite Instability-High/Mismatch Repair Deficient (MSI-H/dMMR) Metastatic Colorectal Cancer (mCRC)

Presentation Number
LBA18_PR
Lecture Time
09:15 - 09:27
Speakers
  • Heinz-Josef J. Lenz (Los Angeles, US)
Location
Hall A2 - Room 18, ICM München, Munich, Germany
Date
22.10.2018
Time
09:15 - 11:00

Abstract

Background

In previously chemotherapy-treated patients with MSI-H/dMMR mCRC from the phase II CheckMate-142 trial, NIVO + low-dose IPI (1 mg/kg) provided durable clinical benefit (investigator-assessed [INV] objective response rate [ORR] 55%, median duration of response [DOR] not reached, 12-month overall survival [OS] rate 85%) and manageable safety. Here we report the first results of the efficacy and safety of NIVO + low-dose IPI as a first-line (1L) therapy for patients with MSI-H/dMMR mCRC from CheckMate-142.

Methods

Patients with no prior treatment for MSI-H/dMMR mCRC were treated with NIVO 3 mg/kg every 2 weeks (Q2W) + low-dose IPI every 6 weeks (Q6W) until disease progression. The primary endpoint was ORR (INV; RECIST v1.1).

Results

Of 45 patients, 51% were male and median age was 66 years. Median follow-up (time from first dose to data cut-off) was 13.8 months (range 9–19). The ORR and disease control rate (DCR) were 60% and 84%, respectively, with a 7% complete response rate (Table). Median DOR was not reached. At 12 months, progression-free survival (PFS) and OS rates were 77% and 83%, respectively. Grade 3–4 treatment-related adverse events (TRAEs) occurred in 16% of patients and 7% of patients had any grade TRAEs leading to discontinuation. Any grade select immune-mediated TRAEs affecting the hepatic (13%), gastrointestinal (11%), pulmonary (2%), and renal (2%) systems resolved in 100% of patients, while those affecting the skin (33%) and endocrine (24%) systems resolved in 45% and 60% of patients, respectively.

Conclusions

NIVO (Q2W) + low-dose IPI (Q6W) demonstrated robust and durable clinical benefit and was well-tolerated as a 1L treatment for MSI-H/dMMR mCRC. These results suggest that NIVO + low-dose IPI may represent a new treatment option for these patients.

Table. Efficacy and Safety
NIVO + IPI (N = 45)

ORRa, n (%)

(95% CI)

27 (60)

(44–74)

Best overall response, n (%)

CR

PR

SD

PD

Not determined

3 (7)

24 (53)

11 (24)

6 (13)

1 (2)

DCRb, n (%)

(95% CI)

38 (84)

(71–94)
Median time to response, months (range) 2.6 (1.2–13.8)
Median DOR, months (95% CI) NR (11.5–NE)

Median PFS, months (95% CI)

12-month rate, % (95% CI)

NR (14.1–NE)

77 (62.0–87.2)

Median OS, months (95% CI)

12-month rate, % (95% CI)

NR (NE)

83 (67.6–91.7)

TRAEs, n (%)

Any grade

Grade 3–4

35 (78)

7 (16)

TRAEs leading to discontinuation, n (%)

Any grade

Grade 3–4

3 (7)

1 (2)

aPatients with CR or PR divided by the number of treated patients

bPatients with a CR, PR, or SD for ≥12 weeks divided by the number of treated patients

CI = confidence interval; CR = complete response; NE = not estimable; NR = not reached; PD = progressive disease; PR = partial response; SD = stable disease

Clinical trial identification

NCT02060188

Editorial Acknowledgement

Professional medical writing assistance and editorial assistance was provided by Tanmayi Mankame, PhD, and Christine Craig of PAREXEL International, funded by Bristol-Myers Squibb.

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Proffered paper session - Gastrointestinal tumours, colorectal Proffered Paper session

LBA19 - Fluoropyrimidine (FP) + bevacizumab (BEV) + atezolizumab vs FP/BEV in BRAFwt metastatic colorectal cancer (mCRC): Findings from Cohort 2 of MODUL – a multicentre, randomized trial of biomarker-driven maintenance treatment following first-line induction therapy

Presentation Number
LBA19
Lecture Time
09:27 - 09:39
Speakers
  • Axel Grothey (Germantown, US)
Location
Hall A2 - Room 18, ICM München, Munich, Germany
Date
22.10.2018
Time
09:15 - 11:00

Abstract

Background

In patients (pts) with mCRC, molecular screening approaches and new biomarkers are required to fully characterize tumours and identify those likely to benefit. The MODUL study (ClinicalTrials.gov: NCT02291289) is highly adaptable, Phase II signal seeking, and evaluates the theory of tumoural heterogeneity under induction chemotherapy via switch maintenance treatment in first-line mCRC.

Methods

MODUL follows an umbrella design; pts with measurable, unresectable, previously untreated mCRC receive 16 weeks of induction treatment with FOLFOX + BEV followed by maintenance randomized to either control (FP/BEV) or experimental treatment in one of four cohorts. Here we report results of Cohort 2 (BRAFwt: FP/BEV + atezolizumab). Primary efficacy endpoint: progression-free survival (PFS, per investigator). Secondary endpoints: overall survival (OS); best overall response rate (ORR); disease control rate (DCR); time to treatment response (TTR); duration of response (DoR); ECOG performance status (PS); safety.

Results

824 pts were screened, 696 of whom were enrolled to receive induction treatment. 445 pts with BRAFwt mCRC were randomized to maintenance treatment in Cohort 2 (297 pts FP/BEV + atezolizumab; 148 pts FP/BEV). In the primary analysis of Cohort 2 (median follow-up 10.5 months), PFS was not met (HR=0.92; 95% CI 0.72–1.17; p=0.48) and OS was immature. ORR, DCR, TTP and DoR showed small numerical differences in favour of experimental treatment. Subgroup treatment interactions were observed for gender, ECOG PS, response at end of induction and initial diagnosis (synchronous vs metachronous disease). In the updated analysis (median follow-up 18.7 months), PFS outcome was unchanged (HR=0.96; 95% CI 0.77–1.20; p=0.727) and OS with 51% of pts with an event was HR=0.86; 95% CI 0.66–1.13; p=0.28. The safety profiles observed are consistent with previous findings with no new safety signals identified.

Conclusions

Adding atezolizumab to FP/BEV (standard of care) as first-line maintenance treatment for pts with BRAFwt mCRC did not lead to improvement in efficacy outcomes.

Clinical trial identification

ClinicalTrials.gov: NCT02291289

Editorial Acknowledgement

Editorial assistance was provided by Lee Miller (Miller Medical Communications).

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Proffered paper session - Gastrointestinal tumours, colorectal Proffered Paper session

Invited Discussant LBA18_PR and LBA19

Lecture Time
09:39 - 09:54
Speakers
  • Julien Taieb (Paris, FR)
Location
Hall A2 - Room 18, ICM München, Munich, Germany
Date
22.10.2018
Time
09:15 - 11:00
Proffered paper session - Gastrointestinal tumours, colorectal Proffered Paper session

LBA20 - TRIBE2: a phase III, randomized strategy study by GONO in the 1st- and 2nd-line treatment of unresectable metastatic colorectal cancer (mCRC) patients (pts).

Presentation Number
LBA20
Lecture Time
09:54 - 10:06
Speakers
  • Chiara Cremolini (Pisa, IT)
Location
Hall A2 - Room 18, ICM München, Munich, Germany
Date
22.10.2018
Time
09:15 - 11:00

Abstract

Background

TRIBE2 aimed at comparing two strategies of 1st and 2nd line treatment of mCRC with different chemotherapy intensity and a prolonged angiogenesis inhibition

Methods

TRIBE2 (NCT02339116) was a phase 3 trial in which previously untreated pts with unresectable mCRC were randomized 1:1 to FOLFOX/bev followed by FOLFIRI/bev after disease progression (PD) (arm A) or FOLFOXIRI/bev followed by the reintroduction of the same regimen after PD (arm B). Combination treatments were administered up to 8 cycles, followed by 5-FU/bev until PD. The primary endpoint was Progression Free Survival 2 (PFS2), defined as the time from randomization to PD on any treatment given after first PD or death. Estimating a median PFS2 in arm A of 15 months, 466 events and 654 pts were required to detect a HR of 0.77 in favor of arm B, with overall 2-sided-α and β errors of 0.05 and 0.20, respectively. An interim analysis at 2/3 of events (303) was planned. According to the O’Brien Fleming spending rule, 2-sided-α levels of 0.0131 and 0.0455 were defined for the interim and final analysis

Results

From February 2015 to May 2017, 679 pts (arm A/B: 342/337) were enrolled in 58 Italian sites. Main patients’ characteristics were (arm A/B): median age 61/60 yrs, ECOG PS 0 86%/87%, right-sided primary 38%/38%, liver-only disease 29%/32%, RAS mutant 65%/63%, BRAF mutant 10%/10%. At a median follow-up of 22.8 mos, 547 (arm A/B 286/261) patients progressed and 423 (arm A/B 235/188) events of PFS2 were reported. As compared with FOLFOX/bev, upfront FOLFOXIRI/bev significantly improved PFS1 (median 9.9 vs 12.0 mos, HR 0.73 [95%CI: 0.62-0.87], p<0.001) and RECIST response rate (61% vs 50%, OR 1.55 [95%CI: 1.14-2.10], p=0.005). 247 (86%) and 197 (75%) patients received a treatment after PD in arm A and B, respectively. Patients in arm B reported significantly longer PFS2 than in arm A (median PFS2 18.9 vs 16.2 mos, HR 0.69 [95%CI: 0.57-0.83], p<0.001)

Conclusions

The primary endpoint was met at the interim analysis: 4-months induction with FOLFOXIRI/bev followed by maintenance and reintroduction improves mCRC patients’ outcome as compared with a sequential strategy of oxaliplatin- and irinotecan-based doublets.

Clinical trial identification

NCT02339116

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Proffered paper session - Gastrointestinal tumours, colorectal Proffered Paper session

452O - DPYD genotype-guided dose individualization of fluoropyrimidine therapy: A prospective safety and cost-analysis on DPYD variants DPYD*2A, c.2846A>T, c.1679T>G and c.1236G>A

Presentation Number
452O
Lecture Time
10:06 - 10:18
Speakers
  • Linda M. Henricks (Amsterdam, NL)
Location
Hall A2 - Room 18, ICM München, Munich, Germany
Date
22.10.2018
Time
09:15 - 11:00

Abstract

Background

Fluoropyrimidines are generally well tolerated drugs, but can result in severe, potentially fatal toxicity in up to 30% of patients. The major cause of toxicity is reduced activity of the key metabolizing enzyme dihydropyrimidine dehydrogenase (DPD), most often the result of genetic DPYD variants. In this prospective clinical trial we determined whether toxicity of fluoropyrimidine treatment can be reduced by upfront screening for 4 relevant DPYD variants and DPYD genotype-guided dosing.

Methods

Prospective genotyping for DPYD*2A, c.2846A>T, c.1679T>G and c.1236G>A was performed in patients prior to start of fluoropyrimidine-based therapy. Heterozygous DPYD variant carriers received an initial dose reduction of 25% (c.2846A>T, c.1236G>A) or 50% (DPYD*2A, c.1679T>G). Incidence of severe (grade ≥3) toxicity in DPYD variant carriers was compared to a historical cohort of DPYD variant carriers treated with full dose.

Results

A total of 1,103 evaluable patients was enrolled, of whom 85 were heterozygous DPYD variant carriers (7.7%). In DPYD variant carriers the overall frequency of grade ≥3 toxicity was 39%. When comparing to the historical cohort, DPYD genotype-guided dosing markedly reduced the risk of grade ≥3 toxicity for DPYD*2A and c.1679T>G carriers, moderately reduced risk for c.2846A>T carriers, and resulted in a similar risk for c.1236G>A carriers. Pharmacokinetic analyses showed that fluoropyrimidine exposure after dose reductions in DPYD variant carriers was comparable to wild-type patients. A cost-analysis showed that the reduced risk in toxicity resulted in average total treatments costs per patient that were even lower for the screening strategy (€2599) compared to non-screening (€2650).

Conclusions

Upfront DPYD genotyping improves patient safety during fluoropyrimidine chemotherapy, is feasible in routine practice, and is cost saving. For heterozygous DPYD*2A and c.1679T>G carriers, a 50% initial dose reduction is recommended. For c.1236G>A and c.2846A>T carriers the applied dose reductions of 25% in this study were not enough to lower the risk of severe toxicity in this group, so more cautious dose reductions of 50% are recommended.

Clinical trial identification

NCT02324452.

Legal entity responsible for the study

The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Funding

Dutch Cancer Society (Alpe d'HuZes/KWF-fund).

Disclosure

C.A.T.C. Lunenburg: Unrestricted grant: Roche Pharmaceuticals. R.H.J. Mathijssen: Research support: Astellas, Bayer, Boehringer Ingelheim, Cristal Therapeutics, Novartis, Pamgene, Pfizer, Roche, Sanofi; Consultation fees: Novartis, Servier; Travel support: Astellas, Pfizer. All other authors have declared no conflicts of interest.

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Proffered paper session - Gastrointestinal tumours, colorectal Proffered Paper session

LBA21 - InterAACT: A multicentre open label randomised phase II advanced anal cancer trial of cisplatin (CDDP) plus 5-fluorouracil (5-FU) vs carboplatin (C) plus weekly paclitaxel (P) in patients (pts) with inoperable locally recurrent (ILR) or metastatic treatment naïve disease - An International Rare Cancers Initiative (IRCI) trial.

Presentation Number
LBA21
Lecture Time
10:18 - 10:30
Speakers
  • Sheela Rao (London, GB)
Location
Hall A2 - Room 18, ICM München, Munich, Germany
Date
22.10.2018
Time
09:15 - 11:00

Abstract

Background

Whilst advanced squamous cell carcinoma of the anal canal (SCCA) is a rare disease incidence has risen by 2%/year for the past decade. There is no consensus on management of these pts who generally have a poor overall survival (OS) and to date no randomised trial has been completed. The combination of fluoropyrimidine /platinum agents is often considered standard 1st line therapy whilst taxanes have shown activity. We conducted a randomised phase II study to establish a standard of care.

Methods

Eligible pts randomised in 1:1 ratio to CDDP (60 mg/m2, D1q21)/5-FU (1000 mg/m2/24h, D1-4q21) or C (AUC 5, D1q28)/P (80 mg/m2, D1,8,15q28). Stratification factors were performance status (PS), extent of disease, HIV status & country. Primary endpoint was response rate (RR). Based on a RR estimate of 40% in the CDDP/5-FU arm, 80 pts were required to detect 10% difference in RR between the 2 arms with 80% power (phase II selection trial pick the winner design). Secondary endpoints include progression-free survival (PFS), OS, toxicity, quality of life & feasibility.

Results

Between 2014-2017, 91 pts were randomised (46 CDDP/5-FU, 45 CP) from 31/60 centres ;Median age 61 yrs ;Female 67%;12% locally advanced, 88% metastatic. RR :57.1% in CDDP/5-FU and 59.0 % in CP. Median PFS: 5.7 mths for CDDP/FU versus 8.1mths for CP, p=0.375. Median OS 12.3 mths for CDDP/FU versus 20 mths for CP, HR 2.0 p =0.014. Grade ≥3 toxicity occurred in 32 pts (76%) in CDDP/5-FU and 30 pts (71%) in CP. Reported Serious Adverse Events : 62% in CDDP/5-FU and 36% in CP, p=0.016.

Conclusions

InterAACT is the first prospective randomised trial in this setting. In this pick the winner design CP demonstrated similar response rate but less toxicity thus is declared the winner. We have successfully demonstrated the feasibility of international collaboration in a rare cancer. These data establish CP as a standard of care for 1st line treatment of advanced SCCA & serve as a future backbone for the addition of novel agents in phase II/III trials.

Clinical trial identification

NCT02051868

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Proffered paper session - Gastrointestinal tumours, colorectal Proffered Paper session

Invited Discussant LBA20, 452O and LBA21

Lecture Time
10:30 - 10:50
Speakers
  • Claus-Henning Koehne (Oldenburg, DE)
Location
Hall A2 - Room 18, ICM München, Munich, Germany
Date
22.10.2018
Time
09:15 - 11:00