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Poster Discussion session - Gastrointestinal tumours, colorectal 1

5012 - Negative hyper-selection of RAS wild-type (wt) metastatic colorectal cancer (mCRC) patients randomized to first-line FOLFOX plus panitumumab (Pan) followed by maintenance therapy with either 5FU/LV plus Pan or single-agent Pan: translational analyses of the VALENTINO study

Date

20 Oct 2018

Session

Poster Discussion session - Gastrointestinal tumours, colorectal 1

Presenters

Federica Morano

Authors

F. Morano1, S. Corallo1, M. Di Bartolomeo1, S. Lonardi2, C. Cremolini3, L. Rimassa4, A. Sartore Bianchi5, R. Murialdo6, A. Zaniboni7, V. Adamo8, G. Tomasello9, M. Tampellini10, L. Fanchini11, M. Schirripa2, M. Clavarezza12, F. Petrelli13, R. Longarini14, S. Cinieri15, F.G.M. de Braud16, F. Pietrantonio1

Author affiliations

  • 1 Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 - Milan/IT
  • 2 Medical Oncology, Istituto Oncologico Veneto IRCCS, 35128 - Padova/IT
  • 3 Polo Oncologico, Azienda Ospedaliera Universitaria S.Chiara, 56100 - Pisa/IT
  • 4 Humanitas Cancer Center, Istituto Clinico Humanitas, 20089 - Rozzano/IT
  • 5 Medical Oncology, ASST Grande Ospedale Metropolitano Niguarda, 20162 - Milan/IT
  • 6 Medical Oncology, IRCCS AOU San Martino - IST-Istituto Nazionale per la Ricerca sul Cancro, 16132 - Genova/IT
  • 7 Medical Oncology, Casa di Cura Poliambulanza, 25124 - Brescia/IT
  • 8 Medical Oncology, AOU Policlinico G. Martino Università di Messina, 98125 - Messina/IT
  • 9 Medical Oncology, Istituti Ospitalieri di Cremona, 26100 - Cremona/IT
  • 10 Medical Oncology, A.O.U. San Luigi Gonzaga, 10043 - Orbassano/IT
  • 11 Medical Oncology, P.O. Ospedale Molinette, 10126 - Torino/IT
  • 12 Oncology Unit, Ospedali Galliera, 16128 - Genova/IT
  • 13 Oncology, Azienda Ospedaliera Treviglio-Caravaggio, 24047 - Treviglio/IT
  • 14 Medical Oncology, AO San Gerardo, Monza/IT
  • 15 Medical Oncology, Perrino Hospital, Brindisi/IT
  • 16 Medical Oncology & Haemathology, Istituto Nazionale dei Tumori di Milano - Fondazione IRCCS, 20133 - Milan/IT
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Abstract 5012

Background

RAS wt unresectable mCRC pts were randomized to FOLFOX + Pan (8 cycles) followed by maintenance with Pan (arm B) or Pan + 5FU/LV (arm A). A prespecified translational endpoint was the evaluation of PRESSING panel, that groups rare genomic markers beyond RAS/BRAFto predict anti-EGFR resistance in addition to primary tumor location (PTL) (Cremolini, Ann Oncol ’17).

Methods

Primary endpoint was PFS. A sample size of 224 pts had 90% power to detect 50% 10-month PFS in arm A, max 15% less in arm B, significance level 0.1 (non-inferiority margin of arm B vs A: 1.515). PRESSING panel analyses: ISH for HER2/METamplification, IHC +/- RNA-seq for ALK/ROS/TRKs/RETfusions, NGS (Hotspot Cancer Panel, Ion Torrent®) for HER2/PI3K/PTEN/low % RAS mutations, PCR for MSI.

Results

229 pts randomized (117 arm A/112 arm B). At updated median follow-up of 18 mos, the upper boundary of 1-sided 90% CI of HR was 1.857. 10-m PFS was 49% in arm B vs 59.9% in arm A (HR=1.51 [1.11-2.07]; p=0.009).

A subgroup of 189 RAS/BRAF wt evaluable pts had available tumor tissue for PRESSING analyses, with 46 (24%) PRESSING-pos tumors.

Table 1 shows PFS according to PTL and PRESSING panel, overall and by treatment arm.

Number Median PFS (95% CI), months HR (95% CI) log-rank test p interaction test p
Right- vs left-sided 40 vs 189 7.4 (6.4-9.3) vs 11.2 (10.5-13.2) 1.83 (1.26-2.68) 0.002 -
Right-sided: arm B vs A 21 vs 19 7.0 (4.5-8.9) vs 8.7 (5.9-NE) 2.10 (1.96-4.16) - 0.369
Left-sided: arm B vs A 91 vs 98 10.6 (9.4-12.6) vs 12.9 (10.6-15.3) 1.45 (1.03-2.05) -
PRESSING-positive vs -negative 46 vs 143 7.7 (6.9-10.3) vs 12.1 (10.8-14.2) 2.07 (1.43-2.99) 0.0001 -
PRESSING-positive: arm B vs A 22 vs 24 7.5 (5.5-8.8) vs 11.1 (6.9-14.6) 2.32 (1.12-4.81) -

0.118

PRESSING-negative: arm B vs A 67 vs 76 11.1 (10.6-13.4) vs 13.4 (10.8-18.7) 1.61 (1.07-2.44) -

In post-hoc combined analyses of PTL and PRESSING, right-sided and/or PRESSING-pos tumors were “predicted resistant (R)” (arm B/A: 31/32); left-sided + PRESSING-neg “predicted sensitive (S)” (arm B/A: 58/68). mPFS: 8.1 vs 13.2 mos for predicted R vs S (HR=2.08 [1.47-2.93]; p<0.0001); 7.7 vs 9.9 mos for arm B vs A in predicted R (HR=2.12 [1.16-3.89]), 12.4 vs 14.2 mos for arm B vs A in predicted S (HR=1.54 [0.98-2.40]) (interaction p=0.126).

Conclusions

RAS/BRAFwt, right-sided and/or PRESSING-pos pts receiving maintenance with Pan alone had extremely poor PFS. The PFS benefit of 5FU/LV added to Pan was consistent in all subgroups.

Clinical trial identification

NCT02476045

Editorial Acknowledgement

None

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