Daniele Santini University Campus Bio-Medico Rome, Italy

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1 Daniele Santini University Campus Bio-Medico Rome, Italy

2 Anti EGFR therapy and colorectal cancer Cetuximab or Panitumumab Adapted from Ciardiello F. and Tortora G. NEJM 2008;358:

3 Who will benefit from treatment with antibodies targeting EGFR in mcrcs? Responders (15-20%) Non-Responders Bardelli and Siena, J Clin Oncol 2010

4 Targeted therapies: primary resistance

5 Genetic alterations of the EGFR signalling pathway predict response to cetuximab Moroni et al., Lancet Oncology 2005 Benvenuti et al., Cancer Research Di Nicolantonio et al., J Clin Oncol Sartore-Bianchi A et al., Cancer Res 2009 EGFR HER2 Siena,Di Nicolantonio and Bardelli JNCI 2009 K-Ras Bardelli and Siena J Clin Oncol 2010 De Roock, Martini et al Lancet Oncology 2010 Di Nicolantonio, Arena et al., JCI 2011 De Roock, Di Nicolantonio et al, JAMA 2011 DUSPs Grb2 Shc SOS B-Raf MEK MAPK PI3K PDK PTEN Bertotti et al., Cancer Discovery 2011 AKT GSK Prahallad et al., Nature 2012 Misale et al., Nature 2012 S6K

6 A new type of primary resistance: KRAS amplification Valtorta E et al. IJC, Feb. 2013

7 Targeted therapies: primary resistance Three small Caveat

8 KRAS p.g13d Mutation and OS With Cetuximab in mcrc Percentage Alive Percentage Alive 100 p.g13d Mutation Any cetuximab therapy No cetuximab therapy* Log-rank P < Months Since Randomization or Start of Cetuximab Cetuximab monotherapy No cetuximab therapy Log-rank P = Months Since Randomization or Start of Cetuximab Other KRAS Mutation Log-rank P = Months Since Randomization or Start of Cetuximab Log-rank P >.99 KRAS WT Log-rank P < Months Since Randomization or Start of Cetuximab Log-rank P < Months Since Randomization Months Since Randomization or Start of Cetuximab or Start of Cetuximab *The no-cetuximab group for all patients from the pooled data set is the best supportive care group from the CO.17 trial. Horizontal axis in blue indicates range of time since randomization from 0 though 6 mos. De Roock W, et al. JAMA. 2010;304:

9 CRYSTAL: OS by BRAF Mutation Status Overall Survival (proportion) FOLFIRI BRAF MT (n = 33) Cetuximab + FOLFIRI BRAF MT (n = 26) FOLFIRI BRAF WT (n = 289) Cetuximab + FOLFIRI BRAF WT (n = 277) Time (months) There was no evidence of an independent treatment by tumor BRAF mutation status interaction. Thus, with the current data set, BRAF mutation status cannot be shown to be predictive of treatment effects of cetuximab plus FOLFIRI. Van Cutsem E, et al. J Clin Oncol. 2011;29: Events Median (months) % CI 8.4 to to to to 28.7

10 Cetuximab e Pyrosequencing Direct sequencing analysis and Real-time PCR are commonly used. The detection limit of these two methods is around 20% of the mutation rate Pyrosequencing has recently emerged as a new powerful sequencing methodology for SNP/mutation analysis. The detection limit is less than 20% of the analysed sample. Risk to overscore KRAS mutated patients?

11 Formalin-fixed paraffin-embedded tumor samples from 29 patients with primary CRC k-ras wild type for codon 12/13 were identified. Other main selection criteria were: tumour tissue availability, clinical response (partial or complete response) following cetuximab + irinotecan after progression on prior irinotecan-based therapy Of 29 patients, 3 (10.3%) were identify as K-ras mutant in codon 12 G for 12D mutation by pyrosequencing whereas all of them were reconfirmed k-ras wild type by Real time-pcr. These observations would advice oncologists in considering critically pyrosequencing as routine diagnostic test to mandatory discriminate patients eligible to receive anti-egfr therapy in clinical practice. Santini D et al. J Clin Oncol, 2011

12 Responder (15%) KRAS-NRAS mutated (35-45%) KRAS/PIK3CA mutated BRAF/PIK3CA mutated BRAF mutated (8%) PIK3CA mutated and/or PTEN loss (15-20%) 20-25%? (quadruple negative) Martini et al., Nat Rev Clin Oncology, 2011

13 Targeted therapies: secondary resistance

14 Secondary resistance to EGFR targeted therapies Responders (15-20%) Non-Responders

15 Secondary resistance to EGFR targeted therapies Responders (15-20%) Non-Responders 6-12 months later

16 Emergence of KRAS mutations and acquired resistance to anti EGFR therapy in colorectal cancer Sandra Misale, Sebastijan Hobor R1 + cetuximab + cetuximab + cetuximab DiFi: 350 nm DiFi: 350 nm DiFi: 350 nm Lim1215: 1400 nm Lim1215: 1400 nm Lim1215: 1400 nm + cetuximab + cetuximab + cetuximab R2 DiFi: 3.5 nm Lim1215: 350 nm DiFi: 35 nm Lim1215: 700 nm DiFi: 350 nm Lim1215: 1400 nm R1: Constant dosage R2: Incremental dosage Misale et al., Nature 2012

17 De novo acquisition of KRAS mutations during cetuximab treatment DiFi DiFi R DiFi EGFR DiFi R KRAS Misale et al., Nature 2012

18 De novo acquisition of KRAS mutations during cetuximab treatment DiFi DiFi R2 KRAS Mutations Lim Lim R1 Lim R2 G12R 0% 20% 0% G13D 0.22% 0% 47% Marcello Gambacorta & Salvatore Siena

19 How about patients?

20 KRAS mutations and acquired resistance to anti EGFR targeted therapies in CRC patients With David Solit MSKCC

21 KRAS mutations and acquired resistance to anti EGFR targeted therapies in CRC patients Misale S et al, Nature, 2012

22 KRAS gene alterations mediates acquired resistance to anti-egfr therapy in CRC patients # Total Patients # Patients who develop KRAS mutations/amplification at resistance % Misale et al., % Diaz et al., % KRAS mediated acquired resistance to anti EGFR therapy

23 How to measure acquired resistance? The potential role of KRAS-mutant ctdna Eduardo Vilar & Josep Tabernero Editorial; Nature 2012

24 Diaz & Vogelstein, Nature 2012

25 The potential role of KRAS-mutant ctdna Misale S et al, Nature, 2012

26 A new type of secondary resistance

27 Acquired EGFR ectodomain mutation (S492R) that prevents cetuximab binding and confers resistance to cetuximab A subject with cetuximab resistance harboring the S492R mutation responded to treatment with panitumumab. Montagut C, Nature Med, 2012

28 How to overcome secondary resistance?

29 Cetuximab treatment and rechallenge in irinotecan refractory mcrc Phase II, multicenter, prospective study Eligibility: patients with KRAS wt irinotecan-refractory mcrc Irinotecanbased CT** PD n=39 n=39 Erbitux* + irinotecanbased CT** SD ( 6 m) or PR/CR, then PD SD: n=4 PR: n=29 CR: n=6 CT *** PD Erbitux* + irinotecanbased CT** Treat until PD or tox Median interval between first Erbitux treatment and rechallenge: 6 months (range 2 12 months) Median no. of therapy lines before Erbitux rechallenge: 4 (range 3 7) *Erbitux: Loading dose 400 mg/m 2 followed by weekly infusions of 250 mg/m 2 **Irinotecan-based CT: irinotecan monotherapy or FOLFIRI; during Erbitux treatment irinotecan was administered at 180 mg/m 2 as a 90-minute infusion ***CT: 5-Fluorouracil- or oxaliplatin- or irinotecan-based CT +/ bevacizumab Santini D, et al. Ann Oncol 2012;Mar 5 [Epub ahead of print]

30 Tumor response after Erbitux treatment and rechallenge: Outcomes Clinical outcomes after Erbitux treatment and rechallenge (n=39) % Patients (95% CI) ORR 53.8 ( ) PR 48.7 CR 5.1 SD 35.9 ( ) DCR 89.8 PD 10.2 Median PFS after first Erbitux therapy: 10 months (range 3 30 months) Median PFS after Erbitux rechallenge: 6.6 months (95% CI: ) Median interval between first Erbitux treatment and rechallenge: 6 months (range 2 12 months) Santini D, et al. Ann Oncol 2012;Mar 5 [Epub ahead of print]

31 Erbitux treatment and rechallenge: Potential benefit for some patients Clinical response after first and second Erbitux based therapy (n=39) Best response: First Erbitux Best response: Erbitux rechallenge No. of patients Total no. of patients (%) PR 1 CR CR 1 2 (5) SD 1 PR PR (49) CR 4 SD 3 PR SD (36) CR 1 PR PD 4 4 (10) Santini D, et al. Ann Oncol 2012;Mar 5 [Epub ahead of print]

32 KRAS and cetuximab-driven selection in CRC cells PD PD 1 st line CT + Erbitux 2 nd line CT -Erbitux 3 rd line CT + Erbitux Erbitux-sensitive clone Erbitux-resistant clone Santini D, et al. Ann Oncol 2012;Mar 5 [Epub ahead of print]

33 Tumor response after cetuximab treatment and panitumumab rechallenge: the PANERB STUDY Among the patients who had an OR with cetuximab, 31% also had an OR with panitumumab and 16% were stabilized with panitumumab (clinical benefit 47%). In case of cetuximab resistance, only 14% of the patients had a clinical benefit with panitumumab. The median OS for the patients who achieved a response with both targeted therapies was 25.4 months IC 95% [ ] vs 15.0 months IC 95% [ ] for the patients who did not (p < ). Porneuf m. et al, ESMO, 2012

34 The Rechallenge Trial Phase II, multicenter, prospective, proof of concept study Eligibility: patients with KRAS wt mcrc 1 line 2 line rechallenge Cetuximab based CT (oxaliplatin or CPT-11 or both) SD ( 6 m) or PR/CR, then PD Inclusion in the study PD Window CT * PD cetuximab + CPT-11 Treat until PD or tox PD Study exit Primary objective: to evaluate the activity in terms of response rate according to RECIST 1.1 Secondary objectives: Progression-free survival; Disease control rate; Safety profile; Traslational studies (KRAS mutated ctdna, tissue samples at different time points) *CT: 5-Fluorouracil- and oxaliplatin or CPT-11- CT +/ bevacizumab (window therapy)

35 Cetuximab beyond progression The CAPRI Trial Phase II, multicenter Eligibility: Patients with KRAS wt mcrc 2nd line 1st line Erbitux + FOLFIRI Treat until PD or tox mfolfox4 + Erbitux mfolfox Treat until PD or tox Primary objectives: Of 1st line treatment: PFS time when treated with Erbitux + FOLFIRI Of 2nd line treatment: PFS when treated with Erbitux + FOLFOX after progression of 1st line treatment with Erbitux + FOLFIRI Screen ~600 for KRAS, enroll at least 320 for 1st line, randomize 240 to 2nd line Enrollment for 1 st line completed in July 2012; 80 patients in 2 nd line.

36 Which are the best patients for rechallenge?

37 Only clinical predictive factors KRAS wild type and First line cetuximab containing therapy achieving response or stable disease 6 months and. Progression after a second window therapy line

38 Thank you very much for your attention