Biomarkers for HER2-directed Therapies : Past Failures and Future Perspectives

Transcription

1 Biomarkers for HER2-directed Therapies : Past Failures and Future Perspectives Ian Krop Dana-Farber Cancer Institute Harvard Medical School Inchon 2018

2 Adjuvant Trastuzumab Improves Outcomes in HER2+ Breast Cancer (N9831 and NSABP B-31) Perez E A et al. JCO 2014;32:

3 Why do we need predictive biomarkers? Identify patients whose cancer is likely to be particularly sensitive to targeted therapy (and can be spared chemotherapy) Identify patients who are not likely to do well on standard HER2-directed therapy Rationally select between multiple second-generation anti-her2 agents Provide potential insight into potential mechanisms of resistance

4 TAILORx: chemotherapy not needed in patients with very low Oncotype RS Secondary Group RS <11 Assigned to Hormonal Therapy Only Distant Relapse Free Survival Invasive Disease Free Survival 5 Year Results 99.3% 93.8% Overall Survival 98.0% Adapted from: Sparano JA et al. NEJM 2015

5 Why do we need predictive biomarkers? Identify patients whose cancer is likely to be particularly sensitive to targeted therapy (and can be spared chemotherapy) Identify patients who are not likely to do well on standard HER2-directed therapy Rationally select between multiple second-generation anti-her2 agents Provide potential insight into potential mechanisms of resistance

6 Why do we need predictive biomarkers? Identify patients whose cancer is likely to be particularly sensitive to targeted therapy (and can be spared chemotherapy) Identify patients who are not likely to do well on standard HER2-directed therapy Rationally select between multiple second-generation anti-her2 agents Provide insight into potential mechanisms of resistance

7 HER2 signaling pathway (simplified) HER2 PI3K AKT Proliferation Adapted from Gluck, Clin Breast Cancer 2016

8 HER2 as a biomarker?

9 CALGB 9840: (paclitaxel ± trastuzumab): No benefit to trastuzumab in HER2-negative MBC Seidman et al, JCO 2008, 26,

10 B-47 Adjuvant Trastuzumab in Patients with Normal/Low HER2 Expression Breast Cancer N=3260 High Risk Primary Breast Cancer IHC 1+ or 2+ for HER2 FISH Negative (and HER2 copy number<4) Randomization Anthracycline/taxane chemotherapy Anthracycline/taxane chemotherapy +Trastuzumab x 1 yr

11 % Disease-Free San Antonio Breast Cancer Symposium, December 5-9, 2017 B-47: Invasive Disease-Free Survival ChemoRx ChemoRx+Trast HR 0.98 (95% CI ) P=0.90 Treatment N Events 5 year EFS % % No. at Risk ChemoRx ChemoRx+Trast Time Since Randomization (months) This presentation is the intellectual property of the presenter. Contact them at Lou.Fehrenbacher@kp.org for permission to reprint and/or distribute

12 Level of HER2 amplification associated with pcr in TAXHER01 and GETNA01 studies LA: low amplification (mean, 6-10 signals) HA: high amplification (mean, >10 signals/nuclei) Arnould et al, Clin Cancer Res 2007;13(21)

13 Level of HER2 mrna and protein associated with pcr in TRYPHAENA (Chemo + trastuzumab+pertuzumab; All arms pooled) *Biomarkers high vs. low with cut point at median value Schneeweiss et al. Breast Cancer Research 2014, 16:R73

14 HER2 FISH ratios are not associated with trastuzumab benefit (DFS) in NCCTG N9831 HER2/ CEP17 n HR 95% CI P NSABP-B-31: no significant association between HER2 copy number and benefit (P = 0.60) Perez et al. JCO 28:

15 HER2 FISH ratios are not associated with trastuzumab benefit (DFS) in HERA Dowsett et al. JCO 27:

16 Very high HER2 protein expression not associated with trastuzumab benefit (DFS) in FinHer Very high HER2 protein ( log H2T 2.1)* Moderate HER2 protein ( log H2T <2.1) *Log H2T =2.1 HER2 protein expression is 22-fold the median of HER2-negative cancers Joensuu et al. Annals of Oncology 22:

17 HER2 FISH ratios are not associated with trastuzumab benefit (DFS) in NCCTG N9831 HER2/ CEP17 n HR 95% CI P NSABP-B-31: no significant association between HER2 copy number and benefit (P = 0.60) Perez et al. JCO 28:

18 HER2 FISH ratios are not associated with trastuzumab benefit (DFS) in HERA Dowsett et al. JCO 27:

19 Baselga SABCS 20129; Cleopatra: Prognostic effects independent of treatment arm (both arms pooled)

20 Baselga SABCS 20129; Cleopatra: Prognostic effects independent of treatment arm (both arms pooled)

21 Biomarkers to predict benefit of T-DM1: Improved outcomes with high HER2 mrna levels Krop et al ASCO 2009, Burris, et al. JCO. 2011;

22 TH3RESA (T-DM1 vs Treatment of Physicians Choice): Increased Benefit of T-DM1 in Cancers with HER2 mrna Level? a Hazard ratios are based on unstratified analyses. Kim et al, Int. J. Cancer: 139, (2016

23 Proportion progression-free EMILIA Biomarker Analysis: PFS by HER2 mrna Level and Treatment Arm HER2 median mrna conc. ratio = 13.3 n Lap + Cap Median (months) n T-DM1 Median (months) Hazard ratio a 95% CI Median > Median No. at risk: Lap + Cap ( Median) Lap + Cap (> Median) T-DM1 ( Median) T-DM1 (> Median) Time (months) Lap + Cap ( Median) Lap + Cap (> Median) T-DM1 ( Median) T-DM1 (> Median) a Hazard ratios are based on unstratified analyses.

24 HER2 as biomarker HER2 levels (mrna, FISH, protein) are associated with higher pcr in neoadjuvant trials HER2 levels do not predict benefit of adjuvant trastuzumab Very high HER2 levels may predict be associated with resistance to adjuvant trastuzumab Needs further validation HER2 mrna levels are associated with response to T- DM1 in MBC

25 HER2 signaling pathway (simplified) HER2 PI3K AKT Proliferation Adapted from Gluck, Clin Breast Cancer 2016

26 PIK3CA mutations within HER2+ disease All patients N=1,324 23% HR+ 24% PIK3CA_MUT PIK3CA_WT HR- 22% TCGA Nature 2012; Ferrari et al. Nat Com 2015; Loibl et al. (adapted Annals Oncol from2016 A Prat SABCS 2016)

27 PIK3CA mutations are associated with reduced pcr rates in pooled analysis of neoadjuvant studies Loibl et al, Annals of Oncology 27: , 2016

28 PI3-KINASE

29 Alterations in the PI3K/PTEN pathway are not associated with resistance to trastuzumab in NSABP B-31 (8 year DFS) WT Hazard ratio: 0.51 MT Hazard ratio: 0.44 PTEN loss had no influence on trastuzumab benefit in N9831 Pogue et al, JCO 33:

30

31

32 Proportion surviving EMILIA Biomarker Analysis: OS by PIK3CA Mutation Status and Treatment Arm 1.0 Lap + Cap T-DM1 PIK3CA mutation status n Median (months) n Median (months) Hazard ratio a 95% CI Mutated NE Wild type NE No. at risk: Lap + Cap (Mutated) Lap + Cap (Wild type) T-DM1 (Mutated) T-DM1 (Wild type) a Hazard ratios are based on unstratified analyses NE, not estimable. Lap + Cap (PIK3CA mutated) Lap + Cap (PIK3CA wild type) T-DM1 (PIK3CA mutated) T-DM1 (PIK3CA wild type) Time (months)

33 TH3RESA Biomarker Analysis: PFS by PIK3CA mutation status and Treatment Arm a Hazard ratios are based on unstratified analyses. Kim et al, Int. J. Cancer: 139, (2016

34 PI3-kinase as biomarker Mutations in PIK3CA are associated with lower pcr across many in neoadjuvant trials of HER2-directed therapy PIK3CA mutations or PTEN loss do not predict benefit of adjuvant trastuzumab PIK3CA mutations do not predict benefit of T-DM1 or pertuzumab in HER2+ MBC

35 HER2 signaling pathway (simplified) HER2 PI3K AKT Proliferation Adapted from Gluck, Clin Breast Cancer 2016

36 HER2 signaling pathway: cross-talk with ER Estradiol HER2 PI3K ER P mtor AKT ER S6K ER ER Proliferation Adapted from Gluck, Clin Breast Cancer 2016

37 San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6 10, 2011 Hormone receptor status and pcr in NeoSphere pcr, % 95% CI 70 p= p= ER or PR positive ER and PR negative TH THP HP TP ER, estrogen receptor; PR, progesterone receptor Gianni L, et al. Lancet Oncol 2011 DOI: /S (11) H, trastuzumab; P, pertuzumab; T, docetaxel (study dosing: q3w x 4 cycles) Copyrights for this presentation are held by the author/presenter. Contact them at gianni.luca@hsr.it for permission to reprint and/or distribute

38 Effect of Hormone Receptor expression on trastuzumab benefit in B-31/N9831 Perez et al, JCO 22:

39 Effect of Hormone Receptor expression on trastuzumab benefit in BCIRG-006 Slamon D, N Engl J Med 2011;365:

40 Effect of Hormone Receptor expression and HER2 copy number on trastuzumab benefit in HERA Loi et al JAMA Oncol. 2016;2(8):1040

41 Nonlinear interaction between expression levels of ESR1 and ERBB2 and trastuzumab benefit in NSABP B-31. Green = high trastuzumab benefit (HR 0.28) Brown = moderate benefit (HR 0.60) Red = no benefit (HR 1.58) Pogue-Geile K L et al. JNCI J Natl Cancer Inst 2013;105:

42 APHINITY: Trial Design Presented By Gunter Von Minckwitz at 2017 ASCO Annual Meeting

43 Presented By Gunter Von Minckwitz at 2017 ASCO Annual Meeting

44 1:1 randomization 2-year follow-up for idfs 5-year follow-up for idfs 5 + year survival Neratinib Extended Study Design Part A Part B Part C HER2+ breast cancer (local) Prior adjuvant trastuzumab & chemotherapy Lymph node /+ or residual invasive disease after neoadjuvant therapy ER/PR + or Neratinib x 1 year 240mg/day Placebo x 1 year Primary endpoint: invasive disease-free survival (idfs) Secondary endpoints: DFS-DCIS, time to distant recurrence, distant DFS, CNS metastases, overall survival, safety Other analyses: biomarkers, health outcome assessment (FACT-B, EQ-5d) Stratified by: nodes 0, 1 3 vs 4+, ER/PR status, concurrent vs sequential trastuzumab

45 Disease-free survival (%) Primary Endpoint: Invasive DFS (ITT) % 95.6% 93.9% 91.6% P-value = HR (95% CI) = 0.67 ( ) Neratinib Placebo Months after randomization No. at risk Neratinib Placebo Chan et al, Lancet Oncology 2016

46 Disease-free survival (%) idfs centrally-confirmed HER2 positive & HR+ idfs centrally-confirmed HR+ and HER2+ (ITT) % 97.0% % 88.4% 8.6% ER-positive: HR (95% CI) = 0.25 ( ) ER-negative: HR (95% CI) = 0.96 ( HR+ and centrally confirmed HER2 positive 60 Events: Neratinib vs Placebo (10 vs 41) Events: Neratinib vs Placebo (23 vs 22) HR+: estrogen and/or progesterone positive 50 Neratinib Placebo Months after randomization No. at risk Neratinib Placebo Adapted from A Chan et al, ASCO Breast 2015

47 Estrogen receptor as biomarker ER+ HER2+ breast cancers have markedly lower rates of pcr than ER-negative HER2+ cancer ER status alone does NOT predict benefit of adjuvant trastuzumab or pertuzumab In cancers with lower levels of HER2 expression and high ER expression, there are some data to suggest lower benefit of trastuzumab Needs validation ER status may predict benefit of neratinib

48 Intrinsic subtype as a biomarker?

49 171 Protein/phospho- Protein Expression Intrinsic subtypes: HER2-enriched by PAM50 Among the different subtypes, the HER2-E is characterized by the highest expression of HER2/EGFR proteins and phospho(p)-her2/p-egfr. Thus, HER2+/HER2-E disease is likely to have the highest activation of the HER2/EGFR pathway. TCGA Nature 2012; N=403 Groups based on Protein Expression Protein Expression TCGA Nature 2012 TCGA Nature 2012 Adapted from A Prat SABCS 2016

50 pcr rate in the breast pcr rate in the breast HER2 enriched subtype has highest rate of pcr in HER2+ cancers treated with neoadjuvant anti- HER2-based chemotherapy 100% NeoALTTO (n=254) Fumagalli et al. JAMA Oncol % CALGB40601 (n=262) Carey et al. J Clin Oncol % 60% 40% 20% 0% 80% 60% 40% 20% 0% 59.4% HER2-E vs. 29.3% Others; p< % HER2-E vs. 36.8% Basal-like; p=0.011 Adapted from A Prat SABCS 2016

51 Intrinsic subtype does not predict trastuzumab benefit in NSABP-B31 HER2 Enriched Basel Luminal A Luminal B Pogue-Geile et al. JCO 33:

52 Intrinsic subtype does not predict trastuzumab benefit in NCCTG-N31 HER2 Enriched Luminal A/B Basel trastuzumab trastuzumab No trastuzumab No trastuzumab No trastuzumab trastuzumab Pogue-Geile et al. JCO 33:

53 Immune activation as a biomarker?

54 Tumor-infiltrating Lymphocytes are associated with pcr in cancers treated with HER2-directed therapy pcr rate NeoALTTO (n=387) Salgado et al. JAMA Oncol 2015 NeoSphere (n=243) Bianchini et al. Annals Oncol 2015 Adapted from A Prat SABCS 2016

55 CALGB 40601: Immune cell signatures are associated with pcr after treatment with HER2-directed therapy 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% P<0.001 IgG Signature High (n=109) Int (n=76) Low (n=80) 66% 61% 62% 53% 50% 39% 40% 39% 31% 24% 25% 17% Overall THL TH TL Activity of 5 immune signatures tested: B-cell T-cell CD8 T-cell IgG HER2+ immune cell All significantly associated with pcr Carey et al, ASCO 2014

56 Loi et al, ASCO 2012 Tumor infiltrating lymphocytes predict trastuzumab benefit in the FinHER trial Lymphocyte Predominant Breast Cancer Phenotype (LPBC) >50% infiltration

57 % RFS NCCTG-N31: No benefit of trastuzumab seen in lymphocyte predominant (LPBC) cancers ( 60% TILS) LPBC (N=94) non-lpbc (N=851) Chemo Chemo+trastu zumab Chemo+trastu zumab Chemo Log Rank = 0.22 Log Rank < Years from Randomization Perez et al, SABCS 2014 Abstract S1-06

58 Immune signature predicts benefit of adjuvant trastuzumab in N9831 Not immune signature enriched Immune signature enriched Interaction term P <.001 Perez E et al. JCO :701

59 This presentation is the intellectual property of the author/presenter. Contact him at for permission to reprint and/or distribute. San Antonio Breast Cancer Symposium, December 5-9, 2017 Immune signature predicts benefit of the addition of lapatinib IgG Low IgG High Krop et al SABCS 2017

60 Summary Predictive biomarkers to allow tailoring HER2-directed therapy to the appropriate patients are needed Multiple biomarkers are associated with rates of pcr in HER2+ cancers treated with HER2-directed therapy HER2 levels (mrna, FISH, protein); Higher pcr PI3-kinase (PIK3CA) mutation; Lower pcr ER positivity; Lower pcr HER2 enriched subtype; Higher pcr However, none of these biomarkers predict benefit of trastuzumab in adjuvant setting 60

61 What explains the difference in biomarker effects between the adjuvant and neoadjuvant settings? In most cases, all patients in neoadjuvant trials received at least one HER2-directed agent Thus generally evaluating prognostic effects of marker, not predictive effect 61

62 What explains the difference in biomarker effects between the adjuvant and neoadjuvant settings? Concurrent endocrine therapy in adjuvant setting Treatment effects on micrometastatic disease may differ from that of the primary cancer Different tumor microenvironment Immunomodulatory effects may differ in location and timeframe 62

63 Summary (2) Markers of immune activation (TILS and immune signatures) are associated with higher rates of pcr These immune markers also are associated with increased benefit from trastuzumab Perez data from N9831 is exception If further validated, immune activation markers could identify patients who are candidates for de-escalation approaches. 63

64 Thank You