Immunoterapia nel carcinoma mammario metastatico triplo negativo

Luisa Carbognin

1

University of Verona, Verona, Italy

2

Division of Gynecologic Oncology, Department of Woman and Child Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy

La Malattia Metastatica – 2° Parte

‘Immunoterapia nel carcinoma

metastatico Triplo Negativo’

• Rational for Immunotherapy in advanced Triple Negative Breast Cancer (TNBC)

• Single Agent anti-PD1/PD-L1Trials

Biomarkers from single agent anti- PD1/PD-L1

• Combination Strategies

Chemotherapy

PARP inhibitors

• Conclusion and Future Directions

Outline

TNBC ER+

(Luminal A)

Mutation rate higher in basal-like and HER2-enriched subtypes compared to other subtypes

Are all cancers equally suitable for immunotherapy?

ER+

(Luminal B)

Banerji S et al, Nature 2012

TILs expression and Mutational Load according to BC subtypes

Higher TILs rates in TNBC Higher Mutational Load in TNBC

Loi S et al, JCO 2013 Luen S et al, Breast 2016

TILs expression as a prognostic marker

Higher TILs rates ad better OS: TIL effect is linear

OS

HR 0.84 0.77-0.92

Loi S et al, SABCS 2015 Loi S et al, JCO 2013; Loi S et al, AO 2014

• Rational for Immunotherapy in advanced Triple Negative Breast Cancer (TNBC)

• Single Agent anti-PD1/PD-L1Trials

Biomarkers from single agent anti- PD1/PD-L1

• Combination Strategies

Chemotherapy

PARP inhibitors

• Conclusion and Future Directions

Outline

Phase I and II studies in advanced TNBC

Phase I studies

• PD-L1 +

• mDOR n.r.

• mPFS 1.9 months

• mOS 11.2 months

• PD-L1 +/-

• mDOR 21 (1L) and 19 months (2L+)

• mPFS 1.4 months

• mOS 8.9 months

Nanda R et al, J Clin Oncol 2016 Emens LA et al, Jama Oncol 2018

ORR%

OS according to response and treatment line (ATEZO)

Emens LA et al, Jama Oncol 2018; Schmid et al, AACR 2017

Phase I and II studies in advanced TNBC

JAVELIN Study

• Phase I

• Avelumab as single agent

• n=168 MBC pts

• PD-L1 +/-

• 1L-4L

• ORR 3% in overall population

• 58 TNBC pts

• 62% PD-L1 + (≥1% IC)

• ORR 5.2%

Phase I and II studies in advanced TNBC

KEYNOTE-086 study

Adams S et al, ASCO 2017; Adams S et al, AACR 2018

*

• Phase II

• 254 TNBC pts

• mOS 16.1 months (Cohort B)

• Rational for Immunotherapy in advanced Triple Negative Breast Cancer (TNBC)

• Single Agent anti-PD1/PD-L1Trials

Biomarkers from single agent anti-PD1/PD-L1

• Combination Strategies

Chemotherapy

PARP inhibitors

• Conclusion and Future Directions

Outline

19%

9%

TIL high¹

Objective Response Rate (%)

10%

20%

30%

0%

6.4%

1.9%

Pembrolizumab

(Cohort A)

Atezolizumab

TIL low

39.1%

8.7%

TIL low TIL high

Pembrolizumab

(Cohort B) 4%

1 ≥ IC 10%; ²</≥ Median (5% in Cohort A and 17.5% in Cohort B)

TIL high² TIL low

TILs and Response to single agent therapy

Emens LA et al, Jama Oncol 2018; Adams S et al, ASCO 2017; Loi S et al, ESMO 2017

TIL positive patients present higher response rate

KEYNOTE-086 study

OS according to PD-L1 and TILs (ATEZO)

Emens LA et al, Jama Oncol 2018

12%

0%

PDL1- PDL1+*

Objective Response Rate (%)

10%

20%

30%

0%

5.7% 4.7%

Pembrolizumab

(Cohort A)

Atezolizumab

*PD-L1+:

baseline PD-L1 expression on ICs ≥ 1%

PDL1- PDL1+

Emens LA et al, Jama Oncol 2018; Adams S et al, ASCO 2017; Loi S et al, ESMO 2017

PD-L1 expression & Response to single agent therapy

PD-L1 expression not good predictive of response

#PD-L1+:

baseline combined

positive score [PD-L1 expression on ICs or TCs ≥ 1%]

#

13%

18%

TMB

TMB

ORR Rate (%)

10%

20%

0%

8%

15%

BCRA- BRCA+

18%

13%

LOH

LOH

0 20 40 60 80

0 5 10 15 20

TILs (% tumor area)

TMB (Mut/Mb)

TMB vs TILs

r = 0.13

p = 0.24 TMB^High

TMB^Low

<14% ≥14%

0 10 20 30 40 50

Genomic Loss of Hetezygosity

TILs (% tumor area)

LOH and TILs ns

0 5 10 15

0 5 10 15 20

TMB vs CD8

CD8 (% tumor center)

TMB (Mut/Mb)

r = 0.10

p = 0.38 TMB^High

TMB^Low

<14% ≥14%

0 2 4 6 8 10

Genomic Loss of Hetezygosity CD8 (% of Tumor Center)

LOH and CD8

0 10 20 30 40 50

0 5 10 15 20

PDL1 IC (% tumor area)

TMB (Mut/Mb)

TMB vs PDL1 IC r = 0.13

p = 0.24 TMB^High

TMB^Low

<14% ≥14%

0 10 20 30 40 50

Genomic Loss of Hetezygosity

PD-L1 IC (% tumor area)

LOH and PDL1 IC ns

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 0

5 10 15 20

TMB (Mutations/Megabase)

Frequency (%)

Distribution of Mutations/Megabase

0 20 40 60 80

0 5 10 15 20

TILs (% tumor area)

TMB (Mut/Mb)

TMB vs TILs r = 0.13

p = 0.24 TMB^High

TMB^Low

<14% ≥14%

0 10 20 30 40 50

Genomic Loss of Hetezygosity

TILs (% tumor area)

LOH and TILs ns

0 5 10 15

0 5 10 15 20

TMB vs CD8

CD8 (% tumor center)

TMB (Mut/Mb)

r = 0.10

p = 0.38 TMB^High

TMB^Low

<14% ≥14%

0 2 4 6 8 10

Genomic Loss of Hetezygosity CD8 (% of Tumor Center)

LOH and CD8

0 10 20 30 40 50

0 5 10 15 20

PDL1 IC (% tumor area)

TMB (Mut/Mb)

TMB vs PDL1 IC r = 0.13

p = 0.24 TMB^High

TMB^Low

<14% ≥14%

0 10 20 30 40 50

Genomic Loss of Hetezygosity

PD-L1 IC (% tumor area)

LOH and PDL1 IC ns

TILs PDL1

Molinero L et al, SABCS 2017

Mutational load & Response to Atezolizumab

• Rational for Immunotherapy in advanced Triple Negative Breast Cancer (TNBC)

• Single Agent anti-PD1/PD-L1Trials

Biomarkers from single agent anti- PD1/PD-L1

• Combination Strategies

Chemotherapy

PARP inhibitors

• Conclusion and Future Directions

Outline

Chemotherapy as a trigger for immune activation

Modified from Curigliano G, ESMO 2018

Modified from Curigliano G, ESMO 2018

Chemotherapy and Immune System

Phase Ib, n=33 PD-L1 +/-

mFU 21.4 months 50% PD-L1 +

ORR 39%

mPFS 5.5 months mOS 14.7 months

Nab-paclitaxel plus Atezolizumab

Pohlmann PR et al, AACR 2018; Adams J et al, JAMA Oncol 2018

OS

Eribulin plus Pembrolizumab (ENHANCE study)

Phase Ib/II, n=107 PD-L1 +/-

ORR 26%

• ORR 1L 29.2%

• ORR 2L+ 22%

mPFS 4.2 months mOS 17.7 months

Tolaney S et al, SABCS 2017

TONIC Trial

ORR

Phase II, n=66

Max 3 lines for MBC; 23% 1L

85% prior anthracyclines (operable); 58% prior platinum (metastatic) Induction  Nivolumab

The doxorubicin cohort as an «immune induction» will be expanded in the stage II of the trial.

Kok M et al, ASCO 2018

IMpassion130 study design

Statistical design

Baseline characteristics

PFS Analysis

Schmid P et al, ESMO 2018

OS Analysis

Schmid P et al, ESMO 2018

Secondary Efficacy Endpoints

Toxicity

PFS subgroup analysis: ITT population

• First Phase III trial demonstrated a benefit with first-line immunotherapy in advanced TNBC

• Atezolizumab + Nab-paclitaxel resulted in statistically significant PFS benefit in ITT (HR=0.80) and PD-L1+ population (HR=0.62)

• At the first interim analysis, OS improvement in PD-L1+ population (mOS 15.5 vs 25.0 months)

• No detrimental effect in PD-L1 negative sub-groups

• The combination was well tolerated Open Question

• Nab-paclitaxel is the optimal chemo backbone?

• Dose of Nab-paclitaxel?

• Formal OS testing in PD-L1+ pts not permitted according to study design

• Duration of atezolizumab (longer=better?)

• Role of Atezolizumab alone?

• BRCA status?

IMpassion130 Conclusions

• Rational for Immunotherapy in advanced Triple Negative Breast Cancer (TNBC)

• Single Agent anti-PD1/PD-L1Trials

Biomarkers from single agent anti- PD1/PD-L1

• Combination Strategies

Chemotherapy

PARP inhibitors

• Conclusion and Future Directions

Outline

Rationale for Parp + Checkpoint Inhibitors

Rationale for combining PARP inhibitors and immune checkpoint inhibitors

Jiao et al, Clin Cancer Res 2017

Accumulating DNA damage has the potential to modify tumor

immunogenicity

Phase II

Basket study gBRCAmut HER2 neg MBC (n=25)

MEDIOLA study

Domcheck et al, SABCS 2017

12/25 (48%) DCR at 7 months

Median DOR/PFS/OS not yet reached

Response independent of HR status and BRCA mutation type

TOPACIO: Niraparib + Pembrolizumab (n=46)

Presented By Kevin Kalinsky at 2018 ASCO Annual Meeting ORR: 28% all; 60% tBRCAmut, 36% PD-L1+

• Rational for Immunotherapy in advanced Triple Negative Breast Cancer (TNBC)

• Single Agent anti-PD1/PD-L1Trials

Biomarkers from single agent anti- PD1/PD-L1

• Combination Strategies

Chemotherapy

PARP inhibitors

• Conclusion and Future Directions

Outline

Single-agent anti-PD-L1/PD1

• Durable response

• Better response in earlier lines of therapy

• Well tolerated

• Biomarkers not good predictive of response Combination of CT and anti-PD-L1/PD1

• First promising results from combination IO + CT for 1 ^st line PD-L1+ advanced TNBC (IMpassion130 study)

• Well tolerated

• Ongoing phase III in metastatic, neoadjuvant and adjuvant studies

Combination of PARPi and anti-PD-L1/PD1

• Further evaluation (small cohort with heterogenous population) and maturity of data in BRCAmut HER2- are needed

Conclusions-1

Biomarkers:

• Optimize patients selection

• Higher evidence for TILs than PD-L1 status as a predictive biomarker of response

• Advanced TNBC presents ‘low’ TILs levels

• Need to increase host anti-tumor immunity

• How to define and best to test PD-L1 positive population?

• Mutational load is not predictive of response

• MSI? MSI-H less than 2%

• Gut microbiome? Ongoing studies in BC

Conclusions-2

Title of the slide

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