Immunoterapia nel carcinoma mammario metastatico triplo negativo

(1)

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’

(2)

• 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

(3)

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

(4)

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

(5)

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

(6)

• 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

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Phase I and II studies in advanced TNBC

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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%

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OS according to response and treatment line (ATEZO)

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

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Phase I and II studies in advanced TNBC

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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%

(12)

Phase I and II studies in advanced TNBC

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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)

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• 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

(15)

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

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OS according to PD-L1 and TILs (ATEZO)

Emens LA et al, Jama Oncol 2018

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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%]

#

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13%

18%

TMB

_low

TMB

_high

ORR Rate (%)

10%

20%

0%

8%

15%

BCRA- BRCA+

18%

13%

LOH

_low

LOH

_high

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

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

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

PD-L1 IC (% tumor area)

LOH and PDL1 IC ns

TILs PDL1

Molinero L et al, SABCS 2017

Mutational load & Response to Atezolizumab

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• 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

(20)

Chemotherapy as a trigger for immune activation

Modified from Curigliano G, ESMO 2018

(21)

Modified from Curigliano G, ESMO 2018

Chemotherapy and Immune System

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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

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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

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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

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IMpassion130 study design

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Statistical design

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Baseline characteristics

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PFS Analysis

Schmid P et al, ESMO 2018

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OS Analysis

Schmid P et al, ESMO 2018

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Secondary Efficacy Endpoints

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Toxicity

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PFS subgroup analysis: ITT population

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• 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

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• 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

(35)

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

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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

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TOPACIO: Niraparib + Pembrolizumab (n=46)

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

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• 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

(39)

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

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