Carcinoma del polmone

(1)

Aggiornamenti in oncologia tra ricerca e clinica:

Carcinoma del polmone

Francesco Grossi

UOS Tumori Polmonari

Azienda Ospedaliera Universitaria San Martino IST Istituto Nazionale per la Ricerca sul Cancro

Genova

Convegno Interregionale AIOM Lombardia, Liguria, Piemonte e Valle D’Aosta

Coniugare innovazione, sostenibilità e continuità di cura in oncologia: il ruolo delle Reti regionali Milano, 19 Novembre 2016

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Treatment strategies in advanced NSCLC in 2016

Patients w/o driver mutation

Patients with driver mutation Chemotherapy

Chemotherapy +Biological

Targeted therapy

Immunotherapy

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Patients w/o driver mutation

Patients with driver mutation Chemotherapy

Immunotherapy

Treatment strategies in advanced

NSCLC in 2016

(4)

1990-2000: chemotherapy oriented research in NSCLC

Grossi F, The Oncologist 2010

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JMDB: OS in non-squamous &

squamous patients

Scagliotti G, JCO 2008

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PARAMOUNT: PFS from

randomization and from induction

Paz-Ares L, Lancet Oncology 2013

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E4599: pre-planned OS analysis in adenocarcinoma subgroup

Sandler A, JTO 2010 & NEJM 2006

(8)

Squire: primary outcome OS

Thatcher N, Lancet Oncol 2015

(9)

REVEL: Randomized phase III of doc +/- ramucirumab in 2 ^nd line NSCLC

Primary endpoint:

OS HR 0.86 (p=.023) Median OS 10.5 vs 9.1m

PFS HR 0.76 (p<.001) Median PFS 4.5 vs 3.0m

Garon EB, Lancet Oncology 2014

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Lume-Lung 1: significant OS benefit in pts with adenocarcinoma histology

Reck M, Lancet Oncol 2014

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NICE guidance on necitumumab, ramucirumab and nintedanib

On Sept 28, 2016, the National Institute for Health and Care Excellence (NICE) published guidance not recommending necitumumab in combination with

gemcitabine and cisplatin for untreated advanced or metastatic EGFR-expressing, squamous non-small-cell lung cancer (NSCLC).

NICE technology appraisal guidance TA412.

On Aug 24, 2016, the NICE published guidance not recommending ramucirumab in combination with docetaxel for the treatment of locally advanced or metastatic non-small-cell lung cancer (NSCLC) in adults whose disease has progressed after platinum-based chemotherapy.

NICE Technology appraisal guidanceTA403

On July 22, 2015, the National Institute for Health and Care Excellence (NICE) published guidance recommending nintedanib for previously treated locally

advanced, metastatic, or locally recurrent non-small-cell lung cancer, providing the company (Boehringer Ingelheim, Bracknell, UK) offers nintedanib with the

discount agreed in the patient access scheme.

NICE Technology appraisal guidanceTA347

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Necitumumab in metastatic squamous cell Lung Cancer:

Establishing a value-based cost

Evaluation of the incremental cost-effectiveness ratios (ICERs) for the use of necitumumab across a range of values for its cost. Model robustness was assessed by probabilistic sensitivity analyses, based on 10 000 Monte Carlo simulations, sampling values from the distributions of all model parameters.

The probabilistic sensitivity analyses established that when necitumumab cost less than $563 and less than $1309 per cycle, there was 90% confidence that the ICER for adding necitumumab would be less than $100 000 per QALY and less than $200 000 per QALY, respectively.

These findings provide a value-based range for the cost of necitumumab from

$563 to $1309 per cycle.

This study provides a framework for establishing value-based pricing for new oncology drugs entering the US marketplace.

Goldstein DA, Jama Oncology 2015

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Treatment strategies in advanced NSCLC in 2016

Immunotherapy

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NSCLC evolution: from single disease to many molecularly defined subsets

Li T, J Clin Oncol. 2013 NSCLC

as 1 disease

Histology-Based Subtyping

Squamous 34%

Other 11%

Adenoca 55%

Adenocarcinoma

Squamous Cell Cancer

ALK HER2 BRAF PIK3CA AKT1 MAP2K1 NRAS ROS1 RET EGFR KRAS Unknown

EGFRvIII PI3KCA EGFR DDR2

FGFR1 Amp Unknown

First-targeted tx ALK

EGFR

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Targeted therapy for adenocarcinoma

Tsao AS, J Thorac Oncol. 2016

EGFR Other 4%

MET 3%

> 1 Mutation 3%

ROS1 2%

BRAF 2%

RET 2%

NTRK1 1%

PIK3CA 1%

MEK1 < 1%

HER2 2%

EGFR Sensitizing

 Gefitinib⁴

 Erlotinib⁴

 Afatinib⁴

 Osimertinib⁴

 Necitumumab⁴

 Rociletinib³

MET

 Crizotinib²

 Cabozantinib² ALK

 Crizotinib⁴

 Alectinib⁴

 Ceritinib⁴

 Lorlatinib²

 Brigatinib²

Key 1. Phase I

2. Phase II

3. Phase III 4. Approved

HER2

 Trastuzumab emtansine²

 Afatinib²

 Dacomitinib²

ROS1

 Crizotinib⁴

 Cabozantinib²

 Ceritinib²

 Lorlatinib²

 DS-6051b¹ BRAF

 Vemurafenib²

 Dabrafenib² RET

 Cabozantinib²

 Alectinib²

 Apatinib²

 Vandetanib²

 Ponatinib²

 Lenvatinib² KRAS

25%

Unknown Oncogenic

Driver 31%

EGFR Sensitizing

17%

ALK 7%

NTRK1

 Entrectinib²

 LOXO-101²

 Cabozantinib²

 DS-6051b¹ MEK1

 Trametinib²

 Selumetinib³

 Cobimetinib¹ PIK3CA

 LY3023414²

 PQR 309¹

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Benefit of first-line EGFR TKIs:

9 randomized phase III studies

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PFS and OS in EGFR mutated pts treated with EGFR TKIs inhibitors

Lin JJ, JTO 2016

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Resistance to EGFR TKI

Regardless of extent of initial response, resistance to TKI develops invariably due to

T790 mutation (~ 50% to 60%) HER 2 mutation (8%-12%)

MET amplification (~ 5% to 20%) Conversion to SCLC (< 5%)

EGFR mutated tumors might progress rapidly upon withdrawal of TKI

Role of continuation of TKI beyond progression is under evaluation

Afatinib, AZ9291, CO1686, HM-61713 targets T790 mutation

EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor.

Sequist LV, et al. Sci Transl Med. 2011;3(75):75ra26 2011.

Pao W, et al. PLoS Med. 2005;2(3):e73.

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AURA (AZD9291): best % change in target-lesion size and PFS

Janne PA, NEJM 2015

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Crizotinib superior to standard chemotherapy

Pfizer 1014: Crizotinib vs. Platinum/Pemetrexed

ORR: Crizotinib 74% vs. Chemo 45%

Mok T, ASCO 2014; Shaw AT, NEJM 2013

Pfizer 1007: Crizotinib vs. Chemotherapy

1^st Line therapy 2nd Line therapy

ORR: Crizotinib 65% vs. Chemo 20%

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Excellent tumor response seen with multiple next generation ALK inhibitors

ceritinib alectinib brigatinib

56% 55% 61%

(22)

Crizotinib in ROS-1 positive NSCLC:

best response and PFS

Shaw AT, NEJM 2014 RR=72%

PFS= 19.2 mos

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BRF113928: Responses With Dabrafenib +Trametinib

Planchard D, Lancet Oncology 2016

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Elenco Centri validati al Controllo di Qualità Nazionale per l'espressione di

ALK in IHC nel carcinoma polmonare

Lombardia= 9 (Milano 6, Pavia, Lecco, Varese) Piemonte e Valle d’Aosta= 4 (Torino 3, Aosta) Liguria= 1 (Genova)

Fonte: AIOM-SIAPEC

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Treatment strategies in advanced NSCLC in 2016

Immunotherapy

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CheckMate 017 and 057 in second- line in unselected patients: design

Brahmer J, NEJM 2015; Borghaei H , NEJM 2015

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CheckMate 017 and 057 in second- line in unselected patients: OS

Borghaei H, ASCO 2016

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CheckMate 017 and 057: OS by PD-L1 expression

Spigel DR , ASCO 2015; Horn L , ECCO/ESMO 2015

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Landmark OS in PD-L1 non-expressors (<1%)

 The majority of patients with no PD-L1 expression are alive at month 3

 OS HR and separation of curves favoring nivolumab are observed in the landmark analysis Randomized Subjects with

PD-L1 Expression <1%

Randomized Subjects with

PD-L1 Expression <1% Alive at Month 3

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0

0 3 6 9 12 15 18 21 24 27

Overall Survival (Months)

Probability of Survival

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0

0 3 6 9 12 15 18 21 24 27

Overall Survival (Months)

Probability of Survival Nivolumab

Docetaxel

Borghaei H, NEJM 2015; Assessment report EMA/246304/2016

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Keynote-010 and OAK in second-line selected/unselected patients: design

Herbst RS, Lancet 2015; Barlesi F, ESMO 2016

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Keynote-010 and OAK in second-line selected or unselected patients

Herbst RS, Lancet 2015; Barlesi F, ESMO 2016

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Relationship between PD-L1 expression and outcome in the Keynote 010 and OAK

Bass P, ASCO 2016;

Barlesi F, ESMO 2016

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KEYNOTE 024 and CheckMate 026:

study design

Reck M, ESMO 2016

Socinski MA, ESMO 2016

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KEYNOTE 024 and CheckMate 026:

Progression-free survival

Reck M, NEJM 2016 Socinski MA, ESMO 2016

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KEYNOTE 024 and CheckMate 026:

Overall survival

Reck M, NEJM 2016 Socinski MA, ESMO 2016

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Candidate predictive PD-L1antibodies

PD-L1 Drug and Vendor

Nivolumab BMS

Pembrolizumab Merck

Atezolizumab Roche

Durvalumab AstraZeneca

Clone and Source

28-8 Abcam

22c3 Dako

SP142 Spring Bio

SP263 Spring Bio IVD Class III

partner

Dako Dako Ventana Ventana

Scoring Method % cells with membrane staining at any intensity

% cells with membrane staining at any intensity

TC =Tumor cell IC= Immune cell Combine both percentage and subjective

intensity

% cells with membrane staining at any intensity

Thresholds 1%, 5%, or 10% >1%

1-49%

>50%

TC3 =TC>50%

IC3 = IC>10%

TC2/IC2 = TC or IC >5%

TC1/IC1 = TC or IC >1%

>25%

Method Pathologist/

Subjective

Pathologist/

Subjective

Pathologist/

Subjective

Pathologist/

Subjective

Rimm DL, WCLC 2015

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MPDL3280A Phase Ia: Response by smoking and mutational status

aORR includes investigator-assessed u/c PR by RECIST 1.1. Patients first dosed at 1-20 mg/kg by Oct 1, 2012. Data cutoff: Apr 30, 2013.

Former / Current Smokers

Never Smokers

Response by Smoking Status (ORR^a) Smoking Status (NSCLC; n = 53)

Pts With PR, %

EGFR Mutant

EGFR Status (NSCLC; n = 53)

Unknown

Response by EGFR Status (ORR^a)

Pts With PR, %

KRAS Status (NSCLC; n = 53) Response by KRAS Status (ORR^a)

Pts With PR, %

KRAS Mutant Unknown

11/43 1/10

9/40 1/6

8/27 1/10

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Slide 3

Spigel DR, ASCO 2016

High versus low TMB according

to molecular alterations

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Potential characteristics of immunogenic and nonimmunogenic tumors

Evaluation of tumor tissues may reveal an immunogenic tumor microenvironment consisting of many immunologic markers, including CD8 T cells, CD4 T cells, PD-L1, granzyme B, and CD45 RO, which may be effectively treated with immune checkpoint therapy to elicit clinical benefit.

Tumor tissues that lack expression of many immunologic markers may indicate a

nonimmunogenic tumor microenvironment, which may require combination therapies consisting of an agent to create an

immunogenic tumor microenvironment plus an immune checkpoint agent to further

enhance the immune response for clinical benefit

Sharma P, Science

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Potential mechanisms of action to mediate synergistic effects of combined therapies

Melero I, Nat Rev Cancer 2015

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Challenges

Pardoll DM, Nature Rev Cancer 2012

Which combination and sequence?

Scientific rationale is lacking With or without chemotherapy Which combination of

checkpoint inhibitor

Sequencing duration of treatment Patient selection → biomarker

Differences per tumor location

Differences within a tumor location

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Examples of phase III anti-PD1/PD-L1

combination trials in 1 ^st -line advanced NSCLC

(43)

Anti CTLA-4+anti PD-1/L1 or CT+ PD-1/L1

Hellmann MD, ASCO 2016;

Antonia S, Lancet Oncol 2016 Langer CJ, Lancet Oncol 2016

(44)

Timeline of key therapeutic advances for advanced-stage disease in predominant

histological subgroups of lung cancer

Tan WL ,

Lancet Oncol 2016

(45)

Immunotherapy vs Targeted therapy vs Chemotherapy

Sharma P, Cell 2015

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Carcinoma del polmone

Aggiornamenti in oncologia tra ricerca e clinica: