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Adjuvant/Neo-adjuvant chemotherapy (and more)

for resected NSCLC

Professor Silvia Novello

University of Turin

20 November 2019

[email protected]

DISCLOSURES

◆ Advisor/Speaker Bureau: Eli Lilly, Bayer, Astra Zeneca, Roche, BMS, MSD, BI, Pfizer, Takeda, Celgene

Lung cancer remains the leading cause of cancer incidence and mortality:

• 2.1 million new lung cancer cases

• 1.8 million deaths

• 1 in 5 (18.4%) cancer deaths

Overall survival by pathologic stage according to the eighth edition

Goldstraw P, JTO 2016GLOBOCAN 2018

• 5yr-OS 90% to 41% post-resection

• Significant fall in OS for stage IB-IIIA

Walking on the knife blade

…..we can do better

Globocan 2018

Stage ISurgery

*Adjuvant ChT should be discussed in resected stage IB patients with primary tumour >4 cm [II, B].

Radiotherapy

Stage IISurgery

Radiotherapy

Adjuvant cisplatin-basedchemotherapy

Stage III AIf resectableand operable

Neoadjuvant cisplatin-basedchemotherapy

SurgeryMediastinal

Radiotherapy (N2)

SurgeryAdjuvant cisplatin-based

chemotherapyMediastinal

Radiotherapy (N2)


MediastinalRadiotherapy (N2) Surgery

+/-

+/-

+/-


Neoadjuvant treatment Adjuvant treatment



Benefit of adjuvant platinum-doublet chemotherapy

Pignon, JCO 2008

Walking on the knife blade: Adjuvant treatment

5 trials – 4584 patientsOS HR 0.89 [0.82-0.96], p= 0.0055% OS benefit at 5 years

Overall Survival

LACELung Adjuvant Cisplatin Evaluation


JBR.10Within stage IB benefit if > 4 cm

(A) Survival comparison for stage IB patients with primary tumor less than 4 cm by treatment arm. (B) Survival comparison for stage IB patients with primary tumor 4 cm or greater by treatment arm.

Butts, JCO 2010

Benefit of adjuvant platinum-doublet chemotherapy


Wakelee – Lancet Oncol 2017

E1505 phase III trial

Resected IB (>/= 4cm)-IIIA

N=1501 (7/07-9/13)

Chemotherapyx 4 cycles*

Chemotherapyx 4 cycles* and Bevacizumab

x 1 yearPrimary endpoint: OS

Stratification: Cisplatin doublet, stage, histology, sex

No DFS (HR 0.99) nor OS (HR 0.99) benefit with BVZ addition regardless of histology

OS by chemo +/- Bev: Non-Squamous


E1505 phase III trial

Significant positive improvement in DFS + OS with bev added to pemetrexed

H. Wakelee, WCLC 2019

Further evaluation of bevacizumab with adjuvant cisplatin/pemetrexedcould be considered in subsets of patients but E1505 was overall negative

and subsets must be interpreted with caution


JIPANG study: Randomized Phase III Study of Pem/Cis vs Vnr/Cis for completely resected stage II-IIIA non-squamous NSCLC

M Tsuboi, ESMO 2019


JIPANG study: EGFRmpts

M Tsuboi, ESMO 2019

Cisplatin doublets standar of care

Adjuvant therapy: what guide lines say..

• Adjuvant ChT should be offered to patients with resected stageII and III NSCLC [I, A] and can be considered in patients withresected stage IB disease and a primary tumour >4 cm [II, B].

• Pre-existing comorbidity, time from surgery and postoperative recovery need to be taken into account in this decision taken in a multidisciplinary tumour board [V, A].

Patient’s selection

• For adjuvant ChT, a two-drug combination with cisplatin is preferable [I, A].

Limited data to supportthe substitution of cis

for carbo

Adj CHT improves survival

Postmus P, 2017

Cisplatin-vinorelbinthe most studied in randomized trials

those who die within 5 years whether they receive chemotherapy or not

those who live without receiving chemotherapy

those who live because of chemotherapy

Pisters, JCO 2007

Benefit of adjuvant platinum-doublet chemotherapy…

those who die because of chemotherapy

…there is still room for improvement…

Despite the use of adjuvant chemotherapy, nearly a third of patients with stage I NSCLC and at least 30% to 50% of patients with stage II and III NSCLC will still die from recurrent disease

Estimated absolute risk and benefit for 100 patients with NSCLC


There is still room for improvement:

• Predictive/Prognostic biomarkers

• Targeted therapies

• Immunotherapy


Room for improvementSCAT AdjTrial

• Majority of reccurrences were single site• No differences in overall reccurrence rate among experimental

customized adjuvant therapy• Bone(37.5%) and brain(34%) metastases were the most frequent

metastatic sites• Brain metastases risk was significantly lower for patients with high

BRCA1 expression treated with single agent Docetaxel

Low BRCA1 expression levels were associated with better OS

B Massouti et al, ESMO 2019

Control = investigators’choice of cisplatin-based doubletTrial was amended with the new Staging System (7 th) on December 2010

Novello S et al, WCLC 2015


Room for improvement

P reliminary R es ults of the International Tailored C hemotherapy Adjuvant Trial: the ITAC A Trial – Silvia Novello

AE Tailored: n=143 Control: n=142 p *

Grade >0 3-5 >0 3-5

Anemia 11.9 0.7 26.8 2.1 <.001

Neutropenia 13.3 7.7 25.4 16.9 .004

Thrombocytopenia 0.0 0.0 21.8 8.5 <.001

Nausea/Vomiting 14.0 0.0 31.7 4.9 <.001

Cardiac 0.7 0.0 5.6 0.7 .042

GI 24.5 0.7 44.4 5.6 <.001

Infections 8.4 1.4 16.2 5.6 .049

SAE leading todiscontinuation

15.7 34.1 .001

Major Adverse Events According to Treatment – Profile 1 (N= 285)

* p value for difference in distribution of SAE grade by treatment

CTONG 1104-ADJUVANT ph III TRIAL in EGFR+ pts


Room for improvement: predictive biomarkers

Background

• Adjuvant TKI: An optimal choice for EGFR-mutated stage II-IIIANSCLC patients from ADJUVANT trial .

• Beneficial Variety: 40% patients treated with gefitinib in ADJUVANT trial experienced disease recurrence within 2yrs

• Tumor Heterogeneity: Predictive markers other than EGFR+ ?

Zhong WZ et al.Lancet Oncol 2018

UPDATE on CTONG 1104-ADJUVANT trial


Room for improvement: predictive biomarkers

Predictive BiomarkersGene-by-Treatment Analysis

• Five predictive biomarkers identified: TP53, NKX2-1, CDK4, MYC & RB1

• RB1mutation or copy number loss was the only predictor in favor of chemotherapy.

Yi-Long Wu et al, ESMO 2019

UPDATE on CTONG 1104-ADJUVANT TRIAL

MEDUSA Model Predicts Treatment Benefits

Yi-Long Wu et al, ESMO 2019





• Immunotherapy


Room for improvement: Targeted therapies

Adj gefitinib in unselected NSCLC patients: JBR.19

Goss GD，et,al. J Clin Oncol.2013

Unselected for EGFR mut+

• Stage IB-III NSCLC• Complete surgical resection• PS 0-2• Adjuvant chemo and/or RT allowed

R

N=503Gefitinib 250 mg x 2 years

Placebo x 2 years

EGFR-mut (15 patients)All patients (503 patients)

Walking on the knife blade: Adjuvant treatmentRoom for improvement: Targeted therapies

Kelly K, et al. J Clin Oncol.2015

Adjuvant erlotinib: RADIANT

Unselected for EGFR mut+Selected for EGFR expression by IHC and/or FISH

Stage IB-IIIA Surgery CHT x4 /No CHT

R

Erlotinib

Placebo

DFS in the ITT population (973 patients) DFS in EGFR-mut (161 patients)

The EGFR-mutant subset results not statisticallysignificant due to the

hierarchical design

SELECT: 2-years adj erlotinib in EGFR-mut patients (after standard adj chemo+/- RT)

Non-randomized prospective trial100 surgically-resected stage I-IIIA patients harboring EGFR mutation



Pennell NA et al. J Clin Oncol. 2019

- improved 2-year DFS compared with historic genotype-matched controls.

- Recurrences were rare - Pts rechallenged with erlotinib after recurrence

experienced durable benefit.



Pem/carbo +/- gefitinib in resected stage IIIA-N2 harboring EGFR-mut: phase II randomized study

• 60 patients; primary endpoint DFS• DFS longer in gefitinib arm (HR 0.37; 0.16-0.85; p 0.014)• 2-yr OS, 92.4% in the gefitinib arm and 77.4% in control arm (HR 0.37; 0.12-1.11; p 0.76)

Li N. Ann Surg Onc, 2014



Raphael J, Am J ClinOncol 2019 May

Forest plot for 2-year DFS in patients harboring an EGFR mutation.

Adjuvant Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (TKIs) in Resected Non–Small Cell Lung Cancer (NSCLC): A Systematic Review and Meta-analysis

- No OS improvement

N= 1860

- adjuvant TKIs decreased the risk of disease recurrence by 48%



Any pending questions?

Which TKI?

In which stages?

Treatment duration? Toxicities?

Costs?

Which patients?

Ongoing studies: ADAURA



A phase III Study of Osimertinib versus Placebo for EGFR-Mutation Positive Stage IB-IIIA NSCLC after complete tumor resectionwith or without adjuvant chemotherapy

• Primary endpoint: disease free survival• Secondary key endpoints: overall survival and quality of life

Frequency EGFRmut stage IB–IIIA NSCLC after complete tumour resection

M Tsuboi et al; ESMO 2019

Ongoing studies: ALCHEMISTAdjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial



• Primary endpoint: OS• Secondary endpoint: DFS, safety

Other adjuvant target therapies trials



Trial Agent (s) Phase Setting N° of pts

Primaryendpoint

EVIDENCE Icotinib vs standard chemo

III Stage II-IIIA post surgery, with EGFR mutation

320 DFS

ICWIP Icotinib vs placebo

III Stage II-IIIA post-surgery post chemo, with EGFR mutation

124 DFS

ICTAN 6 vs 12 monthsicotinib vs chemoalone

III Stage II-IIIA post-surgery with EGFR mutation

318 DFS

RCTACSCNSCLC Gefitinib vs chemo

III Stage II-IIIA post-surgery and chemo, with EGFR mutation

48 DFS

ALINA Alectinib vs chemo

III Stage IB-IIIA post surgery 255 DFS





• Immunotherapy


Room for improvement: Immunotherapy



Walking on the knife blade: Neoadjuvant treatment

Effect of preoperative chemotherapy on survival

Pre-OP CT in operable NSCLC: results of a systematic review and meta-analysis of individual patient data: 15 trials, 2385 patients, 1427 deaths

Burdett , Lancet 2014

• significant benefit ofpreoperative chemotherapy onsurvival (HR: 0·87) with a 13%reduction in the relative risk ofdeath

• absolute survival improvementof 5% at 5 years

• no clear evidence of adifference in the effect onsurvival by chemo, scheduling,N of drugs, platinum agentused, postoperative RT y/n


NATCH Trial

Clinical stageI A (> 2 cm), IB, II, T3N1Stratify by: - Tumor size (<3, 3-5, or >5 cm)- Age (< 60 or > 60 y)

R

Surgery

Paclitaxel/Carboplatin→ Surgery

Surgery→ Paclitaxel/Carboplatin

In this trial, in which the treatment decision was made before surgery, more patients were able to receive preoperative than adjuvant treatment (97 vs 66%, p< 0.0001).

Felip, JCO 2010

No statistically significant

differences in disease-free

survival.

CT compliance

PREOP CT ARM (N= 199)• 193 (97%) of patients started the planned chemotherapy• 180 patients (90.4%) completed all three planned

chemotherapy cycles• 9.3% had dose reductions at some point, and 11.4%

required one dose delay or more.

ADJ CT ARM (N= 210)• 139 pts (66.2%) started the planned chemotherapy• 128 patients (60.9%) received the planned three

chemotherapy cycles• 10.8% had at least one dose reduction, and 15.8%

required one dose delay or more.

• Surgical delays or complications

• Risk of progression on therapy

• No validated predictive endpoints

• No survival advantage over adjuvant therapy


• Earlier treatment of micrometastatic disease

• In vivo assessment of treatment response

• Identification of surrogate endpoints for OS or PFS

• Shorter time frame to completion of clinical trials

• Better tolerability of systemic therapy and increased compliance

• Identification of cohort of patients most likely to benefit from surgical resection

DisadvantagesAdvantages

What guide lines say..


Treatment of early stages (stages I and II)

In view of the equivalence of neoadjuvant and adjuvant ChT for OS, the consistent results and broad evidence base support adjuvant ChT as the timing of

choice [II, C].

(Neo)adjuvant anti-PD(L)-1 checkpoint inhibitors are currently being evaluated in addition to current

standard of care.

Treatment of Resectable LA-NSCLC

For curative-intent management, patients should be able to undergo platinum-based ChT (preferably

cisplatin) [I, A].

(Neo)adjuvant anti PD(L)-1 checkpoint inhibitors are currently being evaluated in addition to current standard

of care.

Postmus, 2017 …moving forward

• Single Immune Checkpoint Blockade- Nivolumab- Atezolizumab (LCMC3)

• Dual Immune Checkpoint Blockade- Nivolumab + Ipilimumab (NEOSTAR)

• Immune Checkpoint Blockade + Chemotherapy- Nivolumab + Chemotherapy (NADIM)


Moving forward: immunotherapy


Moving forward: neoadjuvantIO—>PD-1 Blockade

Neoadjuvant nivolumab in resectable stage I-IIIA NSCLC

Forde, N Engl J Med, 2018

Feasibility: Nivolumab prior to lung cancer resection did not delay surgery in any of the treated patients. Safety: Only 1 ≥ grade 3 AE1 postoperative death, unrelated to study drug

Any Grade 23%


Neoadjuvant nivolumab in resectable stage I-IIIA NSCLC

• 45% of resected tumors demonstrated a major patologic response post-nivolumab, 13% CR (3 pts)

• Responses occurred in both PD-L1–positive/negative tumors

Forde, N Engl J Med, 2018

• Direct evidence for induction of tumor neo-antigen-specific T cells• Clinical follow-up encouraging, but larger trials necessary

• Pathologic response correlated with mutational burden

Moving forward: neoadjuvantIO—>PD-1 Blockade







Moving forward: PDL-1 Blockade

LCMC3 is a phase II study of atezolizumab in stage IB, II, IIIA or selected IIIB resectable and untreated NSCLC (NCT02927301; N=180)

Primary endpointMPR at surgical resection

LCMC3

Kwiatkowski, et al. 2019 ASCO

Walking on the knife blade: Neoadjuvant treatmentMoving forward: immunotherapy

LCMC 3 Study (update): Neoadjuvant Atezolizumab

The 12-month DFS was 89%; in the 39 patients with stage III disease, 12-month DFS was 87%

Oezkan et al, WCLC 2019

Preliminary biomarker data

• Expansion of subsets of NK cells and granulocytes in peripheral blood in patients with MPR after treatment with neoadjuvant atezolizumab

• Expansion of subsets of dendritic cells and granulocytes in peripheral blood in patients who developed irAEs after treatment with neoadjuvant atezolizumab

• Increased frequencies of dendritic cell and B cell subsets in surgical lymph nodes of patients with MPR

• Differential frequencies of various T cell subsets in surgical lymph nodes of patients with MPR







Moving forward: Dual Immune Checkpoint Blockade

NEOSTAR: a phase II study of induction checkpoint blockade for untreated stage I-IIIA NSCLC amenable for surgical resection

Primary endpoint• MPR rate in patients treated with neoadjuvant Nivolumab(N) and Nivolumab+Ipilimumab(NI)

CasconeT, et al. 2019 ASCO.


Pre-specified trial efficacyboundary: ≥ 6 MPRs

NEOSTAR: MPR rate

Cascone. et al., J Thorac Oncol 2019

• Following three cycles of neoadjuvant ICIs 89% of patientsunderwent complete R0 resection

• Five marginally operable patients who didn’t proceed toresection, and one perioperative mortality highlight theimportance of cautious patient selection for neoadjuvantICIs.

NEOSTAR study: surgical outcomes

Boris Sepesi, WCLC 2019

Moving forward: Dual Immune Checkpoint Blockade







Moving forward: chemoimmunotherapy

NADIM ph II study: neo-adjuvant chemo/immunotherapy for the treatment of resectable stage IIIA NSCLC

Mariano Provencio, ASCO 2019

A phase II, single-arm, open-label multicenter study of resectablestage IIIA-N2 NSCLC with chemotherapy + nivolumabfollowed by adjuvant treatment for 1 year



NADIM study: neo-adjuvant chemo/immunotherapy for the treatment of resectable stage IIIA NSCLC

Mariano Provencio, WCLC 2019

• Neoadjuvant CT-IO with nivolumab in stage IIIA yields a complete

pathologic response rate that is higher than ever seen previously.

Pathologic response N=41 % (CI 95%)

Major Pathological Response (MPR)

Complete Response (CR)

34/41

24/41

83 (68-93)

59 (42-74)

> 10% residual viable tumor 7/41 17 (7-32)

PROGRESSION FREE SURVIVAL (ITT)

025

5075

100

46 46 44 43 18 5Number at risk

0 3 6 12 18 24Time from inclusion (months)

OVERALL SURVIVAL (ITT)

025

5075

100

46 46 46 44 20 5Number at risk

0 3 6 12 18 24Time from inclusion (months)

• The 18 m PFS >80% is also promising and may translate into increased

overall survival (>90% at 18 m)

• No new or unexpected safety signals were observed in the neoadjuvant or adjuvant phase of the trial

• A new randomized phase II clinical trial (NADIM-2) comparing the same neo-adjuvant Nivolumab + CT schema followed by a shorter adjuvant Nivolumab monotherapy of 6 months vs. standard CT is currently ongoing

PFS at 12 months: 96% (95% CI: 84; 99)PFS at 18 months: 81% (95% CI: 61; 91)

Overall Survival at 12 months: 98% (95% CI: 85; 100)Overall Survival at 18 months: 91% (95% CI: 73; 97)

Stage ISurgery

*Adjuvant ChT should be discussed in resected stage IB patients with primary tumour >4 cm [II, B].

Radiotherapy

Stage IISurgery

Radiotherapy

Adjuvant cisplatin-basedchemotherapy

Stage III AIf resectableand operable


SurgeryMediastinal

Radiotherapy (N2)

Surgery Adjuvant cisplatin-basedchemotherapy

MediastinalRadiotherapy (N2)


MediastinalRadiotherapy (N2) Surgery

+/-

+/-

+/-



Target therapy

Chemo + IOIO + IO

Immunotherapy

Immunotherapy

Biomarkers

Patients’selection

Target therapy + CHT

New study designs

Documents

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