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ESMO PRECEPTORSHIP ON
Adjuvant/Neo-adjuvant chemotherapy (and more)
for resected NSCLC
Professor Silvia Novello
University of Turin
20 November 2019
silvia.novello@unito.it
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)
Neoadjuvant cisplatin-basedchemotherapy
MediastinalRadiotherapy (N2) Surgery
+/-
+/-
+/-
Walking on the knife blade
Neoadjuvant treatment Adjuvant treatment
Walking on the knife blade
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
Walking on the knife blade: Adjuvant treatment
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
Walking on the knife blade: Adjuvant treatment
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
Walking on the knife blade: Adjuvant treatment
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
Walking on the knife blade: Adjuvant treatment
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
Walking on the knife blade: Adjuvant treatment
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
Walking on the knife blade: Adjuvant treatment
There is still room for improvement:
• Predictive/Prognostic biomarkers
• Targeted therapies
• Immunotherapy
Walking on the knife blade: Adjuvant treatment
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
Walking on the knife blade: Adjuvant treatment
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
Walking on the knife blade: Adjuvant treatment
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
Walking on the knife blade: Adjuvant treatment
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
Walking on the knife blade: Adjuvant treatment
There is still room for improvement:
• Predictive/Prognostic biomarkers
• Targeted therapies
• Immunotherapy
Walking on the knife blade: Adjuvant treatment
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
Walking on the knife blade: Adjuvant treatment
Room for improvement: Targeted therapies
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.
Walking on the knife blade: Adjuvant treatment
Room for improvement: Targeted therapies
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
Walking on the knife blade: Adjuvant treatment
Room for improvement: Targeted therapies
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%
Walking on the knife blade: Adjuvant treatment
Room for improvement: Targeted therapies
Any pending questions?
Which TKI?
In which stages?
Treatment duration? Toxicities?
Costs?
Which patients?
Ongoing studies: ADAURA
Walking on the knife blade: Adjuvant treatment
Room for improvement: Targeted therapies
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
Walking on the knife blade: Adjuvant treatment
Room for improvement: Targeted therapies
• Primary endpoint: OS• Secondary endpoint: DFS, safety
Other adjuvant target therapies trials
Walking on the knife blade: Adjuvant treatment
Room for improvement: Targeted therapies
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
Walking on the knife blade: Adjuvant treatment
There is still room for improvement:
• Predictive/Prognostic biomarkers
• Targeted therapies
• Immunotherapy
Walking on the knife blade: Adjuvant treatment
Room for improvement: Immunotherapy
Walking on the knife blade
Neoadjuvant treatment Adjuvant treatment
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
Walking on the knife blade: Neoadjuvant treatment
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
Walking on the knife blade: Neoadjuvant treatment
• 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..
Walking on the knife blade: Neoadjuvant treatment
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)
Walking on the knife blade: Neoadjuvant treatment
Moving forward: immunotherapy
Walking on the knife blade: Neoadjuvant treatment
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%
Walking on the knife blade: Neoadjuvant treatment
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
• Single Immune Checkpoint Blockade- Nivolumab- Atezolizumab (LCMC3)
• Dual Immune Checkpoint Blockade- Nivolumab + Ipilimumab (NEOSTAR)
• Immune Checkpoint Blockade + Chemotherapy- Nivolumab + Chemotherapy (NADIM)
Walking on the knife blade: Neoadjuvant treatment
Moving forward: immunotherapy
Walking on the knife blade: Neoadjuvant treatment
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
• Single Immune Checkpoint Blockade- Nivolumab- Atezolizumab (LCMC3)
• Dual Immune Checkpoint Blockade- Nivolumab + Ipilimumab (NEOSTAR)
• Immune Checkpoint Blockade + Chemotherapy- Nivolumab + Chemotherapy (NADIM)
Walking on the knife blade: Neoadjuvant treatment
Moving forward: immunotherapy
Walking on the knife blade: Neoadjuvant treatment
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.
Walking on the knife blade: Neoadjuvant treatment
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
• Single Immune Checkpoint Blockade- Nivolumab- Atezolizumab (LCMC3)
• Dual Immune Checkpoint Blockade- Nivolumab + Ipilimumab (NEOSTAR)
• Immune Checkpoint Blockade + Chemotherapy- Nivolumab + Chemotherapy (NADIM)
Walking on the knife blade: Neoadjuvant treatment
Moving forward: immunotherapy
Walking on the knife blade: Neoadjuvant treatment
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
Walking on the knife blade: Neoadjuvant treatment
Moving forward: immunotherapy
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
Neoadjuvant cisplatin-basedchemotherapy
SurgeryMediastinal
Radiotherapy (N2)
Surgery Adjuvant cisplatin-basedchemotherapy
MediastinalRadiotherapy (N2)
Neoadjuvant cisplatin-basedchemotherapy
MediastinalRadiotherapy (N2) Surgery
+/-
+/-
+/-
Walking on the knife blade
Neoadjuvant treatment Adjuvant treatment
Target therapy
Chemo + IOIO + IO
Immunotherapy
Immunotherapy
Biomarkers
Patients’selection
Target therapy + CHT
New study designs
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