Novel molecular target

therapies for NSCLC

Genetic Targets
Imunotherapy
Lung Cancer Classification
• 4 Major histologic types
• Adenocarcinoma 50%
• Squamous cell carcinoma 25%
• Large cell carcinoma 10%
• SCLC 15%
Optimal Treatment for NSCLC
• Amenable to Surgical resection 20%
• Not amenable to Surgical resection 80%
• Standard of Care treatment (Cisplatin or Carboplatin + non-platinum) -
doublet therapy
• OS of less than 2 years

• All form of chemotherapy is targeted therapy

• Topotecan – topoisomerase I
• Cis – cross links DNA bases

• Can the OS be improved?

The Cancer Genome Atlas (TCGA) project in 2005
Molecular biomarkers
• Prognostic biomarkers/measure of aggressiveness
• Low ERCC1 expression correlates with increased sensitivity to platinum-based
therapy and high ERCC1 expression correlates with better overall prognosis in
NSCLC (N Engl J Med. 2006 Sep 7; 355(10):983-91.)
• Predictive biomarkers
• EGFR
Imalumib, the magic bullet
Cancer a genetic driven disease
• Nowell and Hungerford
• Out of a wide array of mutations a dominant oncogene determines survival of
tumor cell
• Imalumib, a TKI of ABL used in BCR-ABL Philadelphia chromosome = “magic
bullet” for CML
Classifying some receptors
Tyrosine kinase R • Check point inhibitors
• EGFR epidermal GF-R • PD-1
• HER2 • PDL1
• MET
• KRAS
• BRAF
• Endothelial receptors
• VEGF vascular endothelial
• GFFGFR fibroblast GF-R
• ALK anaplastic lymphoma kinase
• PDGFR platelet derived GF-R
• ROS
• RET
Biologically distinct subtypes of Lung Cancer
Molecular diagnosis and systemic treatment
targets
• Oncogene alterations
• Gefitinib, Erlotinib, Afatinib (EGFR mutated NSCLC)
• Osimertinib (T790M positive after treatment with EGFR TKI)
• Crizotinib, Alectinib ( ALK TKI for NSCLC) but also for ROS1 )approved by FDA and EMA)
• Ceritinib ( ALK – rearranged after treatment with crizotinib)
• Evasion from Immunity (immune check point inhibitors)
• Nivolumab PD-1
• Pembrolizumab PD1
• Atezolizumab PDL1
• Angiogenesis (Bleeding in squamous cell carcinoma 30% grade 3 hemoptysis but not in non
squamous - only non squamous are eligible)
• Bevacizumab (VEGF) E4599 by ECOG phase III showed OS advantage of Bevacizumab + CT
• Ramucirumab (VEGFR-2) REVEL phase III trial showed Ramucirumab + DOC OS advantage for all histological
types
• Nintedanib ( VEGFR-1,2,3 FGFR 1,2,3, PDGFR alpha, beta) used worldwide for IPF reducing by 50% annual
decline in lung function also used in NSCLC LUME phse 3
The Epidermal GF-R
• 28 exons for EGFR gene
• Exon 18-24 code for
intracellular TK domain
including the ATP binding
pocket comprising 8 aa:
• T790 to C797 where 90% of
mutations occur
• Del in exon 19@ L747 or
@R748,or @ E749 or @ A
are called Del LREA
• Point mutations exon 21
affects L858R substitution
• C terminus has 5 tyrosine
resudues for
autophosphyrylation which
result don downstream
signaling
EGFR TKI’s no response in scuamous histology
(responders were female East Asian non smokers with ADK)
Reversible first generation inhibitors Irreversible inhibitors covalently bind
bind at ATP binding at C797
• Gefitinib (Iressa) • Afatinib
• Erlotinib (Tarceva) • Osimertinib
EGFR TKI’s phase 3 trials: good ORR, PFS but not
OS and all eventually lead to PD
• IPASS (IRESSA Pan-Asia Study) for advanced ADK in non-smoking East
Asians J Clin Oncol. 2010;29:2866–74.
• Carboplatin + paclitaxel vs gef
• ORR 71% for EGFR mutation only 1% in EGFR neg
• NEJ002 N Engl J Med. 2010;362:2380–8, Ann Oncol. 2013;24:54–9
• Carboplatin + Paclitaxel vs gef n 114
• ORR 30 vs 73%
• PFS 5.4M vs 10.8
• Os 26.6 VS 27.7M
EGFR TKI’s phase 3 trials: good ORR, PFS but not
OS and all eventually lead to PD
• WJTOG3405 Lancet Oncol. 2010;11:121–8.
• Cicplatin + Docetaxel vs gef n 86
• ORR 32.2% VS 62.1%
• PFS 6.3m vs 9.2m
• OS 37.3m vs 34.8m
• OPTIMAL Lancet Oncol. 2011;12:735–42, Ann Oncol. 2015;26:1877–83
• Carboplatin + genticabine vs erlotinib
• ORR 36% vs 83%
• PFS 4.6m VS 13.7m
• OS 27.2m vs 22.8m
EGFR TKI’s phase 3 trials: good ORR, PFS but not
OS and all eventually lead to PD
• EURTAC Lancet Oncol. 2012;13:239–46.
• Ciisplatin + Docetaxel/ Cisplatin + Gemcitabine vs Erlotinib n 87
• ORR 14.9% vs 58.1%
• PFS 5.2m vs 9.7m
• OS 19.6m vs 22.9m
• ENSURE Ann Oncol. 2015;26:1883–9.
• CISPLATIN + Gencitabine vs Erlotinib n 110
• ORR 33.6% vs 62.7%
• PFS 5.5m vs 11m
• OS 22.5m vs 26.3m
EGFR TKI’s phase 3 trials: good ORR, PFS but not
OS and all eventually lead to PD after 10-14m
• LUX lung 3 Lancet Oncol. 2015;16:141–51.
• Cisplatin + pemetrexed vs afatibin n230
• ORR 23% vs 56%
• PFS 6.9m vs 11.14m
• OS 28.2m vs 28.2m
• LUX lung 6 Lancet Oncol. 2014;15:213–22.
• Cisplatin + Gemcitabine vs Afatinib n 242
• ORR 23% vs 66.9%
• PFS 5.6m vs 11.0m
• OS 23.5m vs 23.1m
• LUX lung 7 Lancet Oncol. 2016;17:577–89, Ann Oncol. 2016
• Gefitinib vs Afatinib
• ORR 56% vs 70%
• PFS 10.9m vs 11m
• OS 24.5m vs 27.9m
• LUX lung 8 Lancet Oncology 2015
• Erlotinib vs Afatinib n183 stage IIIB or IV with PD after 4 cycles of platinum
Acquired resistance of EGFR-TKI’s
• Target alterations by EGFR gene mutation
• Gene amplification
• Epigenetic changes influencing
• Uptake
• Metabolism
• Export of drugs
• Bypass signaling pathways such as MET
• Phenotype changes to SCLC or epithelial-mesenchymal transition (EMT)

• E.g.:
• T790M gatekeeper, overcome by Afatinib, Osimertinib
Osimertinib – mutation specific or first line
therapy?
• Inhibits mutated EGFR (dLREA or L858R) with or without T790M by
covalently binding to C797

• AURA phase 3 trial

• Cispalting or Carboplatin + Pemetrexed vs Osimertinib in T790M in patients
with PD after first line TKI’s
• PFS 4.4m vs 10.1m
• RE-biopsy to determine type of mechanism responsible for PD!
• FLORA trial – compared first line Osimertinib
• Improvement OS as first line therapy and lower toxicity and also goon CNS
penetration
ALK rearrangements TKI’s
• Accounting for only 3-6% of NSCLC
• ALK expression plays a role in CNS development and is restricted to
CNS
• ALK gene may fuse to another gene resulting in chromosomal
translocations
• Npm1-ALK translocation causeing anaplastic large cell lymphoma
• EML4-ALK translocation found most commonly in NSCLC
• Hyperactive kinase activity
• Non smokers ADK
• KIF5B-ALK, KCL1-ALK translocation identified
• Usually identified using FISH, RT PCR, or IHC using anti-ALK Ab D5F3 or D5A4
Crizotinib (Xalkori) inhibits MET, ALK and
ROS1
• PROFILE 1007 phase 3
• Cis/pemetrexate vs crizotinib n171 ALK + virgin NSCLC
• PFS 7m vs 10.9m
• ORR 45% vs 75%
• PROFILE 1014 PHASE 3
• DOCetaxel or Pemetrexed vs crizo n 173 ALK + progressive disease after one
platinum based chemotherapy
• PFS 3m vs 7.7m
• OS 22.8m vs 20.3m
• J-ALEX phse 3
• Crizo vs Alectinib n 103 in ALK + virgin NSCLC
• ORR 70% vs 85.4%
Despite dramatic response rates, most develop
disease within 1 year due to acquired mechanisms
of resistance (Nat Rev Clin Oncol. 2014;11:473–81)
• New generation ALK-TKI’s for patients who still progress after
crizotinib!
• Ceritinib
• Alectinib much better brain penetration than crizo
• Brigatinib
• ALEX trial – Peters S et. Al NEJM 377:829 2017
• Alectinib vs Crizotinib as first line therapy
• Improved OS
• Improved PFS
• Improved CNS penetration
• Lorlatinib – investigational
Other oncogenetic alterations in 1-2%
• ROS1 rearrangement in never smokers 1-2% of all NSLC
• Crizotininib ORR 80%, Duration of response 18mo then resistance
• Ceritinib has not been aproved
• RET arranged tumour
• Vandetanib
• LOXO-292 demonstrated an overall response rate of 74% and a favorable safety profile
(Oxnard et al., 2018).
• BRAF in smokers 1-2% of all NSCLC
• Dabrafenib
• TRAMETINIB + DABRAFENIB FDA approved for V600E BRAF mutation
• MET exon 14
• Dabrafenib
• Epotinib demonstrate modest anti-tumor activity in MET exon 14-skipping Drilon et al., 2018;
Felip et al., 2018
Cancer Immunity – the use of immune system to
treat cancer
• Steps:
• 1. neo antigens presented to APC’s
• 2. presentation of processed neo-angtigens
to MHC class II and II molecules by APC’s to
T cells
• 3. activation of effector T cells cytotoxic T
cells CTL’s
• 4. binding to cancer cells by CTL’s through
TCR and its antigen on MHC class I
• 5. Killing of target cancer cell

• Cancer cells utilize proteins such as PDL1 to

evade immunity
• Immune checkpoint molecules
• CTLA-4 (CD152) acts at priming cTcell
activation
• PD-1 (CD 279) inhibits immune attack by cTcell
Cancer within the lung can lead to Tcell
inactivation
• Chang S, Lin X, Higashikubo R, et al. Unique pulmonary antigen
presentation may call for an alternative approach toward lung cancer
• immunotherapy. Oncoimmunology 2013;2:e23563.
PDL1 is also a ligand expressed by the tumor
to evade immunity by binding on the T cell
PD
CTLA-4 and PDL1 are tumor antigens which
downregulate immune response
• Check point inhibitors
• PD-1 is a regulator of Tcell activation and interacts with PDL1 which is
expressed by NSCLC
• NIVOLUMAB targets PD-1 for PDL-1 positive tumors
• PEMBROLIZUMAB
• mpdl3280A
• Atezolizumab
• Reverse tumor mediated immunosuppression
• IPILIMUMAB blocks CTLA-4 – extend OS in melanoma and is a phase II trial in NSCLC
• Naïve stage IIIB and IV or recurrent disease randomized to carboplatin and paclitaxel
alone or together with ipilimumab resulting PFS increase
Nivolumab CheckMate trials – phase 3 trials
previously treated NSCLC but had PD @1y
• CheckMate 017 for scuamous n137
• DOCetaxel vs nivolumab
• ORR 9% vs 20%
• OS improval
• CheckMate 057 for non-scuamous n 292
• DOC vs nivolumab
• Study also evaluated expression of PDL-1 by IHC and correlated response rate

• Improve OS
• No significance of PDL1
• As biomarker
Pembro Keynote trials phase 1/2/3 trials for
NSCLC
• Keynote001 phase 1
• Pembrolizumab and PDL1 – benefit only in more than 50%
expression
• Keynote 010 phse 2/3
• DOC vs pembro when PS>1%
• OS 8.5 vs 10.4m but 14m when strong responders PS more than 50%
• Keynote 024 phse 3 Previously untreated NSCLC
(virgin)first line treatment PS>50%
• Chemo vs Pembro
• Improved OS,
• Recommendation: first line treatment for advanced NSCLC without
EGFR or ALK but strong PDL-1
• Pembro better than chemo
• Keynote 021
• Pembro + chemo as first line option for non squamous regardless of
PS%
• Keynote I89 Ghandi et al, NEJM 2018
• Chemo + Pembro superior to chemo alone
• ORR 19% vs 48%
• PFS 8.8mo vs 4.9mo
• OS@1 y 49% vs 69%
Keynote I89 Ghandi et al, NEJM 2018
• Chemo + Pembro superior to chemo alone
• ORR 19% vs 48%
• PFS 8.8mo vs 4.9mo
• OS@1 y 49% vs 69%
Atezolizumab OAK trial, POPLAR trial
OAK TRIAL phase 3 longer OS for previously
treated NSCLC regardless of PDL1 but better
response in PDL1 expressors
POPLAR TRIAL cmplared DOC and
Atezolizumab in previously treated NSCLC
• Better OS with atezolizumab
with higher PDL1 expression
• Increased ORR in PDL1
expression
PACIFIC trial – resectable stage IIIA dz
• Phase III RCT unresectable NSCLC stage III who have not progressed
following definitive platinum based concurrent chemoradiation
therapy n713
• Durvalumab monotherapy vs placebo after chemoradiotherapy in
unresectable dz
• Superior PFS and OS
• HR 30% improvement with immunotherapy in contrast with trimodality where PFS is ony
improved by 14%

• Engl J Med 2017;377:1919-29

Immunotherapy and Surgery (resectable N2)
• Role of Neo-adjuvant chemo-immunotherapy for IIIA N2 followed by
surgery
• SAK16/14 phase II Durvalumab (anti PDL1)/chemo before surgery
• 65% PFS
• NADIM phase II Nivolumab followed by surgery
• 100% at 12months PFS
Immunotherapy for solid organ cancers
Innate Immunity against Lung Cancer
• NK cells – evolved to recognize patterns of stress receptors in viral or
malignant transformed cells
• NK cells rather than T cells play important roles in cancer progression
• IL-2 – activates essential cells especially NK cells
• Higher IL-2 in serum associated with increased median survival
• Several phase I trials using intralesional IL-2 combined with other therapies
• Achilles Trial
• Phase I and IIa to characterize safety and activity of clonal neoantigen T cells
product ATL001 in combination with checkpoint inhibitor
Another mechanism – Tumor suppressor
genes NOT clinically actionable
• TP53
• STK11
• CDKN2A
• KEAP1
• SMARCA4
KRAS
• KRAS – seen in westerner smokers and mutually exclusive with other
driver mutations such as ALK, ROS, EGFR
• NO EFFECTIVE AGENT EXCEPT IN VITRO experiments 2013 KrasG12C binding
molecule
• Difficulty of inhibiting kras directly
• RAF MAPK and PI3K-AKT downstream pathways major signaling mechanism
for targets
• Genetically engineered mouse model instrumental in SELUMETINIB and NVB-BEZ235
inhibitor of PI3K
• NCT00996892, nct01363232, NCT01390818
p53 – the most common mutation (50% of
lung cancers) – the guardian of the genome
• Loss of function mutation
• J Clin Oncol 2012;30:3633–3639
• P53 targeting compound PR-246 (PRIMA derivatives) (prostate cancer and
hematologic malignancies)
• Adenoviral-mediated delivery approved in China
Angiogenesis
• No biological marker usefull in predicting tumor response to
bevacizumab (Clin Cancer Res. 2008;14:1407–12)
• bFGF (VEGF basic fibroblast GF )
• ICAM (soluble intercellular adhesion molecule
• E-selectin
• Serum VEGF – predictive of tumor response to bevacizumab but no survival
benefit
Bevacizumab (VEGF target)
• E4599 phase 3 (N Engl J Med. 2006;355:2542–50)
• Non squamous NSCLC : Carb/Paclitaxel pn433 vs Carb/Paclitax + Bev n417
• PFS 4.5m vs 6.2m
• OS 10m vs 12.3m
• B017704 AVAil phase 3 (J Clin Oncol. 2009;27:1227–34; Ann Oncol.
2010;21:1804–9)
• Non-squamous NSCLC: Cis/Gemcit + Placebo n347 vs Cis/Gemcit + Bev n345
• PFS 6.1 vs Bev 7.5mg/kg 6.7m or bev 15mg/kg 6.5m
• OS 13.1m vs Bev 7.5mg/kg 6.7m or bev 15mg/kg 13.4m
• YO25404 BEYOND phase 3 (J Clin Oncol. 2015;33:2197–204)
• Carb/paclitaxel + placebo n 138 vs Carb/paclitax + Bev 15 n138
• PFS 6.5m vs 9.2m
• OS 17.7m vs 24.3m
Ramucirumab (VEGFR-2 target)
• REVEL phase 3 trial NSCLC, progressive disease after first line chemo
• Docataxel + placebo n625 vs Docataxel + Ram n628
• PFS 3m vs 4.5m
• OS 4.5m vs 9.1m
Nintedanib (multitargeting TKI)
• LUME phase 3 NSCLC progression of disease after first line chemo
• DOCetaxel + placebo n 659 vs DOCetaxel + Nin n655
• PFS 2.7m vs 3.4m
• OS 9.1m vs 10.1m
Neoadjuvant immunotherapy
in NSCLC
Current issues
Curative intent mortality rates for NSCLC
• Surgical resection with curative intent continues to be the mainstay
treatment for early‐stage NSCLC, however, its 5‐year survival rates
remain unsatisfactory, ranging from 36% for stage IIIA disease to 60%
for stage IIA.
• 30% are resectable at diagnosis
• Adjuvant platinum based CT is recommended with RESECTED stage II
to IIIA (some IB disease) but with 16% DFS reduction and 5% OS at 5y.
• Recurrence, Death, CNS and other distant metastasis
 •. 2001 Dec;34 Suppl 2:S155-8.
doi: 10.1016/s0169-5002(01)00361-0.

History of Adjuvant therapy for NSCLC

• PORT meta-analysis/French Trial GETCB
• Postoperative radiotherapy is not effective in case of complete resection
• Cambridge Meta-analysis
• phase III trials have demonstrated that adjuvant chemotherapy can
dramatically increase survival compared with surgery alone, in case of N2
disease
• NSCLC Meta-analysis Collaborative Group
• stage II to IIIB patients demonstrated similar oncological benefit with
neoadjuvant chemotherapy compared to surgery
Concept of adjuvant Chemotherapy
• Early trials with adjuvant chemotherapy seemed to incur harm for stage IA patients and a modest
survival benefit for stage IB–IIIA patients (AJCC 7th ed.) (The Albain et al. study compared chemoradiotherapy alone to
chemoradiotherapy followed by surgery, and demonstrated a potential survival advantage with the addition of surgery in stage IIIA NSCLC as well as
the potential harm of surgery after such a regimen if a pneumonectomy was required)
• The trend has been for “up-front” surgery for early and locally advanced NSCLC followed by adjuvant chemotherapy
• Brandt et al. at Memorial Sloan Kettering Cancer Center has shown that while oncological outcomes are
essentially the same if chemotherapy is administered before or after surgery, adverse events from systemic
therapy occur far more in the adjuvant setting compared to the neoadjuvant setting
• Lead to fewer grade 3 or greater toxicities and to a higher likelihood of receiving full doses and cycles of chemotherapy,
suggesting a potential advantage of neoadjuvant over adjuvant therapy
• Novel ICI as a single modality or in combination with systemic agents and/or radiotherapy.
• Even as a single agent, an immune checkpoint inhibitor (ICI) provides significant benefit over
chemotherapy for stage IV NSCLC .
• better side effect profiles,
• improved disease-specific outcomes,
• prolonged survival;
• the result of which ICI is now first-line therapy in advanced NSCLC
• But what about locally advanced and early NSCLC?
Locally advanced /metastatic NSCLC
• phase III trials OAK trial, Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced
squamous-cell non-small-cell lung cancer. N Engl J Med 2015;373:123-35.
• Monotherapies
• nivolumab (anti-PD-1),
• pembrolizumab (anti-PD-1)
• atezolizumab (anti-PD-L1)
• addition of ICIs to standard chemotherapy compared to chemotherapy alone was safe, and also
resulted in prolonged progression-free survival (PFS) and overall survival (OS)
• Except in cancers with driver mutations (EGFR, ALK), ICIs led to an inferior OS when compared to docetaxel
(most trials exclude these patients as subject is controversial). Lee CK, Man J, Lord S, et al. Checkpoint inhibitors in metastatic EGFR-mutated
non-small cell lung cancer-a meta-analysis. J Thorac Oncol 2017;12:403-7.

• combination of an anti-PD-1 /anti-PD-L1 to an anti-CTLA-4.

• Results have shown improved response and survival with ICI or combination chemotherapy-ICI compared to
chemotherapy alone. Rosner S, Reuss JE, Forde PM. PD-1 blockade in early-stage lung cancer. Annu Rev Med 2019;70:425-35.
10.1146/annurev-med-050217-025205
• for inoperable stage III NSCLC, concurrent or sequential chemoradiation is the standard of care
• recurrence rates are high, and survival is poor
• PACIFIC trial - Durvalumab (anti-PD-L1), as consolidation therapy for patients without progression after
chemoradiation
Rationale for neoadjuvant treatment:
Goldie and Coldman hypothesis :
• “The lesser the tumor size, the better the response, and the fewer
chemo-resistant cells” (tumoral burden)
• one of the first reports exploring peri-operative chemotherapy for
stage III NSCLC, Roth et al. had to abort their study at interim analysis
due to the extreme benefit of peri-operative chemotherapy in their
randomized trial design
• Roth JA, Fossella F, Komaki R, et al. A randomized trial comparing perioperative
chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung
cancer. J Natl Cancer Inst 1994
SAKK experience – surgery for IIIB
• T3,4 N0,1
• T2a,b N2
• T1a,b,cN2
• 2003 Betticher et al – gave 3x neoadjuvant Cis/Tax for IIIA/N2
• 40%OS or better if R0 and downstaged to N0/N1
• SAKK 16/00 – does RT (44Gy) increase OS?
• Although R0, downstaging occurred, there is no difference in OS!
• SAKK 16/01 – can stage IIIb have similar results as SAKK 16/00?
• 30 months survival
• Fruh et al 2016 10 year follow up showed 20% cure rate, COD local recurrence, second primaries
• SAKK 16/08 (Curioni 2019)
• Added Cetuximab as Trimodality treatment with shorter OS
• Fuhrer and Opritz 2022
• T3,T4/N2 resectable selected considered inop resulted in 45% 5y OS, 80% R0 (with extended resections) and
a 7% mortality.
Neo-adjuvant ICI for operable NSCLC
• Forde et al Forde PM, Chaft JE, Smith KN, et al. Neoadjuvant PD-1 blockade in resectable lung
cancer. N Engl J Med 2018;378:1976-86. 10.1056/NEJMoa1716078
• two preoperative doses of nivolumab in stage I to IIIA
• well-tolerated, associated with few side effects, did not delay time to surgery and led
to 45% major pathological response (MPR) in resected tumors, including 15%
pathological complete response (pCR) and 40% pathological downstaging
• MPR occurred in both high and low PD-L1 status
• ADAURA J Clin Oncol 2020;38:LBA5. 10.1200/JCO.2020.38.18_suppl.LBA5
• a phase III double-blind RCT evaluating the efficacy and safety of osimertinib (TKI)
compared to placebo of care in EGFR-positive stage IB–IIIA NSCLC followed by
complete tumor resection with or without adjuvant chemotherapy, have suggested a
strong benefit for neoadjuvant targeted therapy as well in EGFR-positive NSCLC
• IB, II, IIIA EGFRm
• 24 countries, 682 patients
• Study became unblinded due to efficacy (improves DFS vs standard of care)
phase II studies evaluated the use of anti-PD-1, anti-PD-L1
and anti-CTLA-4 monotherapy or combination
immunotherapy as neoadjuvant treatment for resectable
NSCLC
Phase II trials
• NEOSTAR - nivolumab versus combination nivolumab/ipilimumab for stages I–IIIA(N2)
• safety profile with a 29% MPR rate for combination therapy compared to 17% for monotherapy,
and 19% compared to 9% pCR rate, respectively
• LCMC3 trial - atezolizumab for operable stages IB–IIIB NSCLC
• Due to previous evidence indicating a lower efficacy of immunotherapy in patients with EGFR or
ALK mutated NSCLC, eight patients in LCMC3 were excluded from the analysis
• 18% MPR rate, including 5% pCR. PD-L1 positive patients had higher rates of MPR, especially if the
tumor proportion score was over 50%
• NADIM trial - ombination neoadjuvant chemotherapy with nivolumab followed by 1 year
of adjuvant nivolumab for stage IIIA (N2 disease or T4N0) NSCLC
• 46 enrolled patients, 41 surgeries performed) showed an 86% MPR and an unprecedented 71%
pCR with downstaging seen in 93% of cases
• NADIM II trial – phase II comparing neoadjuvant combination chemo-immune vs
neoadjuvant chemo
• ASCO (CHECKMATE 816)
Many tumors are considered to have a non-
immunogenic or “cold” microenvironment for which
immunotherapies may not work
• the effects could be synergistically enhanced by the use of
chemotherapy, radiation or other combination therapies
• Heigener DF, Reck M. Immune checkpoint inhibition in non-metastatic non-
small cell lung cancer: chance for cure? Drugs 2019;79:1937-45.
Issues
• drug regimens (including choice of molecule, number of doses and optimal combinations)
• combination therapies, such as when to give (simultaneous versus sequential) and which
immunotherapy to give in patients who will also receive radiation
• need for adjuvant therapy
• Need of later ICI for stage IV which is standard currently?
• optimal timing of surgery.
• criteria for response and progression assessment
• will radiological and pathological assessments be sufficient to differentiate between progression
versus pseudo-progression or immune flare
• liquid biopsies, using information such as ctDNA assessments, be able to help us avoid invasive
re-staging?
• Hilar fibrosis, more difficult dissections, longer operating time, higher rates thoracotomies. Chaft
JE, Hellmann MD, Velez MJ, et al. Initial experience with lung cancer resection after treatment with T-cell checkpoint
inhibitors. Ann Thorac Surg 2017
Is surgery more difficult after neoadjuvant
treatment
• -Time of surgery as end measure?
• -Length of hospital stay?
• -adverse events?
• -parenchyma sparing surgery?

• Culturallly influenced