This document outlines an NSCLC treatment algorithm based on stage and molecular profiling results. It recommends surgical resection for early stage disease when possible. For later stages, it suggests chemotherapy, immunotherapy, targeted therapy, or combinations based on mutation status and PD-L1 levels. Newer targeted therapies and antibody-drug conjugates are highlighted for specific mutations like EGFR, ALK, ROS1, RET, MET, KRAS G12C, and HER2.

1. NSCLC Treatment Algorithm1
Full abbreviations, accreditation, and disclosure information available at PeerView.com/PJD40
NSCLC treatment algorithm
Stage and workup based on stage
•
cT1abc, N0: PFT, bronch, mediastinal staging, PET
•
cT2a-4, N0-3, M0-1: PFT, bronch, mediastinal staging, PET, brain MRI, and biomarker/mutation testing
Stage IA
Surgical candidate?
Lobectomy (preferred)
or
Segmentectomy/wedge
resection (in select cases)
SBRT
or
conventionally fractionated
RT
Surgical resection
Consider mutation and PD-L1 testing results
EGFR ex19del/ex21 L858R present?
Surgical resection
T1
N0
M0
Operable disease
Yes
Yes
Yes
No
No
No
Multidisciplinary discussion for neoadjuvant candidacy
Stage IB-IIIA (resectable)
Mutation (minimum EGFR; broad NGS
if possible) and PD-L1 testing
T1–2, N1–2, M0
T3–4, N0–1, M0
Neoadjuvant chemoimmunotherapy
Nivolumab + platinum-based chemotherapy x 3 cycles
CheckMate -816: Nivo + chemo vs chemo
mEFS: 31.6 vs 20.8 mo (HR, 0.63)
Adjuvant chemotherapy
Platinum-based chemotherapy
LACE Meta-analysis: 5-y OS improvement of 5.4% vs no chemo
Adjuvant immunotherapy (stage II-IIIA)
Atezolizumab x 16 cycles (PD-L1 1%)
IMpower010: Atezo vs BSC
mDFS: NR vs 35.3 mo (HR, 0.66)
Adjuvant targeted therapy
Osimertinib x 3 y
ADAURA: Osimertinib vs placebo
2-y DFS (stage II-IIIA): 90% vs 44% (HR, 0.17)
Pembrolizumab x 1 y
PEARLS/KEYNOTE-091 :Pembro vs placebo
mDFS: 53.6 vs 42.0 mo (HR, 0.76)

2. NSCLC Treatment Algorithm1
Full abbreviations, accreditation, and disclosure information available at PeerView.com/PJD40
Stage IIIA (unresectable) or IIIB/C
Definitive chemoradiation → durvalumab
Concurrent platinum-based chemotherapy and radiation with
consolidation durvalumab
PACIFIC: Durvalumab vs placebo
mPFS: 16.8 vs 5.6 mo (HR, 0.52)
BRAF V600E
Dabrafenib + trametiniba
BRF113928: Dabrafenib + trametinib single arm
ORR: 64% (95% CI, 46–79)
2nd line: KRAS G12C
Sotorasib
CodeBreaK100: Sotorasib single arm
ORR: 37.1% (95%CI, 29-46); mPFS: 6.8 mo
ALK
Alectiniba
ALEX: Alectinib vs crizotinib
1-y PFS: 68.4% vs 48.7% (HR, 0.47)
Brigatiniba
ALTA-1L: Brigatinib vs crizotinib
mPFS: 24 vs 11.1 mo (HR, 0.48)
Lorlatiniba
CROWN: Lorlatinib vs crizotinib
mPFS: NR vs 9.3 mo, (HR, 0.28); 1-y PFS: 78% vs 39%
Ceritinib
ASCEND-4: Ceritinib vs chemo
mPFS: 16.6 vs 8.1 mo (HR, 0.55)
Crizotinib
PROFILE 1007: Crizotinib vs chemo
mPFS: 7.7 vs 3 mo (HR, 0.49)
NTRK
Larotrecteniba
Entrectiniba
ALKA/STARTRK: Entrectinib single arm
ORR: 70% (NSCLC)
RET
Selpercatiniba
LIBRETTO-001: Selpercatinib single arm
ORR: 64%; mDOR: 17.5 mo
Pralsetiniba
ARROW: Pralsetinib single arm
ORR: 61% (95% CI, 50–71)
2nd line: EGFR (ex20)
Amivantamab
CHRYSALIS: Amivantamab single arm
CBR: 74% (95%CI, 63-83); mPFS: 8.3 mo
Mobocertinib
AP32788-15-101: Mobocertinib single arm
DCR: 78% (95% CI, 69-85); mPFS: 7.3 mos
ROS1
Crizotiniba
PROFILE 1001: Crizotinib single arm
ORR: 72% (95% CI, 58–84)
Entrectiniba
ALKA STARTRK: Entrectinib single arm
ORR: 67.1%; mPFS: 19 mo
Ceritinib
YONSEI: Ceritinib single arm
ORR: 67% (95% CI, 48–81)
EGFR (ex19 del or L858R)
Osimertiniba
FLAURA: Osimertinib vs erlotinib/gefitinib
mPFS: 18.9 vs 10.2 mo (HR, 0.46)
Erlotinib
EURTAC: Erlotinib vs chemo
mPFS: 9.7 vs 5.2 mo (HR, 0.37)
Afatinib
LUX-Lung 3: Afatinib vs cis/pemetrexed
mPFS: 13.6 vs 6.9 mo (HR, 0.47)
Gefitinib
IFUM: Gefitinib single arm
mPFS: 9.7 mo
Dacomitinib
ARCHER 1050: Dacomitinib vs geftinib
mOS: 34.1 vs 27 mo (HR, 0.75)
Erlotinib + ramucirumab
RELAY: Erlotinib + ramucirumab vs elotinib
mPFS: 19.4 vs 12.4 mo (HR, 0.59)
Erlotinib + bevacizumab
ARTEMIS-CTONG1509: Erlotinib + bevacizumab vs erlotinib
mPFS: 17.9 vs 11.2 mo (HR, 0.55)
MET (exon 14)
Capmatiniba
GEOMETRY mono-1: Capmatinib single arm
mPFS: 12.4 mo
Tepotiniba
VISION: Tepotinib single arm
mPFS: 8.5–11 mo
2nd line: HER2
Trastuzumab deruxtecan
DESTINY-Lung01
T-DXd single arm
ORR: 55% (95% CI, 44-65); mPFS: 8.2 mo
T1-2, N2–3, M0
T3, N1–3, M0
T4, N0–3, M0
Tx
Nx
M1
Actionable mutation detected
• EGFR (ex19, ex20ins)
• ALK
• ROS1
• BRAF V600E
• RET
• MET (ex14)
• HER2
• NTRK1/2/3
• KRAS G12C
Mutation (minimum EGFR; broad NGS if possible) and PD-L1 testing
NSCLC treatment algorithm
Stage and workup based on stage
•
cT1abc, N0: PFT, bronch, mediastinal staging, PET
•
cT2a-4, N0-3, M0-1: PFT, bronch, mediastinal staging, PET, brain MRI, and biomarker/mutation testing
Please see the next page for recommendations if no actionable mutation is detected
Stage IV
KRYSTAL-1: Adagrasib single arm
ORR: 43% (95% CI, 34-53); mDOR: 8.5 mo

3. NSCLC Treatment Algorithm1
Full abbreviations, accreditation, and disclosure information available at PeerView.com/PJD40
a
Denotes NCCN-preferred regimens.
1. Created by Aakash Desai, MBBS, MPH, and Matthew Ho, MD, PhD. Used with permission from the authors.
PD-L1 1%
IMMUNOTHERAPY + CHEMOTHERAPY
SQUAMOUS:
• Pembrolizumab + chemotherapya
(carboplatin + paclitaxel/nab-paclitaxel)
KEYNOTE-407: Pembro + chemo vs chemo
mPFS: 6.4 vs 4.8 mo (HR, 0.56); mOS: 15.9 vs 11.3 mo (HR, 0.64)
NONSQUAMOUS:
• Pembrolizumab + chemotherapy (carboplatin + pemetrexed)a
KEYNOTE-189: Pembro + chemo vs chemo
mPFS: 8.8 vs 4.9 mo (HR, 0.52), 12-mo; OS: 69% vs 49% (HR, 0.49)
• Atezolizumab + chemotherapy (carboplatin + paclitaxel + bevacizumab)
IMpower150: Atezo + chemo vs chemo
mPFS: 8.3 vs 6.8 mo (HR, 0.62)
DUAL IMMUNOTHERAPY + CHEMOTHERAPY
Nivolumab + ipilimumab + chemo (2 cycles)
CheckMate -9LA: Nivo/ipi + chemo vs chemo
mOS: 14.1 vs 10.7 mo
Durvalumab + tremelimumab + chemo (4 cycles)
POSEIDON: Durva/treme + chemo vs chemo
mOS: 14 vs 11.7 mo (HR, 0.77)
DUAL IMMUNOTHERAPY
Nivolumab + ipilimumab
CheckMate -227: Nivo/ipi vs chemo
mOS: 17.1 vs 14.9 mo
DUAL IMMUNOTHERAPY + CHEMOTHERAPY
Nivolumab + ipilimumab + chemo (2 cycles)
CheckMate -9LA: Nivo/ipi + chemo vs chemo
mOS: 14.1 vs 10.7 mo
Durvalumab + tremelimumab + chemo (4 cycle)
POSEIDON: Durva/treme + chemo vs chemo
mOS: 14 vs 11.7 mo (HR, 0.77)
IMMUNOTHERAPY MONOTHERAPY
Pembrolizumab
KEYNOTE-042: Pembro vs plat-based chemo
mOS: 16.7 vs 12.1 mo (HR, 0.81)
Ramucirumab + docetaxela
REVEL: Ram/docetaxel vs docetaxel; mOS: 10.5 vs 9.1 mo (HR, 0.86)
Docetaxela
TAX320: Docetaxel vs vinorelbine/ifosfamide; 1-y OS: 32% vs 19%
Gemcitabine
DUAL IMMUNOTHERAPY
Nivolumab + ipilimumab
CheckMate -227: Nivo/ipi vs chemo
mOS: 17.1 vs 14.9 mo
DUAL IMMUNOTHERAPY + CHEMOTHERAPY
Nivolumab + ipilimumab + chemo (2 cycles)
CheckMate -9LA: Nivo/ipi + chemo vs chemo
OS: 14.1 vs 10.7 mo
Durvalumab + tremelimumab + chemo (4 cycles)
POSEIDON: Durva/treme + chemo vs chemo
mOS: 14 vs 11.7 mo (HR, 0.77)
PD-L1 1%-49%
IMMUNOTHERAPY + CHEMOTHERAPY
SQUAMOUS:
• Pembrolizumab+chemotherapya
(carboplatin+paclitaxel/nab-paclitaxel)
KEYNOTE-407: Pembro + chemo vs chemo
mPFS: 6.4 vs 4.8 mo (HR, 0.56); mOS: 15.9 vs 11.3 mo (HR, 0.64)
NONSQUAMOUS:
• Pembrolizumab + chemotherapy (carboplatin + pemetrexed)a
KEYNOTE-189: Pembro + chemo vs chemo
mPFS: 8.8 vs 4.9 mo (HR, 0.52); 12-mo OS: 69% vs 49% (HR, 0.49)
• Atezolizumab + chemotherapy (carboplatin + paclitaxel + bevacizumab)
IMpower150 : Atezo + chemo vs chemo
mPFS: 8.3 vs 6.8 mo (HR, 0.62)
• Cemiplimab + chemotherapy (carboplatin + pemetrexed)
EMPOWER-Lung 3: Cemi + chemo vs chemo
mOS: 21.9 vs 13 mo (HR, 0.7)
PD-L1 50%
IMMUNOTHERAPY MONOTHERAPY
Pembrolizumaba
KEYNOTE-024: Pembro vs platinum-based chemo
mPFS: 10.3 vs 6 mo (HR, 0.50)
Atezolizumaba
IMpower110: Atezo vs platinum-based chemo
mOS: 20.1 vs 13.1 mo (HR, 0.59)
Cemiplimaba
EMPOWER-Lung1: Cemi vs platinum-based chemo
mPFS: 8.2 vs 5.7 mo; mOS: NR vs 14.2 mo (HR, 0.57)
IMMUNOTHERAPY + CHEMOTHERAPY
SQUAMOUS:
• Pembrolizumab + chemotherapya
(carboplatin + paclitaxel/nab-paclitaxel)
KEYNOTE-407: Pembro + chemo vs chemo
mPFS: 6.4 vs 4.8 mo (HR, 0.56); mOS: 15.9 vs 11.3 mo (HR, 0.64)
NONSQUAMOUS:
• Pembrolizumab + chemotherapya
(carboplatin + pemetrexed)
KEYNOTE-189: Pembro + chemo vs chemo
mPFS: 8.8 vs 4.9 mo (HR, 0.52); 12-mo OS: 69% vs 49% (HR, 0.49)
• Atezolizumab + chemotherapy (carboplatin + paclitaxel + bevacizumab)
IMpower150: Atezo + chemo vs chemo
mPFS: 8.3 vs 6.8 mo (HR, 0.62)
No actionable mutation detected (stratify based on PD-L1 staining %)
Second-line therapy

4. The Emerging Role of ADCs
in Lung Cancer
Full abbreviations, accreditation, and disclosure information available at
PeerView.com/PJD40
1. Fu Z et al. Signal Transduct Target Ther. 2022;7:93. 2. Desai A et al. Lung Cancer. 2022;163:96-106.
3. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-her2-mutant-non-small-cell-lung.
Antibody–Drug Conjugates (ADCs): What Are They?1
Landscape of ADCs Under Study in Lung Cancer2
New and First FDA Approval of an ADC for HER2-Mutant NSCLC3
Target antigen
Antibody Guidance system for cytotoxic drugs
Bridge between antibody and drugs
to control the release of drugs inside
cancer cells
Linker
Cytotoxic drug Warhead for destroying cancer cells
Recognition of target cancer cells
Key functions
NSCLC SCLC
Ado-Trastuzumab
Emtansine
(T-DM1)
Trastuzumab
Deruxtecan
(T-DXd)
Patritumab
Deruxtecan
(HER3-DXd)
Datopotamab
Deruxtecan
(Dato-DXd)
Sacituzumab
Govitecan
(SN-38)
SAR408701
(DM4)
Telisotuzumab
Vedotin
(MMAE) Rovalpituzumab Tesirine
(PYRROLO-BZD)
Lorvotuzumab
Mertansine
(DM1)
Sacituzumab
Govitecan
(SN-38)
HER2
HER3
HER2
TROP2
TROP2
CEACAM5
C-MET
DLL-3
CD-56
1. Drug internalized
2. ADC in endosome
3. Drug release from
ADC in lysosome
CYTOTOXIC
EFFECT
• On August 11, 2022, the FDA granted accelerated approval to fam-trastuzumab deruxtecan-nxki for adult patients
with unresectable or metastatic NSCLC whose tumors have activating HER2 (ERBB2) mutations, as detected by
an FDA-approved test, and who have received a prior systemic therapy
• This is the first drug approved for HER2-mutant NSCLC, and also the first ADC approved in NSCLC
• FDA also approved the Oncomine™ Dx Target Test (tissue) and the Guardant360® CDx (plasma) as companion
diagnostics for trastuzumab deruxtecan; if no mutation is detected in a plasma specimen, the tumor tissue should
be tested