Staging
TNM staging system (8th edition), to be enforced from 01/2016.
Rami-Porta, R J Thoraci Oncol, 2015: T descriptor in TNM 8th NSCLC.
New staging system based on 94708 cases.
Some participation from latin america.
For the first time: T3 and T4 have different prognosis.
Smoking cessation and lung-cancer mortality
In the NLST cohort
Lung Cancer incidence in Former-smoker (EX), patients that Quit at the beginning of LD-CT screening (QUIT) or current smoker after LD-CT (CURRENT) are:
--EX: 50
--QUIT: 59
--CURRENT: 150.
Decreased Lung cancer mortality of QUIT vs CURRENT (HR: 0.57)
Conclusion:
Smoking cessation during the initiation of LD-CT screening affords a 43% survival benefit due to lung-cancer.
Smoking cessation strategies should be added to LD-CT screening in HR individuals.
Smoking cessation before chemotherapy improves survival for patients with metastatic NSCLC
Lelievre MH, Retrospective analysis in 237 patients: mOS was 16 mo vs 10 mo in quitters vs current smokers (HR).
- mOS was 15 mo in heavy smokers (30 ppy, or more) who stopped before chemotherapy (compared to 8 mo).
- An 51% increase in mortality in current smokers after adjusting for other factors.
- A detailed smoking history must be a part of the clinical evaluation in NSCLC. Three smoking status must be ascertained: never smoker, former smoker and current smoker,
- Smoking cessation derives benefit even in those patients with metastastic NSCLC.
Pathology
STAS: Spread through aerogenous spaces is a new form of lung cancer disemination mechanism. Relatively frequent in micro-papillary and solid adenocarcinomas.
Main benefit from adjuvant chemotherapy observed in micro-papillary and solid adenocarcinomas (Tsao, J Clin Oncol, 2015).
Surgery
Subcarinal nodes need to be sampled even in mediastinoscopy negative patients.
SBRT is an option in primary tumors for patients that are medically inoperable, oligometastatic disease, symptomatic metastasis, and - possibly - as antigen priming for immunotherapy in advanced NSCLC. Main toxicities: acute (fibrosis) and chronic (radionecrosis).
MINI18.01 [][] SBRT improve OS compared to observation in older than 70.
SBRT improved QoL compared to observation.
Komiyana [019-05 Trial] SBRT exhibits comparable survival to surgery.
Progression after SBRT can be suspected with craneo-caudal growth.
Radiotherapy
ChemoRT for LA NSCLC
Meta-analysis for surgery after chemo-RT in stage IIIA/N2 NSCLC (n=29584).
- Surgery increases OS
- Surgical post-operative mortality not trivial.
PROCLAIM (Cis/Pem + RT vs EP + RT in LA NSCLC (stages 3A and 3B)). Both arms had adjuvant therapy (Pemetrexed in Cis/Pem arm, and Investigators choice in EP arm): No change in mOS (about 2 years). Cis/Pem exhibited less AEs (except por Pneumonitis).
3D Conformal RT vs IMRT in stage III NSCL (RTOG 0617): No difference in outcome (despite poor prognosis patients in the IMRT arm). IMRT exhibited lower pneumonitis and less toxicity.
RTOG 0617: HD RT not superior to conventional-dose RT, no benefit of adding Cetuximab.
RADITUX trial: Hypofractionated CT-RT (66 cGy/24 days) +/- Cetuximab.
- No difference with Cetuximab
- mOS with hypofractionation: 32 mo.
Chemo-RT (Carboplatin + Paclitaxel (PPacl)) vs Chemo-RT (Cisplatin + Etoposide (PE)): Systematic review (n PPacl= 2887 pts, n PE= 3789 pts): ORR 56-58%. No difference in PFS/Relapse.
Conclusion: both are standard of care. Increased toxicity with PE
ECOG1505 [][]: Adjuvant CT + Bevacizumab NOT superior to adjuvant CT in stage IB-IIIA NSCLC.
Adoptive Killer T-Cells with platinum doublets increase 5-yr OS after resection (74.6% vs 40.9%, HR: 0.43)
Small trial
Labor intensive technique.
Pharmacogenomic trial
ERCC1 + TS expression-guided adjuvant therapy.
Low ERCC1 + Low TS appear to benefit more from Cisplatin / Pemetrexed from less AEs (no OS difference).
SCaT Trial
High BRCA1 expression did not receive adjuvant Cisplatinum. NEGATIVE trial.
TREAT
Cis/Pem less toxic and easier to administer compared to Cis/Vin. No OS o DFS advantage.
Antiangiogenics
Bevacizumab suppresses myeloid-derived suppressor cells.
REVEL (Lancet Oncol, 2014)
Docetaxel + Ramucirumab superior to Docetaxel in 2nd-line NSCLC (10.5 mo vs 9.1 mo, HR: 0.86)
Lume-Lux1: Reck (Lancet Oncol, 2014)
Nintedanib + Docetaxel superior to Docetaxel in 2nd-line NSCLC (improves PFS and OS).
Particularly, in early progressors (less than 9 mo from diagnosis to 2nd-line).
BRAIN (Besse, Clinical Cancer Res, 2015)
Bevacizumab is active in brain metastasis to NSCLC.
PRONOUNCE
PRONOUNCE [Zinner RG, J Thoracic Oncol, 2015][P3T, n=381 pts] Carbo + Pem with Pem maintenance was NOT superior to Carbo + Pacl + Bev [ECOG 4599 platform]
Lagner (J Clin Oncol, 2015):
Fit patients up to age 75 are candidates to Bevacizumab.
- 75 is the new 70.
Anti EGFR in non-mutant EGFR patients
S0819 - Cetuximab +/- CT (PCB): no benefit of adding Cetuximab to the ECOG 4599 platform.
- Some trend of OS benefit in FISH+ EGFR expression.
- Bevacizumab may not confer benefit for FISH+ EGFR.
- Cetuximab improves OS in FISH+ EGFR with squamous-cell NSCLC
SQUIRE: Necitumumab positive in squamous-cell NSCLC.
Bevacizumab suppresses myeloid-derived suppressor cells.
REVEL (Lancet Oncol, 2014)
Docetaxel + Ramucirumab superior to Docetaxel in 2nd-line NSCLC (10.5 mo vs 9.1 mo, HR: 0.86)
Lume-Lux1: Reck (Lancet Oncol, 2014)
Nintedanib + Docetaxel superior to Docetaxel in 2nd-line NSCLC (improves PFS and OS).
Particularly, in early progressors (less than 9 mo from diagnosis to 2nd-line).
BRAIN (Besse, Clinical Cancer Res, 2015)
Bevacizumab is active in brain metastasis to NSCLC.
PRONOUNCE
PRONOUNCE [Zinner RG, J Thoracic Oncol, 2015][P3T, n=381 pts] Carbo + Pem with Pem maintenance was NOT superior to Carbo + Pacl + Bev [ECOG 4599 platform]
Lagner (J Clin Oncol, 2015):
Fit patients up to age 75 are candidates to Bevacizumab.
- 75 is the new 70.
Anti EGFR in non-mutant EGFR patients
S0819 - Cetuximab +/- CT (PCB): no benefit of adding Cetuximab to the ECOG 4599 platform.
- Some trend of OS benefit in FISH+ EGFR expression.
- Bevacizumab may not confer benefit for FISH+ EGFR.
- Cetuximab improves OS in FISH+ EGFR with squamous-cell NSCLC
SQUIRE: Necitumumab positive in squamous-cell NSCLC.
Nivolumab
Theme: Nivolumab (N) in NSCLC
CheckMate 017
18 mo OS: 28% vs 13% (HR: 0.62) in favor of N vs Docetaxel.
Independent of PD-L1 expression
Majority of ir-AEs developed during the first 3 months.
Hussein
- PD-L1 expression not correlated with response.
- N can be given to any histology
- There is some response to N even in some patients with mEGFR/mALK
- There is pseudoprogression (about 1/3).
Horn
- Checkmate 063 (N in 3rd-line for squamous-NSCLC, P2T)
- Update in safety and efficacy
- No new signals (ORR: 15%, mO2: 8.2 mo, 1-yr OS: 39%)
- At 18 mo follow-up: 27% are still alive.
Solange Peters (discussant)
- What N brings to the fore is the plateau of the PFS/OS KM curves with low toxicity (only 8% G3/4 toxicity)
- Fragile PS2 (and older) patients can be treated safely with N.
- Biomarkers are not yet a reality (High-mutation burden is unfeasible in the clinical setting, and PD-L1 expression needs further work).
Rivzi
- Checkmate 12 (N + Ipi in 1st line NSCLC, P1/2T)
- Different cohorts with different dosing schedules
- ORR: about 39%, G3/4 toxicities: 29-35%, G3/4 toxicities leading to discontinuation: 3-10%.
- PD-L1- also responded
- In PD-L1 greater than 1%: ORR 48%.
- P3T schedule: Nivo 3 mg/kg q2w + Ipi 1 mg/kg q12w.
- Ongoing P3T with the combination: Checkmate 227.
Anti PD-L1 immunotherapy
Atezolizumab (anti PD-L1) in PD-L1+ (Ventana) NSCLC
Untreated ORR: 29%
Previously treated ORR: 25%.
Apparently: interim PET-CT can predict response (not clear to me)
There is some correlation with PD-L1 expression in the primary tumor and in the metastatic site
FIR study (P2T) with Atezolizumab.
Baseline tumor burden by PET-CT is prognostic.
Atezolizumab + Chemotherapy (CT) in NSCLC (P1T)
CT was Carbo/Pem or Carbo/Pacl or Carbo/nab-Pacl
Toxicity: as expected with CT. No immune related AEs.
ORR: 50-73% (median: 63%).
Very exciting (Gos, discussant).
Mutated EGFR
Icotinib (a new reversible anti EGFR TKI) non-inferior to Getifinib in NS.
JMIT [Ying, C][P2T, 2:1 randomization, n=191] Gefitinib + Pemetrexed increased PFS vs Getinib (15.8 mo vs 10.9 mo, HR: 0.69) in 1st-line mEGFR+ NSCLC (East-Asian study)
J025567 [][] Erlotinib + Bevacizumab increases PFS vs Erlotinib (16 mo vs 9.7 mo, HR: 0.54) in 1st-line mEGFR+ NSCLC. No solid biomarker.
CALGB 30406[][] Erlotinib vs Carbo/Paclitaxel better PFS vs Erlotinib (17 mo vs 14 mo) in 1st-line mEGFR+ NSCLC .
IMPRESS [Soria JC, Lancet Oncol, 2015][P3T, n=265 pts] Continuation Gefitinib + Chemotherapy did not improve PFS vs Chemotherapy (Cisplatin + Pemetrexed) in mEGFR+ NSCLC after progression with Gefitinib (mPFS: 5.4 mo).
- 54% harbored T790M mutation
- Gefitinib was ineffective in T790M+
Inverse correlation with circulating mEGFR Free-Plasma DNA and PFS/OS.
Herbst, R
Erlotinib + Bev with HR: 0.54 for PFS in 1st-line mEGFR+ NSCLC
Seto (Lancet Oncol, 2014): essentially the same results in Asian patients.
Unusual EGFR mutations
Exon 18 mutation in EGFR (3% of EGFR)
Both Afatinib and Neratinib are highly active (ORR: 78%).
MET
cMET may be a driver in some NSCLC
- MET exon 14 splice occurs in 4%.
- MET amplification occurs in 11%
- Crizotinib and Cabozantinib are active.
Moro-Sibilot, D [AcSé trial][1550 pts screened, 113 + for MET amplification, 25 enrolled]: Crizotinib in MET amplification: ORR: 32%, DCR: 60%.
SCLC
Notch pathway may be an important target. DLL3 overexpression found in some SCLC.
Keynote 028
- Pembrolizumab active in SCLC
- No correlation with PD-L1 expression
Mesothelioma
Scherperel, A [IF-CT-GFPC-0701 - MAPS trial] [P2/3T, n=448 pts] Bevacizumab + Pemetrexed + Cisplatin increases mOS in advanced mesothelioma (18.8 mo vs 16 mo, HR: 0.76) and mPFS (9.59 mo vs 7.48 mo, HR: 0.62). Bevacizumab also improved fatighe in QoL analysis.
Anti-Mesothelin drug conjugate displays some activity in malignant mesothelioma.
Keynote 028
- Pembrolizumab some activity in mesothelioma (25 pts)
- No correlation with PD-L1 expression
Thymoma
Arrarubicin (a new anthracycline) with some activity in thymomas.
Afatinib Ad-Board
Lanzamiento en Colombia: 05/2016: "NSCLC con mutación activadora del EGFR".
Generalidades
Mutación del EGFR se observa en 78% de los NSCLC en asiáticos, y en un 15% en Europa/Colombia. Se encuentra más en no fumadores, pero un 33% de las mEGFR se detectan en fumadores. Las mutaciones activantes ocurren en los exones 19 y 21 (L858R, que es la más común). Existen mutaciones que confieren resistencia a los TKIs de primera generación (y al afatinib) como la T790M.
Rosel, R [EURTAC] Erlotinib increases PFS vs CT in mEGFR NSCLC (9.7 mo vs 5.2 mo, HR: 0.37). No diferencias en OS (por crossover). En población caucásica.
Lee, CK - J Clin Oncol, 2015 [Meta-análisis] Inhibidores de EGFR de primera generación incrementan la PFS, pero no impactan en la OS. Alta OS en mEGFR NSCLC.
Afatinib: inhibidor irreversible pan-HER (Her1, Her2, Her4), con mejor actividad contra T790M in-vitro que los inhibidores no reversibles. No activo in-vivo contra progresión por subclone T790M. Mayor toxicidad que los inhibidores de primera generación.
[Lux-Lung 3][n=354] Afatinib (40 mg QD) increases PFS vs Cisplatin / Pemetrexed with advanced (stage IV) mEGFR+ NSCLC in 1st-Line (HR: 0.47).
[Lux-Lung 6][n=354] Afatinib (40 mg QD) increases PFS vs Cisplatin / Gemcitabine with advanced (stage IV) mEGFR+ NSCLC in 1st-Line (HR: 0.58).
Afatinib increases OS in Del-19 mEGFR+ compared to CT (33 mo vs 21 mo, HR: 0.54).
Afatinib improves QoL and Cough. Dyspnea and Pain.
Toxicidades: Acné, diarrea, estomatitis, mucositis.
Manejo de efectos secundarios (Future Oncol, 2015)
Dosis inicial: 40 mg vía oral cada día. Si se tolera muy bien, se puede incrementar a 50 mg cada día. Si hay toxicidad, se reduce a 30 mg cada día. Se puede reducir a 20 mg cada día.
[Lux-Lung 8][n=354] Afatinib (40 mg QD) increases PFS vs Erlotinib with advanced (stage IV) squamous-cell NSCLC in 2nd-Line (2.6 mo vs 1.9 mo, p=0.007). (Off-label en Colombia)
Proposal: Afatinib + CT or Afatinib + anti VEGF may be superior to afatinib alone.
