Comments and Controversies

First-Line Dual Immunotherapy, a Treatment Option in

First-Line Metastatic Non–Small-Cell Lung Cancer: Are We
Ready to Use It?
Dipesh Uprety, MD1 ; Jordi Remon, MD, PhD2 ; and Solange Peters, MD, PhD3

DOI https://doi.org/10.1200/JCO.23.01524

Accepted October 6, 2023

In recent years, the introduction of immune checkpoint blockers (ICBs) has revigorated the Published November 30, 2023
treatment landscape of metastatic non–small-cell lung cancer (NSCLC), improving patients’
J Clin Oncol 00:1-5
outcomes. Data from pivotal phase III studies testing a series of distinct anti–PD-(L)-1 com-
© 2023 by American Society of
pounds either as monotherapy or in combination with chemotherapy (CT) paved the way to
Clinical Oncology
establish ICB as the backbone of first-line therapy of metastatic NSCLC lacking actionable
alterations.1,2 Despite progress made since the introduction of anti–PD-(L)-1 agents in daily
practice, several challenges remain unresolved, including the optimal immune strategy schedule
View Online
for individual patient, as the different ICB-containing treatment options available in the first-line Article
setting have not been compared head-to-head. In this scenario, a dual immunotherapy strategy
(anti–PD-(L)-1 plus anti–cytotoxic T-cell lymphocyte-4 [anti–CTLA-4]) 6 CT has been tested
in several phase III clinical trials as a first-line treatment option in metastatic NSCLC.3-9 In
KEYNOTE-598, conducted specifically in patients with PD-L1 ≥50% NSCLC, ipilimumab (anti–
CTLA-4) and pembrolizumab failed to report an improvement in dual primary end points,
progression-free survival (PFS) and overall survival (OS) compared with pembrolizumab, with
12% increase in the incidence of grade ≥3 adverse events.4 Additionally, MYSTIC did not show an
OS benefit with either durvalumab or durvalumab with tremelimumab (anti–CTLA-4) compared
with CT in patients with PD-L1 ≥25% NSCLC.3 Finally, in the phase III NEPTUNE trial, enrolling
patients with metastatic NSCLC and blood tumor mutational burden of ≥20 mutations/megabase,
durvalumab-tremelimumab did not improve OS compared with CT.9 However, other phase III
trials with dual ICB 6 CT have reported a meaningful long-term clinical benefit and a significant
survival improvement regardless of PD-L1 expression compared with CT, showing a unique
magnitude of benefit in PD-L1–negative NSCLC (Table 1).5-7

Nivolumab-ipilimumab combination in advanced PD-L1 ≥1% NSCLC (CheckMate-227) dem-

onstrated a 5-year OS rate of 24% compared with 14% with CT.5 Expanding upon CheckMate-
227, CheckMate-9LA evaluated the addition of two cycles of histology-specific CT with
nivolumab-ipilimumab. The long-term follow-up demonstrated improved OS with
nivolumab-ipilimumab plus CT versus CT, regardless of tumor PD-L1 expression (4-year OS:
21% with nivolumab-ipilimumab plus CT v 16% with CT).6 Additionally, POSEIDON used four
cycles of CT and durvalumab plus a limited course of tremelimumab.7 The trial demonstrated an
improvement in OS with combination therapy (4-year OS: 20.7% v 8.3% with CT alone).7,8

Despite these evidences regarding the efficacy of dual ICB in the first-line setting, this strategy
is not broadly approved worldwide by health authorities (ie, the European Medicines Agency did
not approve nivolumab-ipilimumab in PD-L1 ≥1% tumors, whereas the US Food and Drug
Administration did). Similarly, this strategy is not broadly adopted by clinicians, particularly
outside of the academy. Some concerns regarding managing unusual and potentially severe
toxicities, as well as the lack of strict comparative trials assessing the survival benefit of dual
ICB 6 CT compared with ICB monotherapy with CT, which have also reported a 5-year OS
between 15% and 20%, might represent the main limitations.10,11

A recent pooled analysis of Checkmate-227, CheckMate-568, and CheckMate-817 assessed the

safety of first-line nivolumab-ipilimumab. Treatment-related adverse events (TRAEs) of any
grade occurred in 78% of patients and grade ≥3 TRAEs in 34% of patients leading to treatment
discontinuation in 21%.12 The safety profile in patients age 75 years and older was similar to the
overall population, but the discontinuation rate was more common (29%) in this age strata.

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2 | © 2023 by American Society of Clinical Oncology

TABLE 1. List of Three Major Phase III Trials That Have Used Dual Immune Checkpoint Blockade With/Without Platinum-Doublet Chemotherapy Along With Three Landmark Phase III Trials That Have
Used Chemotherapy Plus Pembrolizumab or Cemiplimab Followed by Three Negative Trials With Dual Immune Checkpoint Blockade (comparator arm being the standard chemotherapy except
KEYNOTE-598, where the comparator arm was single-agent pembrolizumab)

No. of Patients Randomly Objective Median Progression- Grade ≥3

Assigned to (dual) Treatment Regimen and Response Rate Median Duration of Free Survival, Median OS, HR for Long-Term Survival Rates, Adverse
Trial ICB 6 Chemotherapy Schedule (%) Response, Months Months Months Death % Events, %
CheckMate-227 All patients (N 5 583) Nivolumab once every 2 weeks 33.1 19.6 5.1 17.1 0.73 23% 34.2 (TRAE)
PD-L1 ≥1% (n 5 396) plus ipilimumab 35.9 23.2 5.1 17.1 0.79 24%
PD-L1 <1% (n 5 187) Once every 6 weeks 27.3 18.0 5.1 17.2 0.62 19% (5-year OS)
CheckMate-9LA N 5 361 Nivolumab once every 3 weeks 38.2 11.3 6.8 14.1 0.69 21% 47 (grade 3-4)
plus ipilimumab once every 6 21 (PD-L1 ≥1%) (TRAE)
weeks plus two cycles of 23 (PD-L1 <1%)
platinum doublet (4-year OS)
chemotherapy 6 pemetrexed
for nonsquamous tumor
POSEIDON N 5 338 Durvalumab plus 38.8 9.5 6.2 14.0 0.77 20.7% (4-year OS) 55.1 (TRAE)
tremelimumab plus four
cycles of chemotherapy once
every 3 weeks followed by
durvalumab once every
4 weeks

Uprety, Remon, and Peters

KEYNOTE-189 N 5 410 Platinum-pemetrexed plus 47.6 11.2 8.8 22 0.60 19.4% 52.3 (TRAE)
pembrolizumab once every 29.6 (PD-L1 ≥50%)
3 weeks for four cycles 19.8 (PD-L1 1%-49%)
followed by pembrolizumab- 9.6 (PD-L1 <1%)
pemetrexed once every (5-year OS)
3 weeks
KEYNOTE-407 N 5 278 Carboplatin-(nab)paclitaxel plus 57.9 7.7 6.4 17.2 0.71 18.4% 74.8 (AE)
pembrolizumab once every 23.3 (PD-L1 ≥50%)
3 weeks for four cycles 20.6 (PD-L1 1%-49%)
followed by pembrolizumab 10.7 (PD-L1 <1%)
once every 3 weeks (5-year OS)
EMPOWER-Lung 3 N 5 312 Histology-specific platinum- 43.3 15.6 8.2 21.9 0.71 42.7% (2-year OS) 48.7 (TRAE)
doublet plus cemiplimab for
four cycles followed by
cemiplimab
KEYNOTE-598 (PD-L1 N 5 284 Pembrolizumab once every 45.4 16.1 8.2 21.4 1.08 63.6% (1-year OS) 62.4 (AE)
≥50%) 3 weeks plus ipilimumab
every 6 weeks
MYSTIC (PD-L1 ≥25%) N 5 372 Durvalumab plus 34.4 NR 3.9 11.9 0.85a 35.4% (2-year OS) 22.9 (AE)
tremelimumab once every
4 weeks for four cycles
NEPTUNE (bTMB ≥20 mut/ N 5 69 Durvalumab plus 27.5 11.6 4.2 11.7 0.71a 26.1% (2-year OS) 23.1 (TRAE)
Mb) tremelimumab once every
4 weeks for four cycles

Abbreviations: AE, adverse events of any attribution; bTMB, blood tumor mutation burden; HR, hazard ratio; ICB, immune checkpoint blocker; mut/Mb, mutations per megabase; N, sample size; NR, not
reached; OS, overall survival; TRAE, treatment-related adverse events.
a
Statistically not significant.

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 First-Line Dual Immunotherapy, a Treatment Option in First-Line Metastatic Non–Small-Cell Lung Cancer: Are We Ready to Use It?

However, discontinuation because of TRAEs did not nega- PD-L1–negative. The combination of pembrolizumab plus
tively affect long-term survival, as the 3-year OS in this CT reported a 5-year OS of 19.4% and 18.4% for non-
subgroup was 50%.12 Specifically, in Checkmate-227, in squamous (KEYNOTE-189) and squamous (KEYNOTE-407)
patients who discontinued the treatment because of TRAEs, NSCLC, respectively.10,11 However, in PD-L1 <1% tumors, the
the median OS and 5-year OS rate were 41.5 months and 5-year OS in these trials decreased to 9.6% and 10.7%, re-
39%, respectively.5 Similarly, in CheckMate-9LA, grade 3-4 spectively. Similarly, in EMPOWER-Lung-03, cemiplimab
TRAEs occurred in 48% of patients, with treatment dis- plus CT (both histologies) significantly improved the OS
continuation rates of 18%. In an exploratory analysis of this versus CT alone. However, for PD-L1 <1% tumors, the dif-
study, among patients who discontinued all treatment ference was not significant compared with CT (median OS,
components because of TRAEs, the median OS was 12.8 v 14.2; HR, 0.94 [95% CI, 0.62 to 1.42]).14 As tumors with
27.5 months and the 4-year OS rate was 41%. By contrast, it PD-L1 <1% can be considered cold tumors because of lack of
was 15.8 months and 21%, respectively, in all randomly T-cell infiltration (TILs),15 and CTLA-4 blockade has been
assigned patients.6 Similar data have been reported in the shown to induce an increase in TILs,16 as well as PD-L1
POSEIDON trial, with 58% of grade 3 TRAEs and 9.4% of expression, dual ICB strategy seems an optimal approach in
discontinuations.7 Of note, the incidence of high-grade PD-L1–negative NSCLCs.17-23 Likewise, the potential efficacy
toxicities of dual ICB 6 CT mirrors the safety data re- of dual ICB blockage in this subset is sometimes attributed to
ported in phase III trials with ICB monotherapy plus CT, the broadening of the T-cell repertoire related to CTLA-4
albeit distinct in nature, with a grade ≥3-5 TRAEs of 70% and exposure as well as growth of memory T cells.24 Moreover,
up to one third of patients discontinuing treatment because although exploratory in nature, durable clinical benefit was
of TRAEs (eg, discontinuation rate of any treatment com- observed with dual ICB for PD-L1 <1% NSCLC, evident
ponent in KEYNOTE-189 and KEYNOTE-407 was 27.4% and through a clear separation of the curves between dual
21%, respectively).10,11,13 Therefore, safety profile should not ICB 6 CT and single-agent ICB 1 CT in both CheckMate-227
be a limitation for the widespread utility of dual ICB 6 CT in and POSEIDON trials, respectively.5,8 Finally, the 5-year
daily practice. OS with dual immunotherapy in the CheckMate-227 trial
was similar regardless of the PD-L1 expression (24% in
The main clinical challenge and research opportunity consist PD-L1 ≥1% and 19% in PD-L1 <1%),5 as well as in the
therefore in better selecting the patients extracting a sig- CheckMate-9LA trial (4-year OS 21% and 25%, respec-
nificant benefit from a dual ICB. Patients with squamous tively).6 All these data suggest that dual ICB is an optimal
NSCLC, comprising up to one third of NSCLC, represent an approach in PD-L1–negative NSCLC.
unmet need population characterized by a worse prognosis.
The role of ICB, and particularly dual ICB, in squamous Beyond the specific indication to use such immunotherapy
histology remains controversial. In CheckMate-9LA, where a dual blockade in PD-L1–negative NSCLC, frontline trials
third of patients had squamous histology, dual ICB 1 CT support dual ICB 6 CT for patients with metastatic NSCLC
improved the OS with a higher magnitude of benefit in regardless of brain metastases (BM) status. Indeed, this
squamous tumors (hazard ratio [HR], 0.64 [95% CI, 0.48 to strategy may delay the risk of intracranial progression
0.84], 4-year OS: 20% v 10%) than in nonsquamous tumors compared with CT alone.25,26 In Checkmate-227, nivolumab-
(HR, 0.80 [95% CI, 0.66 to 0.97], 4-year OS: 22% v 19%).6 In ipilimumab prolonged OS versus CT in patients with baseline
POSEIDON, among the subset of patients with squamous and treated BM (HR, 0.63 [95% CI, 0.43 to 0.92]) and in those
histology, the dual ICB 1 CT did not improve OS compared without (HR, 0.76 [95% CI, 0.66 to 0.87]). Likewise, the
with CT alone (HR, 0.88 [95% CI, 0.68 to 1.16]), mirroring 5-year intracranial PFS rate among patients with baseline
the HR for OS reported with durvalumab 1 CT versus CT BM was higher with nivolumab-ipilimumab (16%) than CT
(HR, 0.84 [95% CI, 0.64 to 1.10]), thereby suggesting that (6%). Indeed, fewer patients with baseline BM developed
histology should not be considered as a criterion for a new BM with dual ICB (4%) versus CT (20%).25 Similarly, in
more intensive regimen including dual ICB.7 Finally, in CheckMate-9LA, nivolumab-ipilimumab plus CT provided
CheckMate-227, nivolumab-ipilimumab improved OS in OS benefit versus CT in patients with treated baseline BM
both histologic subtypes, with higher benefit in squamous (HR, 0.43 [95% CI, 0.27 to 0.67]) or without BM (HR, 0.79
(HR, 0.63 [95% CI, 0.50 to 0.80]) than in nonsquamous [95% CI, 0.65 to 0.95]). Among patients with baseline BM,
(HR, 0.78 [95% CI, 0.67 to 0.91]), and in squamous, this the risk of new-onset BM was lower with dual ICB than
benefit was more pronounced for PDL <1% (HR, 0.52 with CT (20% v 30%, respectively), and median time to
[95% CI, 0.34 to 0.82]) than for PD-L1 ≥1% (HR, 0.69 [95% development of new brain lesions was also prolonged in
CI, 0.52 to 0.91]).5 However, subgroup analyses are explor- nivolumab-ipilimumab plus CT versus CT alone (10.9 v
atory and not powered to draw firm conclusions. Although 4.6 months, respectively).26 An exploratory pooled analysis
histology was a stratification factor in all three trials, the among patients with stable BM at baseline reported that the
significant overlap of all confidence intervals suggests that combination of ICB plus CT improved clinical outcomes
the dual ICB decision should not be guided by histology. versus CT alone regardless of PD-L1 expression. However,
this analysis did not report specific intracranial outcomes
While PD-L1 expression is a predictive biomarker for ICB with this strategy, and only a small subset of patients had
efficacy in metastatic NSCLC, one third of tumors are untreated BM.27 In a single-arm phase II trial in patients with

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 Uprety, Remon, and Peters

untreated BM, the combination of ICB plus CT has resulted in immune profiles.32 These data suggest that patients with
an intracranial response rate and PFS of 53% and NSCLC and KRAS, STK11, or KEAP1 comutations may fare better
6.7 months, respectively, and median OS of 21 months; on the drug combination, including an anti–CTLA-4, com-
however, it was a noncomparative trial enrolling only 45 pared with CT alone, and could be a criterion for treatment
patients.28 Therefore, as data with dual ICB in this population selection. However, the small sample sizes, the lack of direct
show a more consistent and impactful signal, the efficacy of comparison with CT plus ICB, the poorly explored biology of
this strategy in patients with asymptomatic untreated BM comutations, and the retrospective analysis warrant a pro-
deserves further evaluation (ClinicalTrials.gov identifier: spective evaluation of dual ICB treatment strategy in STK11,
NCT05012254). KEAP1, and KRAS-mutated NSCLC.

Tumor comutations may negatively affect patients’ outcomes Future challenges with anti–CTLA-4 and anti–PD-(L)-1
and may influence treatment efficacy.29 According to an ex- include the optimal number of cycles of each immune
ploratory analysis from CheckMate-227, survival benefit component with the aim to reduce financial and treatment
with nivolumab-ipilimumab versus CT was observed regard- toxicity, the optimal number of CT cycles when added to dual
less of KRAS, STK11, and KEAP1 mutation status. In tumors immunotherapy approach, and the treatment duration (until
harboring these mutations, the 4-year OS rate was higher with disease progression on the basis of a radiologic and mo-
nivolumab-ipilimumab versus CT alone (27% v 16%, 19% v lecular criterion of circulating tumor DNA). Indeed, in the
5%, and 44% v 0% in KRAS, STK11, and KEAP1-mutant NSCLC, future, new CTLA-4 inhibitors and a new class of agents,
respectively).30 In POSEIDON, tremelimumab-durvalumab plus such as bispecific monoclonal antibodies anti–CTLA-4
CT versus CT alone reported OS benefit irrespective of the and anti–PD-1 in combination with CT, may irrupt in the
mutational status. Specifically, the 2-year OS rate was higher treatment landscape. In a signal-finding study of MEDI5752,
with the dual ICB with CT versus CT alone in all oncogenic- a bispecific monoclonal antibody that binds to PD-1 and
positive NSCLC (STK11-mutant: 32% v 4.5%; HR v CT, 0.56 CTLA-4, the combination of MEDI5752 plus CT showed
[95% CI, 0.30 to 1.03]; KEAP1-mutant: 35% v 0%; HR, 0.43 numerically better response rate and median PFS when
[95% CI, 0.16 to 1.25]; and KRAS-mutant: 52% v 26%; HR, 0.56 compared with CT plus pembrolizumab combination in
[95% CI, 0.36 to 0.88]).31 Finally, in an exploratory analysis in treatment-naı̈ve nonsquamous NSCLC, particularly with
the nonsquamous NSCLCs from Checkmate-9LA, a trend to- PD-L1 <1%.33
ward OS benefit was observed with nivolumab-ipilimumab
plus CT versus CT alone, regardless of KRAS, TP53, or STK11 Although no head-to-head comparison has been performed,
mutations.26 Similarly, retrospective data in real-world pop- current data support dual ICB with or without CT as a feasible
ulation reported that STK11 and KEAP1 comutation had worse upfront treatment strategy. The PD-L1–negative NSCLC and
outcomes to ICB among patients with KRAS-mutant NSCLC tumors with comutations seem to be the most promising
but not in KRAS-wild-type, as tumors harboring concurrent prognostic factors in the clinic helping to decide for an
KRAS/STK11 and KRAS/KEAP1 mutations display distinct upfront dual ICB strategy.

AFFILIATIONS AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS

1
Department of Medical Oncology, Barbara Ann Karmanos Cancer
OF INTEREST
Institute, Detroit, MI Disclosures provided by the authors are available with this article at DOI
2
Department of Cancer Medicine, Gustave Roussy, Villejuif, France https://doi.org/10.1200/JCO.23.01524.
3
Oncology Department, Lausanne University Hospital, Lausanne,
Switzerland AUTHOR CONTRIBUTIONS
Manuscript writing: All authors
CORRESPONDING AUTHOR Final approval of manuscript: All authors
Dipesh Uprety, MD, Department of Medical Oncology, Barbara Ann Accountable for all aspects of the work: All authors
Karmanos Cancer Institute, Wayne State University School of Medicine,
4100 John R, Mail code: HW04HO, Detroit, MI 48201;
e-mail: [email protected].

REFERENCES
1. Singh N, Temin S, Baker S Jr, et al: Therapy for stage IV non–small-cell lung cancer without driver alterations: ASCO living guideline. J Clin Oncol 40:3323-3343, 2022
2. Hendriks LE, Kerr KM, Menis J, et al: Non-oncogene-addicted metastatic non-small-cell lung cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up. Ann Oncol 34:358-376,
2023
3. Rizvi NA, Cho BC, Reinmuth N, et al: Durvalumab with or without tremelimumab vs standard chemotherapy in first-line treatment of metastatic non-small cell lung cancer: The MYSTIC phase 3
randomized clinical trial. JAMA Oncol 6:661-674, 2020
4. Boyer M, Şendur MAN, Rodrı́guez-Abreu D, et al: Pembrolizumab plus ipilimumab or placebo for metastatic non-small-cell lung cancer with PD-L1 tumor proportion score ≥ 50%: Randomized,
double-blind phase III KEYNOTE-598 study. J Clin Oncol 39:2327-2338, 2021
5. Brahmer JR, Lee JS, Ciuleanu TE, et al: Five-year survival outcomes with nivolumab plus ipilimumab versus chemotherapy as first-line treatment for metastatic non-small-cell lung cancer in
CheckMate 227. J Clin Oncol 41:1200-1212, 2023

4 | © 2023 by American Society of Clinical Oncology

Downloaded from ascopubs.org by 42.200.55.113 on January 4, 2024 from 042.200.055.113
Copyright © 2024 American Society of Clinical Oncology. All rights reserved.
 First-Line Dual Immunotherapy, a Treatment Option in First-Line Metastatic Non–Small-Cell Lung Cancer: Are We Ready to Use It?

6. Carbone DP, Ciuleanu TE, Schenker M, et al: First-line (1L) nivolumab (N) 1 ipilimumab (I) 1 chemotherapy (C) vs C alone in patients (pts) with metastatic NSCLC (mNSCLC) from CheckMate 9LA:
4-y clinical update and outcomes by tumor histologic subtype (THS). J Clin Oncol 41, 2023 (suppl 17; abstr LBA9023)
7. Johnson ML, Cho BC, Luft A, et al: Durvalumab with or without tremelimumab in combination with chemotherapy as first-line therapy for metastatic non-small-cell lung cancer: The Phase III
POSEIDON Study. J Clin Oncol 41:1213-1227, 2023
8. Johnson ML, Cho B, Luft A, et al: LBA59 Durvalumab (D) 6 tremelimumab (T) 1 chemotherapy (CT) in 1L metastatic (m) NSCLC: Overall survival (OS) update from POSEIDON after median follow-
up (mFU) of approximately 4 years (y). Ann Oncol 33:S1424-S1425, 2022
9. de Castro G Jr, Rizvi NA, Schmid P, et al: NEPTUNE: Phase 3 study of first-line durvalumab plus tremelimumab in patients with metastatic NSCLC. J Thorac Oncol 18:106-119, 2023
10. Garassino MC, Gadgeel S, Speranza G, et al: Pembrolizumab plus pemetrexed and platinum in nonsquamous non-small-cell lung cancer: 5-year outcomes from the phase 3 KEYNOTE-189 study.
J Clin Oncol 41:1992-1998, 2023
11. Novello S, Kowalski DM, Luft A, et al: Pembrolizumab plus chemotherapy in squamous non-small-cell lung cancer: 5-year update of the Phase III KEYNOTE-407 study. J Clin Oncol 41:1999-2006,
2023
12. Paz-Ares LG, Ciuleanu TE, Pluzanski A, et al: Safety of first-line nivolumab plus ipilimumab in patients with metastatic NSCLC: A pooled analysis of CheckMate 227, CheckMate 568, and CheckMate
817. J Thorac Oncol 18:79-92, 2023
13. Grant MJ, Herbst RS, Goldberg SB: Selecting the optimal immunotherapy regimen in driver-negative metastatic NSCLC. Nat Rev Clin Oncol 18:625-644, 2021
14. Makharadze T, Gogishvili M, Melkadze T, et al: Cemiplimab plus chemotherapy versus chemotherapy alone in advanced NSCLC: 2-year follow-up from the phase 3 EMPOWER-lung 3 part 2 trial.
J Thorac Oncol 18:755-768, 2023
15. Teng MW, Ngiow SF, Ribas A, et al: Classifying cancers based on T-cell infiltration and PD-L1. Cancer Res 75:2139-2145, 2015
16. Huang RR, Jalil J, Economou JS, et al: CTLA4 blockade induces frequent tumor infiltration by activated lymphocytes regardless of clinical responses in humans. Clin Cancer Res 17:4101-4109,
2011
17. Pardoll DM: The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12:252-264, 2012
18. Wei SC, Duffy CR, Allison JP: Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov 8:1069-1086, 2018
19. Wei SC, Sharma R, Anang NAAS, et al: Negative co-stimulation constrains T cell differentiation by imposing boundaries on possible cell states. Immunity 50:1084-1098.e10, 2019
20. Das R, Verma R, Sznol M, et al: Combination therapy with anti-CTLA-4 and anti-PD-1 leads to distinct immunologic changes in vivo. J Immunol 194:950-959, 2015
21. Wang C, Thudium KB, Han M, et al: In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human primates. Cancer Immunol Res 2:846-856, 2014
22. Brahmer JR, Drake CG, Wollner I, et al: Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: Safety, clinical activity, pharmacodynamics, and immunologic
correlates. J Clin Oncol 28:3167-3175, 2010
23. Hamanishi J, Mandai M, Iwasaki M, et al: Programmed cell death 1 ligand 1 and tumor-infiltrating CD81 T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci U S A
104:3360-3365, 2007
24. Robert L, Tsoi J, Wang X, et al: CTLA4 blockade broadens the peripheral T-cell receptor repertoire. Clin Cancer Res 20:2424-2432, 2014
25. Reck M, Ciuleanu TE, Lee JS, et al: Systemic and intracranial outcomes with first-line nivolumab plus ipilimumab in patients with metastatic NSCLC and baseline brain metastases from CheckMate
227 part 1. J Thorac Oncol 18:1055-1069, 2023
26. Paz-Ares LG, Ciuleanu TE, Cobo M, et al: First-line nivolumab plus ipilimumab with chemotherapy versus chemotherapy alone for metastatic NSCLC in CheckMate 9LA: 3-year clinical update and
outcomes in patients with brain metastases or select somatic mutations. J Thorac Oncol 18:204-222, 2023
27. Powell SF, Rodrı́guez-Abreu D, Langer CJ, et al: Outcomes with pembrolizumab plus platinum-based chemotherapy for patients with NSCLC and stable brain metastases: Pooled analysis of
KEYNOTE-021, -189, and -407. J Thorac Oncol 16:1883-1892, 2021
28. Hou X, Zhang XX, Li S, et al: Efficacy, safety, and health-related quality of life with camrelizumab plus pemetrexed and carboplatin as first-line treatment for advanced nonsquamous NSCLC with
brain metastases (CAP-BRAIN): A multicenter, open-label, single-arm, phase 2 study. J Clin Pharmacol 63:769-775, 2023
29. Zhang F, Wang J, Xu Y, et al: Co-occurring genomic alterations and immunotherapy efficacy in NSCLC. NPJ Precis Oncol 6:4, 2022
30. Ramalingam SS, Balli D, Ciuleanu TE, et al: 4O Nivolumab (NIVO) 1 ipilimumab (IPI) versus chemotherapy (chemo) as first-line (1L) treatment for advanced NSCLC (aNSCLC) in CheckMate 227 part
1: Efficacy by KRAS, STK11, and KEAP1 mutation status. Ann Oncol 32:S1375-S1376, 2021
31. Peters S, Cho B, Luft A, et al: OA15.04 Association between KRAS/STK11/KEAP1 mutations and outcomes in POSEIDON: Durvalumab 6 tremelimumab 1 chemotherapy in mNSCLC. J Thorac
Oncol 17:S39-S41, 2022
32. Skoulidis F, Goldberg ME, Greenawalt DM, et al: STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma. Cancer Discov 8:822-835, 2018.
33. Ahn MJ, Kim SW, Costa EC, et al: LBA56 MEDI5752 or pembrolizumab (P) plus carboplatin/pemetrexed (CP) in treatment-naı̈ve (1L) non-small cell lung cancer (NSCLC): A phase Ib/II trial. Ann
Oncol 33:S1423, 2022

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 Uprety, Remon, and Peters

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

First-Line Dual Immunotherapy, a Treatment Option in First-Line Metastatic Non–Small-Cell Lung Cancer: Are We Ready to Use It?

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless
otherwise noted. Relationships are self-held unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the
subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or
ascopubs.org/jco/authors/author-center.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open
Payments).

Dipesh Uprety AstraZeneca (Inst), Janssen (Inst), Regeneron (Inst), Merck Serono
Consulting or Advisory Role: Daiichi Sankyo/Astra Zeneca, (Inst), Boehringer Ingelheim (Inst), Takeda (Inst), Lilly (Inst), Abbvie
AstraZeneca/MedImmune, Jazz Pharmaceuticals, Sanofi (Inst), Bayer (Inst), Biocartis (Inst), Debiopharm Group (Inst), Illumina
(Inst), PharmaMar (Inst), Sanofi (Inst), Seagen (Inst), Blueprint
Jordi Remon Medicines (Inst), Daiichi Sankyo (Inst), Incyte (Inst), Bioinvent (Inst),
Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, MSD Clovis Oncology (Inst), Vaccibody (Inst), Phosplatin Therapeutics (Inst),
Oncology, AstraZeneca, OSE Immunotherapeutics, Janssen Oncology, Foundation Medicine (Inst), Arcus Biosciences (Inst), F-Star
Genmab, Boehringer ingelheim, Sanofi, Roche/Genentech, Merck Biotechnology (Inst), Genzyme (Inst), Gilead Sciences (Inst),
Travel, Accommodations, Expenses: Roche/Genentech, Inivata, OSE GlaxoSmithKline (Inst), Vaccibody (Inst), ITeos Therapeutics (Inst)
Immunotherapeutics, OSE Immunotherapeutics, AstraZeneca Research Funding: roche (Inst), BMS (Inst), MSD (Inst), Amgen (Inst),
Lilly (Inst), AstraZeneca (Inst), Pfizer (Inst), Illumina (Inst), Merck Serono
Solange Peters (Inst), Novartis (Inst), Biodesix (Inst), Boehringer Ingelheim (Inst),
Honoraria: Roche (Inst), Bristol-Myers Squibb (Inst), Novartis (Inst), Boehringer Ingelheim (Inst), Boehringer Ingelheim (Inst), Iovance
Pfizer (Inst), MSD (Inst), AstraZeneca (Inst), Takeda (Inst), Illumina Biotherapeutics (Inst), Phosplatin Therapeutics (Inst)
(Inst), medscape (Inst), Prime Oncology (Inst), RMEI Medical Education Travel, Accommodations, Expenses: Roche, Bristol-Myers Squibb, MSD,
(Inst), Research to Practice (Inst), PER (Inst), Imedex (Inst), Ecancer Sanofi, Incyte
(Inst), Ecancer (Inst), OncologyEducation (Inst), Fishawack Facilitate Uncompensated Relationships: Annals of Oncology, ESMO, ETOP
(Inst), Peerview (Inst), Medtoday (Inst), Mirati Therapeutics (Inst), Scientific chair, JTO Past Deputy Editor, SAMO President
Sanofi (Inst), Incyte (Inst)
Consulting or Advisory Role: Roche/Genentech (Inst), Novartis (Inst), No other potential conflicts of interest were reported.
Bristol-Myers Squibb (Inst), Pfizer (Inst), MSD (Inst), Amgen (Inst),

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