Immune-checkpoint inhibition in first-line treatment of advanced non-small cell lung cancer patients: Current status and future approaches

Lung Cancer 106 (2017) 70–75

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Lung Cancer journal homepage: www.elsevier.com/locate/lungcan

Review

Immune-checkpoint inhibition in first-line treatment of advanced non-small cell lung cancer patients: Current status and future approaches J. Remon, N. Pardo, A. Martinez-Martí, S. Cedrés, A. Navarro, A.M. Martinez de Castro, E. Felip ∗ Hospital Vall d’Hebron, Medical Oncology Department, Passeig de la Vall d’Hebron, 119-129, 08035, Barcelona, Spain

a r t i c l e

i n f o

Article history: Received 11 January 2017 Accepted 4 February 2017 Keywords: Immunotherapy Pembrolizumab Nivolumab First-line Non-small cell lung cancer

a b s t r a c t Immune checkpoint inhibitors are considered standard second-line treatment in advanced non-small cell lung cancer patients. This strategy has also become standard in first-line setting for a subgroup of patients with strongly positive PD-L1 tumors; therefore, PD-L1 status might be considered a new biomarker that deserves upfront testing. New combinations of immune checkpoint inhibitors and with chemotherapy have been tested in first-line treatment. However, some questions remain unanswered such as the best treatment strategy or the real upfront efficacy of these therapeutic strategies in the whole lung cancer population. In this review we summarize the main results in the first-line setting of recent phase III trials with immune checkpoint inhibitors in advanced non-small cell lung cancer patients. © 2017 Elsevier B.V. All rights reserved.

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70 Anti-PD1 or anti-PD-L1 as monotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71 2.1. Pembrolizumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71 2.2. Nivolumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71 2.3. Atezolizumab, avelumab and durvalumab. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .71 3. Anti-PD1 or anti-PD-L1 combined with chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72 4. Combination of anti-PD-1/PD-L1 antibodies with anti-CTLA4 antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72 Financial support and sponsorship . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73 Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73

1. Introduction Modulation of immune response to elicit antitumor activity has been achieved by development of immune checkpoint inhibitors, different monoclonal antibodies that bind either to PD-1 or its ligand the PD-L1 and anti-CTLA4 antibodies hampering immune

∗ Corresponding author. E-mail addresses: [email protected] (J. Remon), [email protected] (N. Pardo), [email protected] (A. Martinez-Martí), [email protected] (S. Cedrés), [email protected] (A. Navarro), [email protected] (A.M. Martinez de Castro), [email protected] (E. Felip). http://dx.doi.org/10.1016/j.lungcan.2017.02.002 0169-5002/© 2017 Elsevier B.V. All rights reserved.

evasion [1–3], changing the landscape treatment of non-small cell lung cancer (NSCLC) patients and other malignancies. Four randomized phase III trials have reported significant overall survival (OS) benefit with immune checkpoint inhibitors (such as: nivolumab an anti-PD-1 in squamous [4] and non-squamous [5] patients; pembrolizumab another anti-PD1, restricted to patients with at least 1% PD-L1 expression on tumor cells [6] and atezolizumab an anti-PD-L1 [7]) compared with single-agent docetaxel as second-line treatment in advanced NSCLC patients. Of note, the magnitude of benefit with pembrolizumab was greater among patients with strong PD-L1 expression (at least 50% of tumour cells expressing PD-L1) [6]. Given the absence of headto-head comparison, the lack of clear biological differences and

J. Remon et al. / Lung Cancer 106 (2017) 70–75

the similarity in toxicity profile [8], one treatment cannot be recommended over another in this setting. Nivolumab and pembrolizumab have received US Food and Drug Administration (FDA) and European Medicines Agency (EMA) approval as second-line therapy, the latter restricted to tumours expressing PD-L1 (≥1%); and FDA has approved atezolizumab in the second-line setting. The results of ATLANTIC phase 2 study recently showed the clear activity of durvalumab, an anti-PD-L1, as third-line treatment or beyond; higher PD-L1 expression levels correlated with improved response rate and OS [9]. All these results spurred numerous efforts to assess immunotherapies in the front-line setting. First-line platinum-based chemotherapy still remains the standard of care in the majority of the advanced NSCLC patients [10] without oncogenic drivers alterations such as the epidermal growth factor receptor (EGFR) mutation (in almost 50% of patients of Asian ethnicity compared to 15% in the Caucasian population [11]) or the anaplastic lymphoma kinase (ALK) re-arrangement (in 5% patients independently of ethnicity [12]). However, efficacy of chemotherapy remains poor [10] and new strategies are awaited. In this review, we summarize recent advances and strategies with immune checkpoint inhibitors as first-line treatment in advanced NSCLC.

2. Anti-PD1 or anti-PD-L1 as monotherapy 2.1. Pembrolizumab Tumours with strong PD-L1 expression (expression on at least 50% of tumour cells, regardless of the staining intensity with the 22C3 clone, which occurs in approximately 23% to 28% of advanced NSCLC [6,13]) has been reported as a predictive marker for better outcome in the pembrolizumab phase I KEYNOTE 001 [13] and phase III KEYNOTE 010 [6] trials, and improving this benefit when pembrolizumab was prescribed upfront [14], with a promising median progression-free survival (PFS) of 12.5 months [13]. On basis of these observations, the phase III KEYNOTE 024 trial [15] randomized 305 NSCLC patients with strong PD-L1 positivity to pembrolizumab (200 mg every 3 weeks up to 35 cycles or until documented progressive disease) versus 4–6 cycles of platinum-based chemotherapy as first-line treatment. Pemetrexed maintenance therapy was permitted for patients with non-squamous histology and pemetrexed induction chemotherapy. Pembrolizumab compared to standard first-line platinum-based chemotherapy significantly improved the median PFS (10.3 vs. 6.0 months, hazard ratio [HR] 0.50 [0.37–0.68], p < 0.001), response rate (RR) by RECIST (44.8% vs. 27.8%, p < 0.001), and OS (not reached in both arms, HR 0.60 [0.41–0.89], p = 0.005), with 1-year OS of 70% vs. 54%, despite 43.7% of patients in the control arm were allowed to crossover to pembrolizumab upon disease progression [15]. Quality of life [16] and grade ≥ 3 treatment-related adverse events (AEs) also favoured pembrolizumab (26.6% vs. 53.3%), with 9.7% of grade 3–4 immune-mediated AEs [15]. The magnitude of benefit in control arm is consistent with historic controls [17], suggesting that pembrolizumab efficacy was not related to infra-therapeutic control arm. Also, it remains unknown whether survival benefit is because pembrolizumab treatment is intrinsically more efficacious as first-line treatment or because more than 50% of the patients in control arm did not receive immune-checkpoint inhibitor at progression. Also, it remains unknown how strong is the tumorimmune addiction reported in KEYNOTE 024 trial and whether it is independent of PD-L1 expression. KEYNOTE 024 results prompted FDA approval of pembrolizumab on October 24, 2016, as the firstline treatment in NSCLC patients with strong PD-L1 positivity, and on December 15th, 2016, EMA CHMP also approved pembrolziumab as monotherapy in the first-line setting of metastatic NSCLC

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in adults whose tumors express PDL1 in a tumor proportion score (TPS) ≥ 50% with no EGFR- or ALK positive tumor mutations. The ongoing phase III KEYNOTE 042 study (NCT02220894) will assess the survival benefit of pembrolizumab over standard first-line platinum-based chemotherapy as first-line treatment in treatment in NSCLC patients with PD-L1 expression of 1% or greater. 2.2. Nivolumab The phase I, multicohort, CheckMate 012 trial evaluated nivolumab in the first-line setting among 52 NSCLC patients. Nivolumab reported a RR of 23%, median PFS of 3.6 months and median and 1-year OS of 21.8 months and 73%, respectively. Trend toward better outcome with nivolumab was reported among 12 patients with PD-L1 ≥ 50% (tumor cell membrane staining any intensity >50% with the 28-8 clone Epitomics) with a RR of 50%, median PFS of 8.4 months and 1-year OS of 83% [18]. The phase III CheckMate 026 trial compared nivolumab with standard first-line chemotherapy in 423 PD-L1-positive (≥5% of expression by 28-8 clone) advanced NSCLC patients [19]. Maintenance treatment was allowed and 38% of patients received pemetrexed-maintenance [19]. Nivolumab did not achieve benefit compared to control arm in terms of PFS (4.2 vs. 5.9 months, HR 1.15 [0.91–1.45], p = 0.251), OS (14.4 vs. 13.2 months, HR 1.02 [0.80–1.30]), or RR (26.1% vs. 33.5%), but reported better toxicity profile (grade ≥ 3 AEs: 17.6% vs. 50.6%) [19]. Imbalances in nivolumab arm compared to control arm according to postdiscontinuation treatment (40% vs. 60%) and percentage of tumours with strong PD-L1 expression (53.2% vs. 74.1%) may explain the lack of survival benefit [19]. The high proportion of lack of post-discontinuation treatment at progression in nivolumab arm may suggest that for some patients upfront immune checkpoint inhibitors is not an appropriate strategy [20]. Differences in population characteristics, previous treatment with radiotherapy, and differences in biomarker tests and in PDL1 expression cut-off point could partially justify the contrasting results between KEYNOTE 024 [15] and Checkmate 026 [19] trials. The ongoing phase III CheckMate 227 (NCT02477826) trial evaluates the best strategy for delivering nivolumab (as monotherapy, combined with ipilimumab or chemotherapy) compared with standard upfront platinum-based chemotherapy in PD-L1 positive advanced NSCLC patients. 2.3. Atezolizumab, avelumab and durvalumab The phase II BIRCH trial tested the anti-PD-L1 atezolizumab (1200 mg iv every 3 weeks), in 142 treatment-naïve PD-L1 positive NSCLC patients. The RR was 25%, median PFS and OS was of 7.3 months and 23.5 months, respectively, with 33% of serious AE’s, suggesting activity in first-line setting [21]. The ongoing IMpower110 (NCT02409342) and IMpower 111 (NCT02409355) phase III trials compare atezolizumab with chemotherapy in PDL1 positive (≥1% on TC or IC with ventana SP142 assay) advanced treatment-naïve NSCLC patients. In the phase I, multicohort, JAVELIN study, including 156 treatment-naïve advanced NSCLC patients and unselected for PDL1 expression, avelumab (10 mg/kg iv biweekly), an anti-PD-L1, achieved a RR of 22.5% and median PFS of 4.4 months with an 11% grade 3 treatment-related AEs [22]. The ongoing phase III JAVELIN Lung 100 trial (NCT02576574) compares in first-line setting avelumab versus chemotherapy in advanced PD-L1 positive NSCLC patients. The anti-PDL1 durvalumab (10 mg/kg every 2 weeks) tested as first-line treatment in 59 advanced NSCLC patients, obtained promising efficacy with a long-lasting RR of 25% irrespective of histologic subtype, and with grade 3 AEs in 9% of patients [23]. The

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ongoing phase III MYSTIC trial (NCT02453282) compares durvalumab with or without ipilimumab versus first-line platinum-based chemotherapy.

3. Anti-PD1 or anti-PD-L1 combined with chemotherapy Preclinical data has shown that chemotherapy and radiation modulate the immune response against tumours [24], and chemotherapy can induce PD-L1 expression on tumour cells [25,26]. Early clinical data for combinations of chemotherapy with anti-PD1 like nivolumab [27,28] and pembrolizumab [29] or anti-PD-L1 such as atezolizumab [30] have reported promising efficacy as first-line treatment and good safety profile. This synergism has been tested in the phase II KEYNOTE 021 trial [31], and 123 treatment-naïve patients were randomized to pembrolizumab 200 mg every 3 weeks for 2 years plus carboplatin and pemetrexed for 4 cycles followed by pemetrexed maintenance therapy or chemotherapy alone. At least 32% of patients in chemotherapy arm crossed over to pembrolizumab at progression as allowed by the study protocol. The combination arm improved RR (55% vs. 29%, p = 0.0016) and PFS (13.0 months vs. 8.9 months, HR 0.53 [0.31–0.91], p = 0.0102) compared to chemotherapy alone, however, grade 3–4 treatment-related AEs were higher in the concomitant arm (39% vs. 26%), but discontinuation because treatment-related AEs were similar in both arms (10% vs. 13%) [31]. In combination arm, the RR achieved 80% within the tumour PD-L1 expression of 50%. However, the limited number of patients and the fact of patients who had a PD-L1 tumor expression <1% achieved a RR of 57%, it is not possible to obtain firm conclusions about the predictive value of PD-L1 expression. Median PFS in control arm exceed the PFS observed in recent clinical trials [32], suggesting a high level of patient selection. Combination arm in KEYNOTE 021 trial [31] reported better RR and PFS than pembrolizumab alone in KEYNOTE 021 trial [15], however these results should be validated in a phase III trial and PFS according PD-L1 scores in KEYNOTE 021 trial remains unknown [31]. The ongoing phase III KEYNOTE-189 (NCT02578680) and KEYNOTE-407 (NCT02775435) trials assess the efficacy of pembrolizumab plus chemotherapy and might assess the relationship between PD-L1 expression and efficacy with combination. Other ongoing randomised phase III clinical trials in first-line setting assess the efficacy of atezolizumab plus chemotherapy such as IMpower 132 (NCT02657434), IMpower 130 (NCT02367781), IMpower 131 (NCT02367794) and IMpower 150 (NCT02366143, which includes bevacizumab) trials. In case of combination arms become a new standard, the best maintenance treatment strategy (chemotherapy vs. chemotherapy plus immune checkpoint inhibitor vs. immune checkpoint inhibitor alone) should be evaluated. Ipilimumab and tremelimumab are recombinant monoclonal antibodies against cytotoxic CTLA-4. Response rate to single agent tremelimumab was disappointing and it was associated with significant toxicity in advanced NSCLC [33]. In a phase II study in first-line setting, ipilimumab with chemotherapy showed a modest improvement in PFS limited to those advanced NSCLC patients who received phased ipilimumab, allowing exposure to chemotherapy before ipilimumab, especially among patients with squamous NSCLC. No survival benefit was reported [34]. The ongoing phase III (NCT02279732 and NCT01285609) trials assess ipilimumab in combination with first-line chemotherapy in squamous advanced NSCLC patients. Unpublished lack of PFS and OS benefit has been reported in the last one compared to standard chemotherapy.

4. Combination of anti-PD-1/PD-L1 antibodies with anti-CTLA4 antibodies Early preclinical studies suggested that combined CTLA-4 and PD-1 pathway blockade produced synergistic anti-tumour activity [2,35]. In patients with metastatic melanoma [36] the combination of nivolumab and ipilimumab reported enhanced activity relative to either monotherapy. The same combination showed antitumor activity with durable responses and manageable safety profiles in recurrent small cell lung cancer [37]. In NSCLC, pembrolizumab and ipilimumab were tested as second-line treatment in 17 advanced NSCLC patients in the multicohort phase I KEYNOTE 021 trial. The combination reported a RR of 55% (9% of complete responses) while disease control was seen in all patients (100%), with 11% of grade 3 AEs [38]. These results suggested a robust antitumor activity for pembrolizumab plus ipilimumab in recurrent NSCLC patients and this strategy is ongoing in the phase II KEYNOTE 021 trial-cohort H (NCT02039674) in the first-line setting. Nivolumab plus ipilimumab as first-line treatment for advanced NSCLC has been tested in the multicohort phase I CheckMate 012 study [39]. 78 patients were randomly assigned to receive nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 12 weeks (n = 38) or every 6 weeks (n = 40). Confirmed RR were of 47% and 38% in the schedule arm of every 12-weeks and in the schedule of 6-weeks cohorts, respectively. Median duration of response was not reached in either cohort. Median PFS was longer in the ipilimumab every-12-weeks than in the every-6-weeks (8.1 months vs. 3.9 months). Overall survival in both cohorts has not been reported due to large proportion of patients 3 having been censored at the time of the analysis. Similar proportion of grade 3–4 treatment-related AEs were reported in both cohorts (37% in the ipilimumab every 12-weeks vs. 33% in the cohort of every-6-weeks); being the most commonly reported grade 3–4 AEs increased lipase, pneumonitis, adrenal insufficiency and colitis. Treatment-related serious AEs were reported in 32% and 28% of both cohorts, respectively (Table 1). No treatmentrelated deaths occurred. PD-L1 expression was not used to select patients, but approximately 20% of patients were strong PD-L1 positive expression (by Dako, clone 28-8, Epitomics). The magnitude of clinical benefit achieved with the combination treatment was enhanced with higher PD-L1 expression. Pooling the two cohorts, in patients with 1% or greater tumour PD-L1 expression the RR was 57% compared to RR of 92% reported among 12 patients with PD-L1 expression ≥ 50%. Disease progression in the ipilimumab every-6weeks cohort occurred early, with 44% of patients with disease progression experiencing progression or dying before their first imaging assessment (compared with 18% in the ipilimumab every12-weeks cohort) [39], suggesting a potential deleterious effect of upfront immunotherapy in some patients and the need of better patient selection for these therapeutic strategies [20], rather than suggesting intrinsic differences in clinical activity between ipilimumab given every 6-weeks or every 12-weeks. After integrating observations from other tumour types in which greater ipilimumab exposure was associated with improved activity, the nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks regimen was chosen for further development in NSCLC [39]. In a phase Ib trial, in 102 immunotherapy-naïve advanced NSCLC patients, the combination of durvalumab and tremelimumab was tested [40]. PD-L1 expression was tested in archival or fresh tissue biopsy by Ventana SP263 immunohistochemistry assay. Samples were judged positive if 25% or more of tumour cells showed membrane staining for PD-L1. Serious AEs occurred in 36% of patients, and 28% of patients discontinued treatment because of AEs. Based on the available safety and clinical data, durvalumab 20 mg/kg every 4 weeks plus tremelimumab 1 mg/kg every 4 weeks was selected for dose expansion. Among 63 response-evaluable

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Table 1 Immune checkpoint inhibitors in first-line treatment in advanced non-small cell lung cancer patients. Study

Phase

N

RR (%)

PFS (months)

OS (months)

AE’s ≥ grade 3 (%)

KEYNOTE 001 [13,14] Pembrolizumab (up-front cohort) CheckMate 012 [18] Nivolumab

I

101

24.8 (50 in PD-L1 ≥ 50%)

6 (12.5 in PD-L1 ≥ 50%)

22.1 (NR in PD-L1 ≥ 50%)

9.5

I

52

23 (50 in PD-L1 ≥ 50%)

3.6 (8.4 in PD-L1 ≥ 50%)

19

142 PD-L1 +* 156

25

7.3

21.8 (1-y OS: 83% in PD-L1 ≥ 50%) 23.5

22.5

4.4

NR

59 305 PD-L1 ≥ 50%** 423 PD-L1 ≥ 5%*** 123

25 44.8 vs. 27.8 p < 0.001 26.1 vs. 33.5 55 vs. 29 p = 0.0016

NR 10.3 vs. 6.0 HR 0.50, p < 0.001 4.2 vs. 5.9 HR 1.15, p = 0.251 13.0 vs. 8.9 HR 0.53, p = 0.0102

NR HR 0.60, p = 0.005 1-year OS: 70% vs. 54%, 14.4 vs. 13.2 months HR 1.02 HR 0.90, p = 0.39

47 38

8.1 3.9

Not calculated

II BIRCH [21] Atezolizumab I JAVELIN [22] Avelumab I DURVALUAMB [23] III KEYNOTE 024 [15] Pembrolizumab vs. CT III CheckMate 026 [19] Nivolumab + CT vs. CT KEYNOTE 021 [31] II Pembrolizumab + CT vs. CT I CheckMate 012 [39] Nivolumab + Ipilimumab/12w Nivolumab + Ipilimumab/6 w

38 40

Serious AE’s 33 11 9 26.6 vs. 53.3 17.6 vs. 50.6 39 vs. 26%

37 33

RR: Response Rate; PFS: progression-Free Survival; OS: Overall Survival; AE’s: Adverse Event’s; NR: not reported. * TC3 or IC3 = TC ≥ 50% or IC ≥ 10% PD-L1–expressing cells; TC2 and IC2 = ≥ 5% but IC < 10% and TC < 50% PD-L1–expressing cells; TC2/3 or IC2/3 = TC or IC ≥ 5% PD-L1–expressing. **Expression on at least 50% of tumour cells, regardless of the staining intensity with the 22C3 clone. *** tumor cell membrane staining any intensity > 1% with the 28-8 clone Epitomics.

patients, the ORR was 23%, and anti-tumour activity was observed independently of PD-L1 status [40]. Several phase 3 studies are ongoing to assess dual checkpoint inhibitor blockade (NCT02453282, MYSTIC trial with durvalumab with or without tremelimumab versus chemotherapy, NCT 02542293, NEPTUNE trial comparing the combination of durvalumab and tremelimumab to platinum-based chemotherapy; and NCT02477826, the CheckMate 227 trial, a prospective phase 3 study in PD-L1 positive tumours of nivolumab, nivolumab plus ipilimumab, or nivolumab plus chemotherapy versus chemotherapy for the first-line treatment of patients with advanced NSCLC). These trials will elucidate the first-line strategy for patients with advanced NSCLC. However, toxicity profile of these combinations might be a limitation for its whole applicability. Future perspectives in first-line treatment with immune checkpoint inhibitors PD-L1 status in first-line should be considered a new predictive biomarker as well as EGFR mutation and ALK translocation for guiding treatment of advanced NSCLC patients and should be requested upfront. In light of recent positive results from KEYNOTE 024 trial in tumours with strong PD-L1 expression [15], randomised studies would be needed to examine whether the addition of anti-CTLA4 to anti-PD-1 indeed expands benefit compared with anti-PD-1 monotherapy in this subgroup, as well as across the range of levels of PD-L1 expression. However, the safety profile of combinations and the costs of these strategies together with patients’ quality of life should also be evaluated. An urgent clinical challenge in NSCLC is the identification of optimal combination strategies in the first-line setting to expand the breadth of patients who can benefit from these strategies, and define the best treatment approach for patients with PDL1-negative tumours. If immunotherapeutic strategies become standard first-line treatment in the majority of NSCLC patients, knowledge of mechanisms of acquired resistance; efficacy of local therapies combined with immunotherapies and new treatment strategies will be needed. The potential activity of immune checkpoint inhibitors after resistance to immune-checkpoint-inhibitor treatment and the role of sequential strategies should also be defined. Furthermore, in order to better select patients and given the risk of hyper-progression on anti-PD-1/anti-PD-L1 [20] clinical characteristics others than PD-L1 expression should be clearly

defined. Treatment duration with immune checkpoint inhibitors is a key with a direct impact on cost; detailed health economic analyses are therefore needed to ensure equal access to such treatments [41]. Finally, because of the low mutational burden in EGFR-mutant and ALK-rearranged NSCLC patients [42], the optimal placement of immunotherapies remains to be determined among these molecularly selected patients. Moreover, the optimal sequence of treatment combining immune checkpoint inhibitors and radiotherapy in patients with brain metastases is a future challenge. Financial support and sponsorship None. Conflict of interest There are no conflicts of interest. Acknowledgments None References [1] S.L. Topalian, C.G. Drake, D.M. Pardoll, Immune checkpoint blockade: a common denominator approach to cancer therapy, Cancer Cell 27 (2015) 450–461, http://dx.doi.org/10.1016/j.ccell.2015.03.001. [2] D.M. Pardoll, The blockade of immune checkpoints in cancer immunotherapy, Nat. Rev. Cancer 12 (2012) 252–264, http://dx.doi.org/10.1038/nrc3239. [3] D. Hanahan, R.A. Weinberg, Hallmarks of cancer: the next generation, Cell 144 (2011) 646–674, http://dx.doi.org/10.1016/j.cell.2011.02.013. [4] J. Brahmer, K.L. Reckamp, P. Baas, L. Crinò, W.E.E. Eberhardt, E. Poddubskaya, S. Antonia, A. Pluzanski, E.E. Vokes, E. Holgado, D. Waterhouse, N. Ready, J. Gainor, O. Arén Frontera, L. Havel, M. Steins, M.C. Garassino, J.G. Aerts, M. Domine, L. Paz-Ares, M. Reck, C. Baudelet, C.T. Harbison, B. Lestini, D.R. Spigel, Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer, N. Engl. J. Med. 373 (2015) 123–135, http://dx.doi.org/10.1056/ NEJMoa1504627. [5] H. Borghaei, L. Paz-Ares, L. Horn, D.R. Spigel, M. Steins, N.E. Ready, L.Q. Chow, E.E. Vokes, E. Felip, E. Holgado, F. Barlesi, M. Kohlhäufl, O. Arrieta, M.A. Burgio, J. Fayette, H. Lena, E. Poddubskaya, D.E. Gerber, S.N. Gettinger, C.M. Rudin, N. Rizvi, L. Crinò, G.R. Blumenschein, S.J. Antonia, C. Dorange, C.T. Harbison, F. Graf Finckenstein, J.R. Brahmer, Nivolumab versus docetaxel in advanced

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