The randomized phase III MYSTIC trial assessed the efficacy of durvalumab (20 mg/kg Q4W) monotherapy or durvalumab and tremelimumab (D: 20 mg/kg Q4W, T: 1 mg/kg Q4W up to four doses) compared with standard of care platinum-based chemotherapy in 1118 immunotherapy- and chemotherapy-naive stage IV NSCLC patients. Primary endpoints were assessed in patients with PD-L1 expression ≥25% (by SP263 IHC, N=488) and were OS for durvalumab versus chemotherapy, and OS and PFS for durvalumab and tremelimumab arm versus chemotherapy. Both co-primary PFS and OS endpoints were not met for either durvalumab monotherapy (PFS: 4.7 vs 5.4 months, HR 0.87; 99.5% CI, 0.593–1.285; p=0.324; OS: 16.3 vs 12.9 months, HR 0.76, 97.54% CI 0.564–1.019; nominal p=0.036) or durvalumab and tremelimumab (PFS: 3.9 vs 5.4 months, HR 1.05; 99.5% CI, 0.722, 1.534; p=0.705 and OS: 11.9 vs 12.9 months HR 0.85, 98.77% CI 0.611–1.173; nominal p=0.202) compared with chemotherapy. These results do not currently support the use of durvalumab as a single agent or in combination with tremelimumab in this patient population. The ongoing randomized phase III trial NEPTUNE (NCT02542293) is assessing durvalumab and tremelimumab vs chemotherapy.

An exploratory analysis of the MYSTIC trial15 examined the OS according to high blood (b)TMB (≥16 Mut/Mb). More than 70% of patients had bTMB evaluation, 40% of whom had high bTMB; for these patients OS was 16.5 months with the combination of durvalumab and tremelimumab versus 10.5 months with chemotherapy (HR 0.62; 95%CI: 0.45–0.86), but durvalumab monotherapy did not improve the OS compared with chemotherapy (11 vs 10.5 months, HR 0.80; 95%CI: 0.59–1.07). The 2-year OS in high bTMB was 39% with the combination, 30% with durvalumab and 18% with chemotherapy. For patients with low bTMB, no survival differences were reported between arms, and median OS was 8.5 months with durvalumab and tremelimumab, 12.2 months with durvalumab alone and 11.6 months with chemotherapy.15 Similarly, in a recent exploratorty analysis with bTMB ≥ 20 mut/Mb survival benefit has been reported with durvalumab and tremelimumab compared with chemotherapy.15 Contrary to CheckMate 227, results from the MYSTIC trial show a potential role for TMB as a predictive biomarker for survival benefit from a combination of immunotherapies; however, it was an exploratory analysis and these results would require prospective validation.

At least four randomized phase III clinical trials have reported that the combination of anti-PD(L)1 and chemotherapy with57 or without bevacizumab2,4,58 improved the OS compared with standard of care regardless of histology and PD-L1 expression. The purpose of the ongoing phase III CheckMate 9LA trial (NCT03215706) is to determine whether nivolumab plus Ipilimumab plus chemotherapy improves the OS compared with chemotherapy alone in the first-line setting. Similarly, the randomized phase III POSEIDON trial (NCT03164616) evaluates durvalumab plus chemotherapy with or without tremelimumab or chemotherapy alone in the same population. Patients are not selected according to PD-L1 expression or high TMB in any of both trials. For instance, different first-line strategies are available; therefore, the magnitude of benefit according to validated and accepted scales59 and toxicity profile may help to elucidate the best treatment approach.

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Patients with brain metastases

Up to 30% of advanced NSCLC patients have BM at baseline, with a 3-year OS <10%,60 suggesting that new systemic treatment options are eagerly awaited. In a series of matched BM and primary NSCLC samples, PD-L1 positive samples (≥5% with E1L3N antibody) was lower for the BM compared to the paired primary (33 vs 44%).61 Conversely, TMB was significantly higher in the BM specimens.62This observation may suggest a potentially differing RR with ICI in BM compared with the primary tumor. The majority of clinical trials exclude patients with BM; however, retrospective data,63expanded access programs cohorts,64,65 and data from randomized phase III clinical trials in pre-treated advanced NSCLC patients66 suggest that central nervous system (CNS) involvement does not negatively impact the outcome on ICI, although CNS failure is more common in patients with BM at baseline compared to those without BM at baseline.63 For monotherapy with ICI there has been activity reported in a phase II trial enrolling melanoma and lung cancer patients with BM. For pembrolizumab an intracranial RR of 33% was reported in 18 PD-L1-positive NSCLC patients with untreated (N=8) or progressive asymptomatic BM between 5 and 20 mm in diameter, with a duration of response of more than 6 months. Neurological AEs were uncommon and manageable without grade 3 AEs.67 In the randomized phase III trials in first-line (KEYNOTE 189 (N=108),2 KEYNOTE 024 (N=28))1 or second-line treatment (OAK trial (N=203)),8 patients with BM were enrolled, and BM did not negatively impact in the outcome with ICI. The combination of nivolumab and ipilimumab has shown the most impressive CNS response rates to immunotherapy in two phase II trials.68,69 In the phase II CheckMate 204 study, 94 metastatic melanoma patients given nivolumab plus ipilimumab for up to four doses, followed by nivolumab until progression, reported an intracranial RR of 55%, with a treatment-related ≥ grade 3 AEs in 55% of patients. Five patients (5%) discontinued therapy due to immune-related neurologic adverse events.68 These results were confirmed in the second phase II trial69 in 36 patients with metastatic melanoma. Both trials suggest the activity and safety of nivolumab and ipilimumab in patients with untreated and asymptomatic BM. However, combination ICI treatment in NSCLC patients with BM is scarce. In the CheckMate 227 trial patients with BM were eligible if they were adequately treated and did not report neurological symptoms 2 weeks before randomization. However, efficacy in this population has not been reported.

For instance, it remains unknown to what extent the therapeutic effect of ICIs in BM relies on the local activity of ICI in the primary tumor or whether the use of previous radiotherapy may help to enhance the central activity of ICIs,70 as well as whether ICI combination strategies might also increase brain activity. The ongoing NCT02696993 trial and the CheckMate 817 trial (NCT 02869789, arm A1) are addressing these questions. Another challenge is to establish the place of RT with ICI. There is preclinical71 and clinical72,73 evidence suggesting that the concurrent strategy may have synergistic activity and favorable survival outcome compared with the sequential strategy; however, weighed activity and toxicity, mainly radionecrosis,74,75 should be carefully evaluated. Different clinical trials are ongoing about the efficacy of radiotherapy and ICI, and results of some of these trials have been summarized in a recent review.76

Elderly population

The elderly population, patients older than 70 years, are underrepresented in clinical trials, and represent a low proportion of all study populations in some studies. The median age of patients enrolled in clinical trials assessing nivolumab and ipilimumab was 68 years in CheckMate 012,46 66 years in CheckMate 058,77 65 years in CheckMate 817 with 53% of patients older than 65,54 and 64 years in the phase III CheckMate 227 trial, which includes 38% of patients between 65 and 75 years and 9.4% of patients older than 75 years.9 It has been suggested that elderly patients may derive less benefit from ICI78 or may have increased risk of hyper-progressive disease on treatment,79 but this association between age and risk of hyper-progressive disease has not been observed in a cohort of NSCLC patients.80 It has been suggested that the benefit of ICI is more related to the “age” of the immune system (immunosenescence) rather than patients’ age. The immunosenescence phenotype occurs in one-third of NSCLC patients, and it is independent of age and correlates with lower disease control rate in NSCLC patients treated with anti-PD(L)1 treatment.81 The HR for PFS according to age in the CheckMate 227 trial was 0.51 (0.34–0.77), 0.62 (0.4–0.97) and 0.42 (0.14–1.30), for patients of ≤65 years, from 65 to 75 years and ≥75 years, respectively. However, the limited number of patients older than 75 years (N=27) does not lead to any firm conclusions. As the elderly population may have more comorbidities, toxicity and efficacy ratio must be weighted as well as quality of life before the broad acceptance of nivolumab plus ipilimumab combination regardless of age. Specific clinical trials in elderly populations are awaited.

PD-L1 expression ≥50%

One clinical question is what is the best treatment strategy in NSCLC patients with PD-L1 expression ≥50%, monotherapy with pembrolizumab,1,82 combination strategy of ICI with chemotherapy with or without bevacizumab,2–4 or nivolumab and ipilimumab combination.9 Although TMB and PD-L1 are independent biomarkers, in the CheckMate 026 trial approximately 10% of patients shared both biomarkers (high TMB and PD-L1≥50%) and those patients derived the maximum benefit of nivolumab.13 In the KEYNOTE 024 trial, pembrolizumab in PD-L1≥50% reported a RR of 45%, median PFS and OS of 10 months and 30 months, respectively, with 1-year OS of 70% despite 54% of crossover to ICI in the control arm.1,82 In the CheckMate 227 trial9 nivolumab and ipilimumab in high TMB reported similar outcomes (RR of 45%, PFS of 7.1 months, and 1-year of OS 67%). However, the efficacy has not been reported according to PD-L1 expression strata, crossover was not allowed, and contrary to the KEYNOTE 024 trial, there is no survival benefit with a combination of nivolumab and ipilimumab and PFS curves in the CheckMate 227 trial crosses, not reinforcing that double immunotherapy strategy is better than monotherapy in this subgroup of NSCLC patients. The ongoing phase III KEYNOTE 589 trial (NCT03302234) may in part answer this question. The trial randomizes patients with PD-L1≥50% to pembrolizumab and ipilimumab versus pembrolizumab and placebo. However, TMB is not a stratification criterion.

Treatment duration

Treatment duration is a challenge in ICI strategy. Indeed, NSCLC patients treated with atezolizumab83or nivolumab84 achieve long-term survival despite discontinuing treatment for ir-AEs and receiving corticosteroids, but it remains unknown whether this survival benefit is linked to the time of treatment exposure or to the onset of ir-AEs, which correlates with a better outcome in NSCLC patients.85–94 In previously treated NSCLC patients the CheckMate 153 trial95 suggests that stopping nivolumab treatment after one year in the case of clinical and radiological benefit could be harmful, with shorter PFS compared with prolonged treatment beyond one year. In the melanoma, a treatment of 6 months of ipilimumab demonstrated its efficacy. The objective of the randomized phase III DICIPLE trial (NCT03469960) is to demonstrate that a treatment of 6 months of nivolumab plus ipilimumab followed by an observation (stop and go) is not less effective than nivolumab plus ipilimumab treatment given until progression or toxicity. This strategy would allow the accumulated toxicities to decrease, improve the quality of life and decrease the costs. The primary endpoint is PFS and 1,360 advanced treatment-naive PD-L1≥1% but <50% NSCLC patients will be enrolled.

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