Phase II trials

In the single-arm, phase II CheckMate 568 trial, 288 chemotherapy-naive stage IV NSCLC patients received nivolumab 3 mg/kg Q2W plus ipilimumab 1 mg/kg Q6W for up to 2 years. EGFR– and ALK-targetable NSCLC patients were not allowed. The primary endpoint was objective response rate (ORR) in patients with 1% or more and less than 1% tumor PD-L1 expression. Efficacy according to the TMB assessed by FoundationOne CDx assay was a secondary endpoint. TMB classification performance with receiver operating characteristic (ROC) curves was used to determine an appropriate and clinically validated TMB cut-off associated with enhanced activity of immunotherapy combination in the first-line setting in NSCLC patients.14 Of treated patients with tumor available for testing, 252 patients (88%) of 288 were evaluable for PD-L1 expression (55% PD-L1≥1% and 45% PD-L1<1%) and 98 patients (34%) for TMB (49% with TMB ≥10 mutations per megabase, Mut/Mb). In all treated patients, the RR was 30%, reaching 41% in patients with 1% or greater and 15% in patients with less than 1% tumor PD-L1 expression. Median PFS was longer (6.8 months vs 2.8 months) in patients with 1% or greater vs less than 1% tumor PD-L1 expression. In the TMB-evaluable population, RR increased in subgroups of patients with higher TMB, plateauing at 10 or more Mut/Mb (RR: 9%, 15%, 44%, and 39% in patients with TMB <5, 5–10, ≥10, and ≥15 Mut/Mb, respectively). The association of efficacy with TMB did not depend on tumor PD-L1 expression. Regardless of PD-L1 expression, RR was greater in patients with TMB of 10 or more Mut/Mb (42% PD-L1≥1% and 47% PD-L1<1%) versus TMB of fewer than 10 Mut/Mb (18% PD-L1≥1% and 5% PD-L1<1%). Median PFS was longer in patients with TMB ≥10 Mut/Mb, 7.1 months compared with 2.8 in patients with TMB <10 Mut/Mb. ROC analysis of TMB vs RR for nivolumab and ipilimumab demonstrated optimal classification performance at 10 Mut/Mb.14 The safety profile for nivolumab and ipilimumab was consistent with previous reports, and no new safety signals were observed, with grade 3≥ AEs in 29% of patients in the whole population, leading to treatment discontinuation in 9% of cases.14 This cutoff point of TMB was subsequently validated through a preplanned analysis in the randomized phase III CheckMate 227 trial.9

Phase III & IV trials

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Several phase III and IV studies have assessed the activity and safety of dual checkpoint inhibitor blockade in first-line setting of advanced NSCLC patients, such as the CheckMate 227 trial (NCT02477826), CheckMate 817 trial (NCT 02869789), DICIPLE trial (NCT03469960), CheckMate 9LA trial (NCT03215706), the MYSTIC trial (NCT02453282), NEPTUNE trial (NCT 02542293), and POSEIDON trial (NCT03164616).

The phase III CheckMate 227 trial assessed multiple hypotheses regarding the efficacy of nivolumab or nivolumab-based regimens in first-line treatment in biomarker-selected advanced NSCLC patients without EGFR– or ALK-positive tumors. The trial randomized 1,739 patients not selected according to PD-L1 expression; however, 68% of randomized patients (N=1189) had tumors with PD-L1 expression ≥1% by 28–8 Dako IHC.9 According to emerging data reported in the CheckMate 568 trial regarding the correlation between high TMB and efficacy,14 the CheckMate 227 trial protocol was amended and PFS (assessed by blinded independent central review) with nivolumab (3 mg/kg Q2W) and ipilimumab (1 mg/kg Q6W until PD or toxicity) versus chemotherapy based on tumor histologic type in patients with TMB ≥10 Mut/Mb (by FoundationOne CDx assay) regardless of PD-L1 expression was added as coprimary endpoint. The other co-primary endpoint was OS with nivolumab plus ipilimumab in a population selected on the basis of PD-L1 expression.9

Of the 1,739 patients enrolled in the trial, only 1,004 (58%) patients had valid results for assessing TMB. Of them, 44% were classified as TMB-high (24% of the intent-to-treat population), and just 299 were selected for evaluating the coprimary PFS endpoint.9 Crossover between treatment groups within the trial was not allowed, but almost 30% of patients assigned to chemotherapy arm received subsequent immunotherapy. One-third of patients had PD-L1 expression <1%, squamous histology subtype, and were females. Nivolumab plus ipilimumab in high TMB was associated with longer PFS (7.2 vs 5.5 months, HR 0.58; 97.5% CI, 0.41 to 0.81; p<0.001) and increased RR (45% vs 27%) compared with chemotherapy. The PFS benefit was observed for all TMB-high subgroups regardless of PD-L1 expression (≥1%, HR: 0.62 (95% CI, 0.44–0.88) or <1%, HR 0.48 (95% CI, 0.27–0.85)); however, the percentage of patients with tumors with PD-L1≥50% is not reported; histologic subtype (squamous, HR 0.63 95%CI, [0.39–1.04]; nonsquamous, HR 0.55; 95%CI [0.38–0.80]), sex (male, HR 0.52; 95%CI [0.36–0.74]; female HR 0.70; 95%CI [0.41–1.20]), and performance status (PS 0, HR 0.62; 95%CI [0.38–1.02]; PS 1, HR 0.55; 95%CI [0.38–0.80]). It is noteworthy that PFS curves cross during the first four months of treatment, suggesting that selected patients according to high TMB criteria may not overcome the risk of rapid progression or lack of response with immunotherapy combination. The rate of grade ≥3 treatment-related AEs was 31.2% with immune combination vs 36.1% with chemotherapy, mainly hepatic events. However, a higher proportion of patients discontinued treatment as a consequence of AEs in nivolumab and ipilimumab arm than in the chemotherapy arm (17.4% vs 8.9%).9

A recent press release about a CheckMate 227 trial on 19 October 201852 reported an updated descriptive analysis showing that the HR for OS with nivolumab and ipilimumab versus chemotherapy in patients with TMB ≥10 Mut/Mb was 0.77 (95% CI: 0.56–1.06), with a median OS of 23.3 months and 16.7 months, respectively. Of note, among patients with TMB <10 Mut/Mb the HR for OS (HR 0.78, 95% CI 0.61–1.00) was comparable to that observed in patients with high TMB,52 suggesting a potential prognostic value rather predictive value for high TMB. Based on this lack of statistically significant benefit in OS, the company believes further evidence on the relationship between TMB and PD-L1 is required to fully evaluate the impact of nivoluamb  plus ipilimumab on OS in first-line NSCLC patients with high TMB, and the sponsor has withdrawn regulatory applications for lung cancer drug combination with nivolumab and ipilimumab in this population.

Approximately one-third of NSCLC tumors do not express PD-L1. In the first-line setting, in PD-L1 negative tumors, the combination of pembrolizumab and chemotherapy significantly improves the outcome compared with chemotherapy regardless of the histological subtype.2,4 One secondary endpoint in the CheckMate 227 trial was to assess in first-line setting the efficacy of nivolumab in combination either with ipilimumab (N=187) or with chemotherapy (N=177) and compared with chemotherapy alone (N=186) in PD-L1 negative NSCLC patients. In patients with TMB ≥10 Mut/Mb and PD-L1 expression <1%, the PFS was longer with nivolumab in combination with either chemotherapy (6.2 months vs 5.3 months, HR 0.56, 95%CI 0.35–0.91) or ipilimumab (7.7 months vs 5.3 months, HR 0.48, 95%CI 0.27–0.85) compared with chemotherapy alone; the RR was also higher (61% vs 37% and 21%, respectively). Conversely, in the subset of patients with <10 Mut/Mb and <1% PD-L1 expression, the addition of nivolumab to either chemotherapy or ipilimumab did not appear to have any PFS benefit in comparison with chemotherapy alone (HR 0.87, 95%CI 0.57–1.33 for nivolumab plus chemotherapy and HR 1.17, 95%CI 0.76–1.81 for nivolumab–ipilimumab combination).53 These results could suggest that TMB may play a role in selecting negative PD-L1 NSCLC patients suitable for receiving immune checkpoint inhibitors. However, contrary to other trials,2,4 no survival data have been reported; therefore, it remains unknown whether or not TMB should be used in PD-L1 negative patients as a predictive marker. The outcome, the treatment cost, and the safety may help to elucidate the best upfront strategy in this population.

Other ongoing first-line clinical trials are assessing the role of nivolumab and ipilimumab with or without chemotherapy (Table 3), such as the multi-cohort phase III/IV CheckMate 877 trial (NCT02869789),54 and the CheckMate 9LA trial (NCT03215706), as well as the MYSTIC trial assessing the role of durvalumab and tremelimumab in this scenario. Recent data have reported comparable exposure, safety and efficacy between flat dose nivolumab compared to the weight-based regimen.55,56 This schedule is being prospectively evaluated in the multi-cohort CheckMate 817 phase IIIB/IV trial, which assesses the efficacy of flat dose nivolumab (240 mg Q2W) plus ipilimumab (1 mg/kg Q6W) until progression in PD-L1 positive or negative, chemotherapy naive NSCLC patients (arm A). Other cohorts included in the CheckMate 817 trial were: cohort A1 testing the combination in special populations (HIV patients, patients with BM, and patients with renal or hepatic failure), cohort B testing the combination in previously treated patients with at least one platinum-based chemotherapy, and cohort C enrolling patients whose tumors have high TMB (≥10 Mut/Mb). The primary endpoint of the trial is the proportion grade ≥3 of treatment-related AEs (TR-AEs) and ir-AEs. Secondary endpoints include RR, duration of response (DoR), PFS, and OS. For instance, only results from cohort A, enrolling 391 treatment naive patients, have been reported. The majority of patients in this cohort were current or former smokers (91%) and had an adenocarcinoma lung cancer (72%). PD-L1≥1% expression (tested by 28–8 IHC) was reported in 49% of patients, including 18% of patients with PD-L1 expression ≥50%. The TMB (by FoundationOne CDx assay) was evaluable in 39% of patients (N=151) and among these patients, 48% had high TMB. All grades of TR-AEs occurred in 75% of patients, with 32% of grade ≥3 TR-AEs leading to treatment discontinuation in 18% of cases. The median time to onset TR-selected AEs ranged from 2.1 to 19.2 weeks. The median PFS was 6 months, and median RR was 35%, the without differences according to histologic subtype. For efficacy in biomarker-selected patients, better RR and PFS were reported in PD-L1≥1% verses PD-L1<1% tumors (41% vs 28% and 8.1 vs 5.3 months), as well as in TMB high versus low tumors (54% vs 29% and 10.9 vs 4.2 months).54 These results report comparable clinical activity (PFS and RR) in patients with high TMB across CheckMate 227, 568 and 817 (Table 2).

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