Novel Checkpoints Could Broaden the Benefit of Immunotherapy in NSCLC

Martin E. Gutierrez, MD, discusses some of the most encouraging ongoing clinical trials in metastatic NSCLC.

Novel agents targeting LAG-3, TIGIT, and TIM-3 in combination with established checkpoints, such as PD-1/PD-L1 and CTLA-4, are under investigation in the first- and second-line settings of advanced non–small cell lung cancer (NSCLC), explained Martin E. Gutierrez, MD, who added that certain combinations are already slated for further study in phase 3 trials. 

During a 2020 Institutional Perspectives in Cancer webinar on lung cancer, Gutierrez, co-chief of Thoracic Oncology and director of the Phase I Program at Hackensack Medical Center, discussed some of the most encouraging ongoing clinical trials in metastatic NSCLC. 

Research Builds Upon Checkpoint Inhibition in the First-Line Metastatic Setting

The first-line combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) set the stage for some of the ongoing research in frontline metastatic NSCLC, said Gutierrez.

Findings from the open-label phase 2 CheckMate-568 trial showed that patients with PD-L1 expression of 1% or greater (n = 138) had a median progression-free survival (PFS) of 6.8 months (95% CI, 4.0-11.3) compared with 2.8 months (95% CI, 2.1-4.0) in patients with PD-L1 expression of less than 1% (n = 114).1 Additionally, patients with a tumor mutational burden (TMB) of 10 or more mutations/Mb (n = 48) had a median PFS of 7.1 months (95% CI, 3.6-11.3) versus 2.6 months (95% CI, 1.4-5.4) in patients with a TMB less than 10 mutations/Mb. 

The objective response rate (ORR) was 29.9% overall (n = 288), 14.9% in patients with less than 1% PD-L1 expression (n = 114), 41.3% in patients with 1% or greater PD-L1 expression (n = 138), 50% in patients with 50% or greater PD-L1 expression (n = 68), and 33.3% in patients whose PD-L1 expression was not quantifiable (n = 36). 

Regarding TMB, the ORR was 8.7% in patients with TMB less than 5 mutations/Mb (n = 23), 14.8% in patients with TMB of 5 or greater but less than 10 mutations/Mb (n = 27), 43.8% in patients with TMB of 10 or greater mutations/Mb (n = 48), 50% in patients with TMB of 10 or greater but less than 15 mutations/Mb (n = 20), and 39.3% in patients with TMB of 15 or greater mutations/Mb (n = 28). 

“CheckMate-568 provided the background on the newly approved nivolumab and ipilimumab combination in NSCLC [based on] CheckMate-227,” explained Gutierrez.

The CheckMate-227 trial demonstrated improved overall survival (OS) with nivolumab/ipilimumab versus chemotherapy among patients with at least 1% PD-L1 expression.2 On May 15, 2020, the FDA approved the combination for use as frontline therapy in patients with metastatic NSCLC whose tumors do not harbor EGFR or ALK genomic aberrations, and whose tumors express a PD-L1 level of at least 1%, as determined by an FDA-approved test.3 

Research efforts are ongoing to build upon the benefits that have been demonstrated with immunotherapy, explained Gutierrez.

For example, findings from an ongoing phase 1/2 trial of quavonlimab (MK-1308; NCT03179436), a novel CTLA-4 inhibitor, showed early efficacy signals with the agent in combination with pembrolizumab (Keytruda) as a first-line regimen for patients with advanced solid tumors.4 

Updated interim results from the dose-escalation trial revealed a 6-month PFS rate of 67% and a 6-month OS rate of 89% when quavonlimab was dosed at 25 mg every 6 weeks. Additionally, a 25% ORR was observed in patients with PD-L1–negative disease. The ORR was 39% when quavonlimab was given at a dose of 25 mg every 3 weeks, 33% at 25 mg every 6 weeks, 22% at 75 mg given every 6 weeks, and 25% at 75 mg given every 3 weeks. 

Regarding safety, no unexpected toxicities were observed; the rate of grade 3 or greater treatment-related adverse effects (TRAEs) was 0% at the 25 mg every-3-week dosing schedule and 25% at 25 mg every 6 weeks. The highest rate of grade 3 or greater TRAEs (75%) was observed when quavonlimab was given at 200 mg every 3 weeks. 

Additionally, the adaptative, phase 2 KEYNOTE-495/KeyImPaCT trial (NCT03516981) is ongoing and recruiting patients.5 The biomarker-driven study will randomize patients to receive pembrolizumab in combination with the LAG-3 inhibitor MK-4280, lenvatinib (Lenvima), or quavonlimab. After biomarker screening, patients will be assigned to groups based on their TMB and gene expression profiling statuses. Moreover, adaptative design elements, based on objective responses, will be used to adjust patient randomization. 

Other novel agents are also under evaluation in the frontline space, including MK-4830, an immunoglobulin-like transcript 4 inhibitor, and BMS-986207. The latter monoclonal antibody inhibits TIGIT, which is emerging as an immune checkpoint in this space. 

“Although the roles of TIGIT and CD96 as immune checkpoint receptors in T-cell and natural killer [NK] cell biology are just beginning to be uncovered, accumulating data has been quite promising. That is the reason that these studies are moving toward first-line phase 3 [studies] in NSCLC,” said Gutierrez.

Ongoing Trials Focus on Novel Immunotherapies in the Second-Line Setting and Beyond 

The second-line setting of NSCLC is also rich with investigational regimens, many of which are being evaluated in first-in-human trials, Gutierrez explained.

For example, BMS-986218, which is an investigational non-fucosylated anti–CTLA-4 antibody, is being evaluated in an ongoing, first-in-human, phase 1/2a study (NCT03110107) with or without nivolumab in patients with advanced solid tumors who have received at least 2 standard treatment regimens in the advanced or metastatic setting.6 The single-agent and combination regimens will also be compared with ipilimumab monotherapy in a third experimental arm. The phase 1 portion of the study demonstrated good pharmacodynamic activity, and the phase 2 portion is currently enrolling, said Gutierrez.

Another novel approach to second-line NSCLC treatment is being evaluated in an ongoing phase 1/2 trial (NCT04370704).7 The study combines 3 novel checkpoint inhibitors, INCMGA00012, which inhibits PD-1, INCAGN02385, which inhibits LAG-3, and INCAGN02390, which inhibits TIM-3, in patients with select advanced malignancies. The primary end points of the phase 1 portion include safety, and key primary end points of the phase 2 portion include ORR, duration of response, and disease control rate. 

“This study asks the question: Can we reverse PD-1 failure? We know that PD-1 and TIM-3 have been demonstrated to be co-expressed with LAG-3 on the surface of exhausted tumor infiltrating lymphocytes. The idea [of this trial] is that co-stimulating those 3 molecules will simultaneously overcome [PD-1 inhibitor] resistance.”

Finally, Gutierrez highlighted another investigational agent, FT-516, which is an off-the-shelf, NK cell product.8 The agent is being evaluated in a phase 1 dose-finding study (NCT04551885) in combination with monoclonal antibodies, including avelumab (Bavencio), for patients with advanced solid tumors.


  1. Ready N, Hellmann MD, Awad MM, et al. First-line nivolumab plus ipilimumab in advanced non-small-cell lung cancer (CheckMate 568): outcomes by programmed death ligand 1 and tumor mutational burden as biomarkers. J Clin Oncol. 2019;37(12):992-1000. doi:10.1200/JCO.18.01042
  2. Hellmann MD, Paz-Ares L, Caro RB, et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. New Eng J Med. 2019;381(21):2020-2031. doi:10.1056/NEJMoa1910231
  3. U.S. Food and Drug Administration approves Opdivo (nivolumab) + Yervoy (ipilimumab) as first-line treatment of patients with metastatic non-small cell lung cancer whose tumors express PD-L1 ≥ 1%. May 15, 2020. Accessed January 15, 2021.
  4. Perets R, Yoh K, Kim DW, et al. Antitumor activity and safety of MK-1308 (anti-CTLA-4) plus pembrolizumab (pembro) in patients (pts) with non-small cell lung cancer (NSCLC): updated interim results from a phase I study. J Clin Oncol. 2019;37(15):2558-2558. doi:10.1200/JCO.2019.37.15_suppl.2558
  5. A study of biomarker-directed, pembrolizumab (MK-3475) based combination therapy for advanced non-small cell lung cancer (MK-3475-495/KEYNOTE-495). Posted May 7, 2018. Updated January 8, 2021.
  6. First-in-human study of monoclonal antibody BMS-986218 by itself and in combination with nivolumab in patients with advanced solid tumors. Posted April 12, 2017. Updated November 4, 2020.
  7. Study of combination therapy with INCMGA00012 (anti-PD-1), INCAGN02385 (anti-LAG-3), and INCAGN02390 (anti-TIM-3) in participants with select advanced malignancies. Posted May 1, 2020. Updated December 19, 2020.
  8. FT516 in combination with monoclonal antibodies in advanced solid tumors. Posted September 16, 2020. Updated November 2, 2020.