Pembrolizumab/Chemo Continues to Impress in NSCLC With 5-Year Updates

Ticiana Leal, MD

Associate Professor

Department of Hematology and Medical Oncology

Director

Thoracic Medical Oncology Program

Emory University School of Medicine

Winship Cancer Institute

Atlanta, GA

Targeted Oncology: Please discuss the long-term data from the KEYNOTE-407 trial (NCT02775435) evaluating chemotherapy plus pembrolizumab.

Ticiana Leal, MD: Data from the KEYNOTE-407 study led to FDA approval of the combination of chemotherapy plus pembrolizumab [Keytruda] for patients who were treatment naive with non–small cell lung cancer [NSCLC] and squamous histology.¹ In this trial, patients who had stage IV disease and had no symptomatic brain metastases were included.

Patients were a randomly assigned 1:1 to receive pembrolizumab plus chemotherapy with the backbone of carboplatin plus paclitaxel followed by pembrolizumab maintenance for up to 31 cycles vs placebo plus chemotherapy and followed by placebo maintenance. In this study, they did allow optional crossover of pembrolizumab for up to 35 cycles. The primary end points were progression-free survival [PFS] and overall survival [OS].

The 5-year OS and PFS data from the KEYNOTE-407 trial showed sustained benefit in the squamous cell population with an OS of 18.4% with pembrolizumab vs 9.7% with placebo and an HR of 0.71.² The PFS was also improved in the treatment arm at 10.8% months vs 3.5%, respectively.

How does PD-L1 expression affect the efficacy for patients with NSCLC?

When evaluating the breakdown by PD-L1 expression, what has been demonstrated across the KEYNOTE trials is that the higher the PD-L1 expression, the greater the magnitude of benefit from the combination.

In the population with a PD-L1 expression of 50% or greater, the 5-year updated OS rate is 23% [in the experimental arm] vs 8.3%. In the population with a PD-L1 of 1% to 49%, the OS update is 20.6% vs 7.5%. In the population with a PD-L1 negative expression, the OS rates are 10.7% vs 13%, and the median was 15 months of follow-up. For the PD-L1 negative subgroup, especially in frontline, monotherapy is not recommended.

Regarding the PFS, the greater the PD-L1 expression, the greater the magnitude in terms of PFS benefit. For patients with a PD-L1 expression of greater than 50%, the PFS is 15% vs not reached [NR]. For those with a PD-L1 expression of 1% to 49%, the PFS was 11.8% [vs NR], and then for the patients with a negative PD-L1 expression the PFS was 7.1% [vs 6.7%]. For patients with a PD-L1 less than 1% the median is 7.1 months vs 6.7 months.

What were the adverse events (AEs) seen on KEYNOTE-407?

In terms of AEs, we have all been accustomed to using this regimen. The majority of the AEs are from the chemotherapy backbone [occurring in 20% of patients in the experimental vs control arms]. These AEs include anemia [53.2% vs 51.8%], alopecia [46.0% vs 36.4%], neutropenia [38.7% vs 32.9%], nausea [35.6% vs 32.1%], and thrombocytopenia [30.6% vs 23.2%; in each arm respectively].¹

For the immune mediated AEs, the grade 3 to 5 AEs were lower [than the grade 1 and 2 AEs]. Pneumonitis was 2.1% with chemotherapy alone and 6.5% with pembrolizumab plus chemotherapy. [Other most common immune-mediated AEs included hypothyroidism (1.8% vs 7.9%, respectively) and hyperthyroidism (0.7% vs 7.2%)].

What were the long-term data from the phase 3 POSEIDON trial (NCT03164616) evaluating durvalumab with or without tremelimumab plus chemotherapy?

The phase 3 POSEIDON trial is an open-label, global, randomized study evaluating patients with metastatic NSCLC in the front line.³ Patients were also stratified by PD-L1 expression, disease stage, and histology.

In this trial, the study design is a little bit different, because patients were randomly assigned 1:1:1. In the first arm, patients received tremelimumab [Imjudo], the CTLA-4 inhibitor, plus durvalumab [Imfinzi], the PD-L1 inhibitor, plus chemotherapy for 4 cycles. This was followed with tremelimumab for only 1 additional dose on cycle 5, and then continued with durvalumab monotherapy maintenance. In the second arm, patients received durvalumab plus chemotherapy for 4 cycles, followed by durvalumab maintenance. In the control arm, patients received platinum-based chemotherapy for up to 5 or 6 cycles. The end points for the durvalumab/chemotherapy vs chemotherapy arm were PFS and OS as well as for the quadruplet, tremelimumab/durvalumab/chemotherapy vs chemotherapy.

In terms of PFS and OS, the durvalumab/tremelimumab plus or minus chemotherapy 4-year update showed durable benefit for PFS and OS for the quadruplet. For the triplet, which was durvalumab/chemotherapy vs chemotherapy, the PFS rate was improved but did not meet OS. Thus, we do not have approval for this combination, but we do have approval for the quadruplet.

At the 4-year update, the HR was 0.77 and the 24-month OS was 32.9 months in the quadruplet vs 22.1 in the triplet.

What did the 5-year update of POSEIDON show?

For the updated OS rate at 5 years, at the 60-month landmark analysis, the probability of OS with tremelimumab/durvalumab/chemotherapy vs chemotherapy was 15.7 months vs 6.8 in all comers.⁴

Although numerically improved, the durvalumab/chemotherapy vs chemotherapy did not meet statistical significance in terms of OS by histology. At the 60-month update for the non–squamous population, the OS rate was 20.5% in the quadruplet vs 9.1% chemotherapy alone. In the squamous population at the 60-month analysis, the OS rate was 7.6% vs 2.9%, respectively. The OS was 10.4 months for the squamous population with the quadruplet vs 10.5 months with chemotherapy alone. It is important to note that the greater benefit was in the non–squamous population here, with an OS rate of 20% vs 9%.

In terms of the 5-year OS for the PD-L1 negative population receiving tremelimumab/durvalumab/chemotherapy the OS rate was 6.1% vs 4% in the chemotherapy-alone arm.

In terms of subsequent anti-cancer therapy, data showed that for the patients receiving the tremelimumab/durvalumab/chemotherapy vs chemotherapy alone, approximately 19 patients were still receiving chemotherapy in the tremelimumab/durvalumab/chemotherapy arm at the data cutoff vs 0 patients in the chemotherapy-alone arm. There were approximately 10 patients who were still ongoing with maintenance pemetrexed, and approximately 35% of patients received subsequent therapies, including a small number of patients that received subsequent immunotherapy.

There were higher rates of patients receiving immunotherapy in the chemotherapy arm, which are quite low. This was a global study, and even though you might expect more patients would have received immune therapy, this was not the case.

In terms of safety, overall, when adding the CTLA-4 inhibitor and comparing with chemotherapy, the treatment-related AEs leading to death were comparable to the chemotherapy-alone arm. In the longer-term follow-up, there was no additional signal of increased toxicity with this combination strategy.

REFERENCES:

1. Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med. 2018;379(21):2040-2051. doi:10.1056/NEJMoa1810865

2. 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. 2023;41(11):1999-2006. doi:10.1200/JCO.22.01990

3. 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. 2023;41(6):1213-1227. doi:10.1200/JCO.22.00975

4. Peters S, Cho BC, Luft AV, et al. Durvalumab with or without tremelimumab in combination with chemotherapy in first-line metastatic NSCLC: five-year overall survival outcomes from the phase 3 POSEIDON trial. J Thorac Oncol. Published online September 5, 2024. doi:10.1016/j.jtho.2024.09.1381