Concomitant Proton Pump Inhibitor Use With Pembrolizumab Monotherapy vs Immune Checkpoint Inhibitor Plus Chemotherapy in Patients With Non−Small Cell Lung Cancer

Abstract

ImportanceImmune checkpoint inhibitor (ICI) monotherapy with pembrolizumab and ICI plus chemotherapy have been approved as first-line treatments for non–small cell lung cancer (NSCLC) for patients with a programmed cell death ligand–1 (PD-L1) tumor proportion score (TPS) of 50% or more, but the choice between these 2 therapeutic options is unclear.ObjectiveTo clarify the association of a history of concurrent medication use with treatment outcomes for ICIs with or without chemotherapy in patients with NSCLC with a high PD-L1 TPS and to determine whether these clinical histories are biomarkers for appropriate treatment selection.Design, Setting, and ParticipantsThis retrospective, multicenter cohort study at 13 hospitals in Japan included patients with advanced NSCLC with a PD-L1 TPS of 50% or more who had received pembrolizumab ICI monotherapy or ICI plus chemotherapy as the initial treatment between March 2017 and December 2020. The median (IQR) follow-up duration was 18.5 (9.2-31.2) months. Data were analyzed from April 2022 through May 2023.ExposureICI monotherapy with pembrolizumab or ICI plus chemotherapy as first-line treatment.Main Outcomes and MeasuresThe primary analysis was the association of treatment outcomes with baseline patient characteristics, including concomitant drug history, after propensity score matching. Cox proportional hazard models were used to determine the associations of patient characteristics with survival outcomes. Logistic regression analysis was used to determine the association of concomitant medication history with treatment outcomes and other patient characteristics.ResultsA total of 425 patients with NSCLC were enrolled in the study including 271 patients (median [range] age, 72 [43-90] years; 215 [79%] men) who were treated with pembrolizumab monotherapy as the first-line treatment and 154 patients (median [range] age, 69 [36-86] years; 121 [79%] men) who were treated with ICI plus chemotherapy as the first-line treatment. In multivariable analysis, a history of proton pump inhibitor (PPI) use was independently associated with shorter progression-free survival (PFS) in the pembrolizumab monotherapy group (hazard ratio [HR], 1.38; 95% CI, 1.00-1.91; P = .048), but not in the ICI plus chemotherapy group. In patients with a PPI history, both the median (IQR) PFS (19.3 [9.0 to not reached] months vs 5.7 [2.4 to 15.2] months; HR, 0.38; 95% CI, 0.20-0.72; P = .002) and the median (IQR) overall survival (not reached [9.0 months to not reached) vs 18.4 [10.5 to 50.0] months; HR, 0.43; 95% CI, 0.20-0.92; P = .03) were significantly longer in the ICI plus chemotherapy group than in the pembrolizumab monotherapy group. In patients without a history of PPI use, both the median (IQR) PFS (18.8 months [6.6 months to not reached] vs 10.6 months [2.7 months to not reached]; HR, 0.81; 95% CI, 0.56-1.17; P = .26) and the median (IQR) overall survival (not reached [12.6 months to not reached] vs 29.9 [13.3 to 54.3] months, HR, 0.75; 95% CI, 0.48-1.18; P = .21) did not differ between groups.Conclusions and RelevanceThis cohort study found that a history of PPI use could be an important clinical factor in treatment decision-making for patients with NSCLC with a PD-L1 TPS of 50% or more.

Effect of Concomitant Use of Proton Pump Inhibitors on Immunotherapy Clinical Response in Advanced Cancer Patients: Real-Life Setting

“…This phenomenon could be due to the combination of pembrolizumab and conventional chemotherapy. In this sense, the present study shows a high percentage of patients benefiting from this combination regimen, and recent studies have been able to demonstrate the potential attenuating effect of chemotherapy on the effect of PPIs when associated with concomitant treatment with ICIs 27,28 …”

Is Immunotherapy With Concomitant Proton Pump Inhibitor Use a Viable Combination?

“…Kawachi and colleagues retrospectively evaluated clinical factors associated with outcomes of first-line anticancer treatment in 2 groups of patients (balanced by propensity score matching) with advanced NSCLC and PD-L1 levels of 50% or more treated with ICI monotherapy or a combination of ICI and chemotherapy. In the ICI monotherapy group, factors associated with a poorer PFS at a multivariate level were lower PD-L1 (50%-89%) and the use of concomitant PPI, whereas in the ICI and chemotherapy group, only smoking history and Eastern Cooperative Oncology Group performance status were associated with PFS.…”

“…The new hypothesis emerging from the article by Kawachi and colleagues is that when ICIs are combined with chemotherapy, the possible detrimental outcomes of PPI appear attenuated, hinting at a futuristic approach of treatment selection based not only on clinical pathological factors, but also on concomitant medications. These studies share common limitations, including their retrospective nature, the different definitions of the timing of concomitant use, the different races and ethnicities among the cohorts (and consequently different microbiomes), and the association of PPI use with other potential variables (eg, advanced age, poorer Eastern Cooperative Oncology Group performance status, the use of steroids, and additional comorbidities).…”

Readily available drugs and other interventions to potentially improve the efficacy of immune checkpoint blockade in cancer

“…While it may be advised to stop PPI usage before and during immunotherapy, patients may find reducing or avoiding PPI usage difficult. In another retrospective multivariable analysis of NSCLC patients (n=425), a history of PPIs was independently associated with shorter PFS survival when compared to ICI monotherapy in patients without PPI usage [HR 1.38, 95% CI (1.00-1.91), P =0.048] ( 80 ). Interestingly, patients with a history of PPI usage who received both ICIs and chemotherapy had similar outcomes to patients who did not take PPIs.…”

“…Interestingly, patients with a history of PPI usage who received both ICIs and chemotherapy had similar outcomes to patients who did not take PPIs. These findings suggest that the deleterious effects of PPI usage on immunotherapy is mitigated by additional treatment types, such as chemotherapy ( 80 ). However, chemotherapy in addition to ICIs may not be suitable for all patients.…”