Durvalumab with or without tremelimumab vs platinum-based chemotherapy as first-line treatment for metastatic non-small cell lung cancer: MYSTIC

Abstract

Background: PD1 inhibitors as well as PD1/CTLA4 combinations have shown remarkable efficacy in the first-line treatment of metastatic melanoma. The impact of many concomitant medications on the clinical outcomes from PD1 based therapies remains elusive. Methods: We retrospectively analyzed 140 patients included in the Checkmate 069 phase II clinical trial as a discovery cohort, comparing ipilimumab monotherapy with ipilimumab combined with nivolumab. We compared response rates, progression-free survival and overall survival of patients treated or not with 11 different classes of comedications at immune therapy initiation. Disease stage, LDH levels, BRAF status, sex, age, and body mass index were also compared. Furthermore, a protein array was performed for 440 analytes in a subset of 135 patients for whom pretreatment serum was available. We validated the impact of proton pump inhibitors in an independent cohort of 68 PD1 monotherapy (pembrolizumab or nivolumab) treated patients. Results: In univariate analysis, baseline proton pump inhibitor treatment almost halved the objective response rates, reduced progression-free and overall survival of patients treated with ipilimumab and nivolumab but not with ipilimumab alone. This effect was maintained when accounted for multiple comparisons and in a multivariate analysis. Pretreatment serum protein analysis showed increased NCAM1 and CSF3R levels in PPI users. We found increased baseline blood leukocyte and neutrophil levels in correlation with PPI use. The results were confirmed in an independent cohort of 68, first-line melanoma patients. Conclusions: Our analysis shows that proton pump inhibitors could negatively impact on the benefit from PD1 based therapies both for monotherapy and also for ipilimumab and nivolumab combination therapy. PPIs might establish a unique inflammatory immune status, prior to immune therapy initiation that interferes with treatment efficacy. These results suggest that if possible PPIs should be avoided in patients who are destined for PD1-based immunetherapies. Also, the results will have important implication for design of future clinical trials.

Clinical Activity, Tolerability, and Long-Term Follow-Up of Durvalumab in Patients With Advanced NSCLC

“…The phase III MYSTIC trial of first-line durvalumab monotherapy or durvalumab þ tremelimumab versus standard of care chemotherapy did not show a statistically significant PFS or OS advantage for either arm in patients with greater than or equal to 25% PD-L1 expression; however, durvalumab showed a clinically meaningful improvement in OS compared to chemotherapy (hazard ratio ¼ 0.76, 97.54% CI: 0.564-1.019; p ¼ 0.036). 36 The phase III PACIFIC trial of durvalumab following concurrent chemoradiotherapy in stage III, unresectable NSCLC showed statistically significant improvements in PFS and OS over placebo leading to registration for this indication. 15,37…”

The value of immunotherapy for survivors of stage IV non-small cell lung cancer: patient perspectives on quality of life

“…IO targets immune pathways allowing the body to recognize cancer cells as foreign and attack them (e.g., immune checkpoint inhibitors) or enhance overall immune functioning without targeting specific cancer cells (e.g., interleukins, interferons). When administered as monotherapy for treating advanced NSCLC, IO has been associated with response rates of approximately 20% in previously treated patients [4][5][6][7][8] and more than 25% in those who are treatment naive [9][10][11][12]. Compared with conventional chemotherapy, IO has been shown to have a comparatively benign safety profile, though the management of immune-related adverse events, which are frequently grades 1-2 but can affect multiple organ systems, is a prevalent concern [13,14].…”

Nivolumab plus Ipilimumab in Non–Small-Cell Lung Cancer

“…As discussed in detail in a subsequent section, the utility of TMB as a clinically meaningful biomarker for PD-1/CTLA-4 combination immunotherapy was demonstrated by primary results from CheckMate 227 part 1, which showed that the study met the coprimary end point of significantly longer PFS with nivolumab plus ipilimumab versus chemotherapy in patients with TMB ≥10 mutations/Mb [47]. Although the Phase III MYSTIC study failed to show a significant OS advantage with first-line durvalumab plus tremelimumab versus chemotherapy in patients with ≥25% PD-L1 expression (coprimary end point), recent results of an exploratory analysis showed improved OS with the combination therapy versus chemotherapy in patients with a blood TMB ≥16 mutations/Mb (HR: 0.62; 95% CI: 0.45-0.86) [48].…”

“…A current limitation in comparing TMB-related outcomes across studies in NSCLC is the lack of a universally adopted standard for the definition and determination of TMB. Both whole-exome sequencing (WES) [38,39,46] and next-generation sequencing using specific gene panels [47,48] have been used to determine TMB expressed as mutations per whole exome or mutations per megabase, respectively. In addition, the type of mutations included for the determination of TMB may vary between studies.…”

“…Appropriate cut-offs for patient selection in clinical trials thus may need to be determined experimentally for each agent, including the use of receiver operating characteristic analyses in the targeted patient population. Currently, tumor biopsies are generally used to determine TMB; however, a blood-based assay was recently used in the MYSTIC study [48].…”