Pembrolizumab Plus Chemotherapy Per PD-L1 Stratum In Patients With Metastatic Non-Small Cell Lung Cancer: Real-World Effectiveness Versus Trial Efficacy.

BACKGROUND: Clinical trial efficacy and real-world effectiveness of oncological treatments can differ. This study assessed the real-world survival outcomes of first-line pembrolizumab plus chemotherapy per PD-L1 stratum in patients with metastatic non-small cell lung cancer (mNSCLC) and compared them to clinical trial results. PATIENTS AND METHODS: All patients with nonsquamous and squamous mNSCLC who received first-line pembrolizumab plus chemotherapy in 7 Dutch teaching hospitals between January 1, 2019 and December 31, 2021 were included. Hazard ratios (HR) with confidence intervals (95% CI) for overall survival (OS) and progression-free survival (PFS) were estimated to determine the efficacy-effectiveness gap (EE gap) between real-world and clinical trial, stratified by PD-L1 stratum. RESULTS: The nonsquamous cohort (n = 486) consisted of 269 patients with PD-L1 < 1%, 158 with PD-L1 1% to 49%, and 59 with PD-L1 ≥ 50%. The squamous cohort (n = 117) consisted of 70 patients with PD-L1 < 1% and 47 with PD-L1 ≥ 1%. For OS, an EE gap was observed in nonsquamous patients with PD-L1 < 1% (HR 1.38 (95% CI 1.06-1.78; median OS 10 vs. 17.2 months) and HRs consistently >1 in all other nonsquamous and squamous PD-L1 strata, although not statistically significant. No EE-gap for PFS was observed in any stratum. CONCLUSION: No significant EE gap was found for pembrolizumab plus chemotherapy, except in the stratum nonsquamous mNSCLC with <1% PD-L1 tumor expression. In these patients, the survival in real-world was considerably shorter compared to the clinical trial results. Further studies are needed to determine which patient, treatment and or context factors contribute to this disparity.

Durvalumab after chemoradiotherapy in patients with stage III non-small-cell lung cancer: real-world outcomes versus clinical trial results.

Aim: We investigated the effectiveness of durvalumab post-concurrent CRT (cCRT) and post-sequential CRT (sCRT) versus cCRT and sCRT alone and compared these outcomes with the PACIFIC trial. Methods: Four cohorts of stage III NSCLC patients who received CRT were included: cCRT with and without durvalumab, sCRT with and without durvalumab. PFS and OS were analyzed using Cox regression. Results: Durvalumab improved PFS (cCRT: aHR = 0.69, sCRT: aHR = 0.71) and OS (cCRT: aHR = 0.71, sCRT: aHR = 0.32), although not all results were significant. PFS was longer in the real-world than in the trial, while OS did not differ. Conclusion: Durvalumab after CRT improved the survival outcomes. The difference between PFS in our study and the trial may be due to differences in follow-up methods.

We assessed a medicine called durvalumab on patients with non-small cell lung cancer who received chemoradiotherapy in a real-world setting. We compared their outcomes with those from a clinical trial. Patients who received two types of chemoradiotherapy with or without durvalumab were included, and their progression-free survival (PFS) and overall survival (OS) outcomes were analyzed. We found that patients treated with durvalumab had better PFS and OS than those treated without durvalumab. PFS was longer in the real-world than in the clinical trial, but OS was similar. The difference in PFS may be due to differences in measuring PFS.

Taxol(®)-induced phosphatidylserine exposure and microvesicle formation in red blood cells is mediated by its vehicle Cremophor(®) EL.

AIM: The conventional clinical formulation of paclitaxel (PTX), Taxol®, consists of Cremophor® EL (CrEL) and ethanol. CrEL-formulated PTX is associated with acute hypersensitivity reactions, anemia and cardiovascular events. In this study, the authors investigated the effects of CrEL-PTX on red blood cells (RBCs) and compared these with the effects observed after exposure to the novel nanoparticle albumin-bound PTX, marketed as Abraxane®. RESULTS: The authors demonstrate that CrEL is primarily responsible for RBC lysis and induction of phosphatidylserine exposure. Phosphatidylserine-exposing RBCs showed increased association with endothelial cells in culture. The authors also identified CrEL as being responsible for vesiculation of RBCs. This is the first time that excipients have been shown to be involved in microvesicle formation. Microvesicles were taken up by endothelial cells. CONCLUSION: These results offer new insights into the side effect profile of Taxol, which is likely to have implications for patients with erythrocyte disorders. Abraxane did not induce any of these effects on RBCs, indicating that the choice of excipients can have a pronounced influence on the efficacy and side effects of drug molecules.

Potential of adaptive clinical trial designs in pharmacogenetic research.

Adaptive trial designs can be beneficial in pharmacogenetic research when prior uncertainty exists regarding the exact role and clinical relevance of genetic variability in drug response. This type of design enables us to learn about the effect of the genetic variability on drug response and to immediately use this information for the remainder of the study. For different types of adaptive trial designs, we discuss when and how the designs are suitable for pharmacogenetic research: adaptation of randomization, adaptation of patient enrollment and adaptive enrichment. To illustrate the potential benefits of an adaptive design over a fixed design, we simulated an adaptive trial based on the results of the IPASS trial. With a simple model we show that for this example an adaptive enrichment design would have led to a smaller trial, with less EGF receptor mutation-negative patients unnecessarily exposed to the drug, without compromising the α level or reducing power.

Difference in risks of allergic reaction to sulfonamide drugs based on chemical structure.

BACKGROUND: The chemical structure of sulfonamide antibiotics and sulfonamide nonantibiotics can affect the potential for adverse reactions. OBJECTIVE: To assess whether differences in chemical structure of the various sulfonamide drugs influence the risk of allergic events. METHODS: A case-control study was conducted among patients with diabetes mellitus (DM) using data from the General Practice Research Database. Cases were defined as patients with a diagnosis of hypersensitivity or allergic reaction. The date of the last event was the index date. Controls were matched on practice, type of DM, and index date. Current use of sulfonamides was defined as use in a 14 day time window before the index date. Sulfonamides were classified according to the presence/absence of an N1 substituent (N1(+)/(-)) and/or an arylamine (N4(+)/(-)). Conditional logistic regression was used to estimate strength of association and expressed as odds ratios and 95% confidence intervals. RESULTS: Overall, current use of N1(+) N4(+) sulfonamide drugs was associated with the outcome (adjusted OR 3.71; 95% CI 1.40 to 9.81). Current use of N1(+) N4(-) and N1(-) N4(-) sulfonamide drugs was also associated with the occurrence of allergic reactions, although not as strongly: adjusted OR 2.48 (95% CI 2.12 to 2.89) and 2.07 (95% CI 1.74 to 2.46), respectively. Sex and age seemed to be effect modifiers. There was no clear evidence for effect modification by immune disease state. CONCLUSIONS: Although we did not identify major differences between the groups, we believe that this approach is an innovative manner to examine adverse drug reactions by using chemical structure instead of therapeutic drug classes to classify exposure.

Drug-drug interactions as a determinant of elevated lithium serum levels in daily clinical practice.

OBJECTIVE: Lithium is a drug with a narrow therapeutic window. Concomitantly used medication is a potentially influencing factor of lithium serum concentrations. We conducted a multicentre retrospective case-control study with the aim of investigating lithium-related drug interactions as determinants of elevated lithium serum levels in daily clinical practice. METHODS: Cases were patients with an increase of at least 50% in lithium serum concentrations resulting in an elevated lithium serum level of at least 1.3 mmol/L, and who were not suspected of a suicide attempt. Controls were patients who showed stable lithium serum levels within the therapeutic range. Use and start of non-steroidal anti-inflammatory drugs, diuretics, renin-angiotensin inhibitors, theophyllin and antibiotics were investigated as potential determinants of the elevated lithium serum levels. Irregularity in lithium dispensing pattern, change in lithium dosing regimen, age, gender, prescribing physician and laboratory parameters were investigated as potential confounders. RESULTS: We included 51 cases and 51 controls in our study. Five (9.8%) controls and 15 (29.4%) cases used potentially interacting co-medication [OR of 3.83 (95%CI 1.28-11.48)]. Start of potentially interacting co-medication was observed in eight (15.7%) cases and in zero (0%) controls resulting in an OR of 20.13 (95% CI 1.13-359). After adjustment for co-medication, irregularity in lithium dispensing pattern, change in lithium dosing regimen, and age, the statistically significant association was lost. We report an OR of 2.70 (95% CI 0.78-9.31) for use of concomitant medication, with a large contribution of antibiotic agents, and an OR of 3.14 (95% CI 1.15-8.61) for irregularity in lithium dispensing pattern. CONCLUSION: Use of co-medication, especially antibiotics, tends to be associated with elevated lithium serum levels.