The review, led by Lotte M.G. Hulskotte and colleagues in the Netherlands, systematically searched PubMed and Embase for evidence on drug–drug and food–drug interactions and pharmacodynamic adverse effects of all thirty SMIs approved by the US Food and Drug Administration and the European Medicines Agency for non-small cell lung cancer, from long-standing agents such as erlotinib and crizotinib to newcomers including zongertinib, sevabertinib and sunvozertinib. The searches, initiated in October 2025 and finalised in July 2026, were supplemented with regulatory documents from both agencies, and the authors applied a pragmatic hierarchy of evidence ranking pharmacokinetic studies and meta-analyses above phase 1/2 trials, observational data, label information and expert opinion.

At the heart of the pharmacokinetic problem lies chemistry. Most SMIs are weakly basic, lipophilic molecules whose absorption depends delicately on the acidity of the stomach. When acid-reducing agents such as proton pump inhibitors raise gastric pH, the drugs shift toward a less soluble, non-ionised form that dissolves poorly, cutting systemic exposure. The magnitude is striking: selpercatinib exposure fell by roughly 70 percent when omeprazole was given in the fasted state, and sotorasib lost 57 percent of its exposure with omeprazole even when taken with food. Erlotinib, co-administered with esomeprazole, lost nearly half its area under the curve. Bioequivalence standards allow exposure to vary only within 80 to 125 percent of the reference value, so deviations of this size translate directly into subtherapeutic concentrations, lost efficacy and, ultimately, disease progression.

Liver enzymes provide the second major axis of interaction. Most SMIs are metabolised primarily by cytochrome P450 iso-enzymes, above all CYP3A, so potent inducers such as rifampicin can collapse drug levels while inhibitors such as itraconazole can push them to toxic heights. Rifampicin cut adagrasib exposure by 95 percent, while itraconazole raised repotrectinib exposure nearly sevenfold. Compounding the problem, several agents are themselves auto-inducers or auto-inhibitors of CYP enzymes — dabrafenib, encorafenib, lorlatinib and osimertinib induce their own clearance, while adagrasib, ceritinib and taletrectinib inhibit it — meaning that single-dose interaction studies may not predict steady-state behaviour. Transporters such as P-glycoprotein and breast cancer resistance protein add further complexity, although their intestinal contribution is generally considered minor.

Food, by contrast, can be an ally. High-fat meals delay gastric emptying, increase bile flow and create a lipophilic environment that enhances solubilisation of many of these drugs. Alectinib is the poster child: a high-fat meal raised its systemic exposure by roughly 230 to 250 percent, and a clinical crossover study showed that 35 percent of patients failed to reach the alectinib exposure threshold when taking the drug with low-fat yoghurt, compared with only 5 percent eating a continental breakfast or lunch. This very property has been exploited therapeutically — ceritinib’s approved dose fell from 750 mg fasted to 450 mg with food after feeding studies showed comparable exposure with less gastrointestinal toxicity, and the FDA has required a post-marketing evaluation of taletrectinib dosing with food for the same reason. Food also reduced inter-individual variability for several agents, improving predictability of therapeutic exposure.

The interplay between food and acid suppression, however, is drug-specific and sometimes counterintuitive. Selpercatinib’s PPI-induced exposure loss is largely rescued by co-administration with a meal. Sotorasib behaves in the opposite way, losing even more exposure when food and a PPI are combined. For erlotinib, an acidic glass of cola partially reversed the damage done by esomeprazole, restoring roughly 40 percent of lost exposure. The authors conclude that when PPI use is unavoidable, clinicians should weigh the individual pharmacokinetics of each SMI, considering food co-administration, acidic beverages or staggered dosing as mitigation strategies.

Turning to the drugs’ intrinsic toxicities, the review paints a landscape where class effects mask considerable agent-to-agent variation. Corrected QT interval prolongation, which can degenerate into dangerous arrhythmias, affects the entire class but is most pronounced with adagrasib, ceritinib, crizotinib, encorafenib, osimertinib and taletrectinib, with median increases exceeding ten milliseconds and the highest rates of clinically significant prolongation seen with adagrasib, encorafenib, taletrectinib, entrectinib and selpercatinib. Because the effect is largely exposure-dependent, any interaction that raises drug levels also raises arrhythmia risk. Others, including alectinib, gefitinib, capmatinib and the newer HER2 inhibitors, showed no clinically meaningful QTc changes. Management centres on electrocardiographic monitoring, correction of concomitant QT-prolonging factors, and dose interruption or discontinuation when the QTc exceeds 500 milliseconds.

Pneumonitis, the non-infectious inflammation of lung tissue that can prove fatal, occurs with most SMIs but clusters around particular agents. Brigatinib carried the highest trial incidence at 9 percent of all-grade events, with an unusual early onset within the first week — the rationale for its mandatory one-week 90 mg lead-in dose before escalation. Pralsetinib affected about 12 percent of patients including one fatal case, while adagrasib, capmatinib, ensartinib and sunvozertinib each produced events in 5 to 6 percent. Strikingly, ethnicity emerged as an independent risk factor: all-grade interstitial lung disease was reported in up to 15 percent of Japanese patients on gefitinib and 17 percent on osimertinib. Rechallenge after pneumonitis remains fraught — one real-world study found a 50 percent twelve-month recurrence rate when patients were rechallenged with osimertinib itself, versus 15 percent with alternative EGFR inhibitors.

Among the quieter but increasingly recognised toxicities is weight gain. NTRK inhibitors cause weight gain in 53 percent of patients, likely through on-target inhibition of TRKB, a hypothalamic receptor governing appetite, with entrectinib reaching roughly 66 percent incidence. Among ALK inhibitors, lorlatinib produced all-grade weight gain in up to 81 percent of patients, with grade 3 events in up to 23 percent and a median gain of 4.5 kilograms in a prospective study; alectinib added an average 9 centimetres of waist circumference over a year. The irony is acute for alectinib, whose absorption depends on high-fat meals. Management spans lifestyle counselling, systematic weight monitoring and, where needed, GLP-1 receptor agonists — though even here caution is warranted, as semaglutide was recently shown to reduce alectinib exposure by 32 percent.

Further distinguishing the class, EGFR inhibitors uniquely damage the ocular surface — keratitis in 1 to 3 percent of patients and conjunctivitis up to 24 percent with dacomitinib — because EGFR sustains corneal epithelium and tear production, while BRAF/MEK combinations bring uveitis and retinal pigment epithelial detachment, the latter affecting roughly 30 percent of patients on encorafenib plus binimetinib. Central neurotoxicity, including cognitive disorders in up to a third of patients on capmatinib, entrectinib, lorlatinib and repotrectinib, peripheral neuropathy in up to 44 percent on lorlatinib, dabrafenib-driven pyrexia in 39 percent of combination-treated patients, severe stomatitis with second-generation EGFR inhibitors, and hepatotoxicity necessitating intra-class switches — erlotinib after gefitinib injury, adagrasib after sotorasib injury — complete the picture. The authors’ overarching message is that safe prescribing of these transformative drugs demands equal attention to what patients eat, what else they swallow, and which specific molecule sits in the capsule: pharmacokinetic–pharmacodynamic associations remain under-studied, and filling that gap could enable personalised dosing that maximises efficacy while sparing patients avoidable harm.

Subject of Research: Pharmacokinetic and pharmacodynamic considerations for prescribing small molecule kinase inhibitors in non-small cell lung cancer

Article Title: Pharmacological considerations for prescribing of small molecule inhibitors in patients with non-small cell lung cancer

Article References: Hulskotte, L. M., Veerman, G. M., Lanser, D. A., Reyners, A. K., van Schaik, R. H., Dingemans, A.-M. C., Taxis, K., Mathijssen, R. H., & Jansman, F. G. (2026). Pharmacological considerations for prescribing of small molecule inhibitors in patients with non-small cell lung cancer. eClinicalMedicine, 100, Article 104199. https://doi.org/10.1016/j.eclinm.2026.104199

Image Credits: AI Generated

DOI: 10.1016/j.eclinm.2026.104199

Keywords: non-small cell lung cancer, small molecule inhibitors, drug-drug interactions, pharmacokinetics, CYP3A, proton pump inhibitors, food-drug interactions, QTc prolongation, pneumonitis, weight gain, ocular toxicity, targeted therapy