IMPORTANCEMetastatic non-small cell lung cancer (mNSCLC) with EGFR exon 20 insertion (EGFRex20ins) mutations is associated with a poor prognosis. Mobocertinib is an oral tyrosine kinase inhibitor designed to selectively target EGFRex20ins mutations.OBJECTIVE To evaluate treatment outcomes and safety of mobocertinib in patients with previously treated EGFRex20ins-positive mNSCLC.DESIGN, SETTING, AND PARTICIPANTS This 3-part, open-label, phase 1/2 nonrandomized clinical trial with dose-escalation/dose-expansion cohorts (28 sites in the US) and a single-arm extension cohort (EXCLAIM; 40 sites in Asia, Europe, and North America) was conducted between June 2016 and November 2020 (data cutoff date). The primary analysis populations were the platinum-pretreated patients (PPP) cohort and the EXCLAIM cohort. The PPP cohort included 114 patients with platinum-pretreated EGFRex20ins-positive mNSCLC who received mobocertinib 160 mg once daily from the dose-escalation (n = 6), dose-expansion (n = 22), and EXCLAIM (n = 86) cohorts. The EXCLAIM cohort included 96 patients with previously treated EGFRex20ins-positive mNSCLC (10 were not platinum pretreated and thus were excluded from the PPP cohort). INTERVENTIONS Mobocertinib 160 mg once daily. MAIN OUTCOMES AND MEASURESThe primary end point of the PPP and EXCLAIM cohorts was confirmed objective response rate (ORR) assessed by independent review committee (IRC). Secondary end points included confirmed ORR by investigator, duration of response, progression-free survival, overall survival, and safety. RESULTS Among the PPP (n = 114) and EXCLAIM (n = 96) cohorts, the median (range) age was 60 (27-84) and 59 (27-80) years, respectively; most patients were women (75 [66%] and 62 [65%], respectively) and of Asian race (68 [60%] and 66 [69%], respectively). At data cutoff, median follow-up was 14.2 months in the PPP cohort (median 2 prior anticancer regimens; 40 [35%] had baseline brain metastases), with confirmed ORR of 28% (95% CI, 20%-37%) by IRC assessment and 35% (95% CI, 26%-45%) by investigator assessment; median duration of response by IRC assessment was 17.5 months (95% CI, 7.4-20.3). Median progression-free survival by IRC assessment was 7.3 months (95% CI, 5.5-9.2). Median overall survival was 24.0 months (95% CI, 14.6-28.8). In the EXCLAIM cohort, median follow-up was 13.0 months, with confirmed ORR by IRC assessment of 25% (95% CI, 17%-35%) and by investigator assessment of 32% (95% CI, 23%-43%). The most common treatment-related adverse events were diarrhea and rash. CONCLUSIONS AND RELEVANCEIn this open-label, phase 1/2 nonrandomized clinical trial, mobocertinib was associated with clinically meaningful benefit in patients with previously treated EGFRex20ins-positive mNSCLC, with a manageable safety profile.

Mobocertinib, an oral epidermal growth factor receptor (EGFR) inhibitor targeting EGFR gene mutations, including exon 20 insertions (EGFRex20ins), in non–small cell lung cancer, was evaluated in a phase I/II dose-escalation/expansion trial (ClinicalTrials.gov NCT02716116). Dose escalation identified 160 mg/d as the recommended phase 2 dose and maximum tolerated dose. Among 136 patients treated with 160 mg/d, the most common any-grade treatment-related adverse events (TRAE; >25%) were diarrhea (83%), nausea (43%), rash (33%), and vomiting (26%), with diarrhea (21%) the only grade ≥3 TRAE >5%. Among 28 EGFRex20ins patients treated at 160 mg/d, the investigator-assessed confirmed response rate was 43% (12/28; 95% confidence interval, 24%–63%) with median duration of response of 14 months (5.0–not reached) and median progression-free survival of 7.3 months (4.4–15.6). Mobocertinib demonstrated antitumor activity in patients with diverse EGFRex20ins variants with a safety profile consistent with other EGFR inhibitors. Significance: No oral EGFR-targeted therapies are currently approved for patients with EGFRex20ins NSCLC. Mobocertinib demonstrated antitumor activity with manageable toxicity in patients with advanced EGFRex20ins NSCLC in this study, supporting additional development of mobocertinib in this patient population. See related commentary by Pacheco, p. 1617. This article is highlighted in the In This Issue feature, p. 1601

No abstract

is an investigational oral tyrosine kinase inhibitor targeting epidermal growth factor receptor and human epidermal growth factor 2. A phase 1 open-label, 2-period, fixed-sequence, 2-part study (NCT03928327) characterized effects of a strong CYP3A4 inhibitor (itraconazole) and inducer (rifampin) on the pharmacokinetics (PK) of mobocertinib and its active metabolites, AP32960 and AP32914. Healthy volunteers (n = 12 per part) received a single dose of mobocertinib alone (20 mg, part 1; 160 mg, part 2) and with multiple doses of itraconazole 200 mg once daily (part 1) or rifampin 600 mg once daily (part 2). Coadministration of itraconazole with mobocertinib increased the combined molar area under the plasma concentration-time curve from time 0 to infinity (AUC 0-∞ ) of mobocertinib, AP32960, and AP32914 by 527% (geometric least-squares mean [LSM] ratio, 6.27; 90% confidence interval [CI],. Coadministration of rifampin with mobocertinib decreased the combined molar AUC 0-∞ of mobocertinib, AP32960, and AP32914 by 95% (geometric LSM ratio, 0.05; 90%CI, 0.04-0.07). Based on these results, the strong CYP3A inhibitor itraconazole and inducer rifampin significantly influenced the PK of mobocertinib and its active metabolites. Coadministration of mobocertinib with moderate and strong CYP3A inhibitors or inducers is not recommended in ongoing clinical trials.

The role of Th17 cells and Th17-associated cytokines in the development of acute graft-versus-host disease (aGVHD) in clinical allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients is not well established. In the current study, a cohort of 69 allo-HSCT patients was examined for the percentages of Th17 and FoxP3(+) Treg cells and the expressions of RORγt and FoxP3 in peripheral blood mononuclear cells (PBMCs). The Th17 percentage and RORγt expression were significantly higher, whereas Treg percentage and FoxP3 expression were significantly lower in severe aGVHD (grade 3 to 4) and mild aGVHD (grade 1 to 2) patients than in patients without aGVHD (grade 0) and healthy donors. We then investigated the expressions of Th17-associated cytokines, including TGF-β, IL-6, IL-1β, IL-17, IL-21, IL-22, IL-23, as well as IL-23R in the PBMCs of patients after allo-HSCT. The expressions of IL-17 and IL-22 in CD4(+) T cells were also examined. The results showed that the expressions of IL-6, IL-1β, IL-17, IL-21, IL-23, and IL-23R were all increased, whereas IL-22 expression was decreased in aGVHD patients. The changes were also correlated with the severity of aGVHD. We also investigated the dynamic changes of Th17/Treg cells and Th17-associated cytokines in patients during the onset and resolution of aGVHD. The results demonstrated a reciprocal relationship between Treg and Th17 cells. Th17-associated cytokine expressions, namely IL-17 and IL-23, were closely related to the occurrence and resolution of aGVHD. We conclude that the dynamic balance between the Th17 and FoxP3(+) Treg cells and the changes of Th17-associated cytokines could be the indicators of the disease progression and promising candidates of prognostic biomarkers of aGVHD.

9098 Background: There is currently no targeted therapy approved for patients with EGFR exon 20 insertion mutations (exon20ins) in NSCLC. Real world treatment outcome evidence for this rare population is limited. This study describes treatment patterns and outcomes in US patients with advanced NSCLC with EGFR exon20ins. Methods: The nationwide Flatiron Health electronic health record-derived deidentified database (cut-off 29 Feb 2020) was used to select 4 separate cohorts: (1) first-line (1L): patients receiving 1L therapy after documented exon20ins (1L start date as index date); (2) second or later line (≥2L): patients receiving ≥2L therapy after documented exon20ins (start date of ≥2L as index date); (3) ≥2L trial-aligned: ≥2L patients with baseline characteristics aligned with the key eligibility criteria of mobocertinib Trial NCT02716116 Part 3; and (4) ≥2L post platinum: ≥2L trial-aligned patients previously treated with platinum-based chemotherapy. Real-world endpoints were: confirmed overall response rate (cORR), PFS, and OS. Additional analyses were conducted for patients treated with immune-oncology therapy (IO). Results: Of 237 EGFR exon20ins patients, 129 patients were included in 1L cohort and 114 were in ≥2L cohort, including 63 ≥2L trial-aligned and 50 ≥2L post platinum patients. In 1L patients, EGFR TKI (28.7%) and platinum-based chemotherapy ± IO (56.6%) were the most common 1L regimens. In ≥2L patients, 28.1% received IO monotherapy, 17.5% received EGFR TKI, and 23.7% received platinum-based chemotherapy ± IO as index treatment. In the 1L setting, median PFS (mPFS) was 5.7 months for platinum-based chemotherapy and 4.5 months for IO + platinum-based chemotherapy. In the ≥2L setting, mPFS was 3.7 months for any therapy and 2.3 months for IO monotherapy. Full effectiveness data are provided in the accompanying table. Conclusions: This real world study provided a benchmark on the treatment outcome in patients with advanced NSCLC with EGFR exon20ins. Platinum-based chemotherapy was the most common 1L therapy and provided the longest mPFS. Immunotherapy, either as monotherapy or in combination with chemotherapy, appeared less effective for treatment of NSCLC with EGFR exon20ins. There is an unmet medical need for improved therapeutic options.[Table: see text]

Mobocertinib (TAK-788) is a tyrosine kinase inhibitor under investigation for treatment of non-small cell lung cancer with activating EGFR exon 20 insertions.This study examined the safety;tolerability;pharmacokinetics (PK),including food effects; and bioavailability of mobocertinib in healthy volunteers. In part 1, fasted volunteers were randomized to placebo or mobocertinib in single-ascending-dose cohorts (20-160 mg). In part 2, mobocertinib (120/160 mg) was administered on day 1 of periods 1 and 2 under fasted or low-fat meal conditions (2-period, 2-sequence crossover design). In part 3, fasted volunteers received mobocertinib 160 mg in 1 of 2 capsule products on day 1 of periods 1 and 2 with 7-day washout. Safety and PK parameters were assessed. Sixty-nine volunteers were enrolled (mean age, 29 years; 75% male). The most common adverse events (AEs; ≥10% of volunteers) were gastrointestinal AEs (25%-50%) and headache (8%-31%). No serious AEs were reported. A low-fat meal did not affect the PK of mobocertinib or its active metabolites. The geometric mean terminal disposition phase half-life (20 hours) supported once-daily dosing. The 2 capsule products were bioequivalent. These data guided dosing and supported administration of mobocertinib without regard to low-fat meal intake in ongoing and planned clinical studies.

No abstract