Preclinical and clinical activity of DZD1516, a full blood-brain barrier-penetrant, highly selective HER2 inhibitor.

BACKGROUND: Patients with HER2-positive metastatic breast cancer (MBC) are at high risk of developing central nervous system (CNS) metastases. A potent and selective HER2 inhibitor with good blood-brain barrier (BBB) penetration is highly desirable. METHODS: The design and structure-activity relationship of DZD1516 was described. The potency and selectivity of DZD1516 were determined by enzymatic and cellular assays. The antitumor activity of DZD1516 monotherapy or in combination with HER2 antibody-drug conjugate was assessed in CNS and subcutaneous xenograft mouse models. A phase 1 first-in-human study evaluated the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of DZD1516 in patients with HER2+ MBC who relapsed from standard of care. RESULTS: DZD1516 showed good selectivity against HER2 over wild-type EGFR in vitro and potent antitumor activity in vivo. Twenty-three patients were enrolled and received DZD1516 monotherapy treatment across six dose levels (25-300 mg, twice daily). Dose-limiting toxicities were reported at 300 mg, and thus 250 mg was defined as the maximum tolerated dose. The most common adverse events included headache, vomiting, and hemoglobin decreased. No diarrhea or skin rash was observed at ≤ 250 mg. The mean Kp,uu,CSF was 2.1 for DZD1516 and 0.76 for its active metabolite DZ2678. With median seven lines of prior systemic therapy, the best antitumor efficacy in intracranial, extracranial and overall lesions was stable disease. CONCLUSIONS: DZD1516 provides positive proof of concept for an optimal HER2 inhibitor with high BBB penetration and HER2 selectivity. Further clinical evaluation of DZD1516 is warranted, with the RP2D being 250 mg BID. CLINICALTRIALS: gov identifier NCT04509596. Registered on August 12, 2020; Chinadrugtrial: CTR20202424 Registered on December 18, 2020.

Pathologic and molecular responses to neoadjuvant trastuzumab and/or lapatinib from a phase II randomized trial in HER2-positive breast cancer (TRIO-US B07).

In this multicenter, open-label, randomized phase II investigator-sponsored neoadjuvant trial with funding provided by Sanofi and GlaxoSmithKline (TRIO-US B07, Clinical Trials NCT00769470), participants with early-stage HER2-positive breast cancer (N = 128) were recruited from 13 United States oncology centers throughout the Translational Research in Oncology network. Participants were randomized to receive trastuzumab (T; N = 34), lapatinib (L; N = 36), or both (TL; N = 58) as HER2-targeted therapy, with each participant given one cycle of this designated anti-HER2 therapy alone followed by six cycles of standard combination chemotherapy with the same anti-HER2 therapy. The primary objective was to estimate the rate of pathologic complete response (pCR) at the time of surgery in each of the three arms. In the intent-to-treat population, we observed similar pCR rates between T (47%, 95% confidence interval [CI] 30-65%) and TL (52%, 95% CI 38-65%), and a lower pCR rate with L (25%, 95% CI 13-43%). In the T arm, 100% of participants completed all protocol-specified treatment prior to surgery, as compared to 69% in the L arm and 74% in the TL arm. Tumor or tumor bed tissue was collected whenever possible pre-treatment (N = 110), after one cycle of HER2-targeted therapy alone (N = 89), and at time of surgery (N = 59). Higher-level amplification of HER2 and hormone receptor (HR)-negative status were associated with a higher pCR rate. Large shifts in the tumor, immune, and stromal gene expression occurred after one cycle of HER2-targeted therapy. In contrast to pCR rates, the L-containing arms exhibited greater proliferation reduction than T at this timepoint. Immune expression signatures increased in all arms after one cycle of HER2-targeted therapy, decreasing again by the time of surgery. Our results inform approaches to early assessment of sensitivity to anti-HER2 therapy and shed light on the role of the immune microenvironment in response to HER2-targeted agents.

Luminespib plus pemetrexed in patients with non-squamous non-small cell lung cancer.

BACKGROUND: Luminespib (AUY922) is a second-generation heat shock protein 90 (HSP90) inhibitor with demonstrated activity in non-small cell lung cancer (NSCLC). Since luminespib reduces levels of dihydrofolate reductase (DHFR), a key enzymatic target of pemetrexed, we assessed the safety and tolerability of luminespib in combination with pemetrexed in patients with previously treated metastatic non-squamous non-small cell lung cancer (NSCLC). We also sought to study the pharmacokinetics and correlate tumor dihydrofolate reductase (DHFR) expression with clinical response. METHODS: Patients received weekly luminespib at either 40 mg/m2, 55 mg/m2, or 70 mg/m2 according to a standard 3 + 3 dose-escalation design along with pemetrexed at 500 mg/m2 followed by an expansion at the maximum tolerated dose (MTD). RESULTS: Two-dose limiting toxicities (DLTs) were experienced in the 70 mg/m2 cohort, therefore the MTD was determined to be 55 mg/m2. 69% (N = 9) of patients experienced ophthalmologic toxicity related to luminespib. Maximum serum concentration (Cmax) of luminespib was associated with increased grade 2 drug related adverse events (DRAEs) (rs = 0.74, P < 0.01), with volume of distribution (VD) inversely associated with the number of DRAEs (rs = - 0.81, P = 0.004) and ophthalmologic related DRAEs (rs = - 0.65, P = 0.04). The best response was partial response in one patient for 20 months, prior to expiration of all luminespib. Amongst patients treated at the MTD, the objective response rate was 14%. CONCLUSION: In patients with previously treated metastatic NSCLC, the MTD of luminespib in combination with pemetrexed was 55 mg/m2 per week. The combination of luminespib and pemetrexed demonstrated clinical activity. Tolerability of luminespib with pemetrexed is limited by ocular toxicity.

Phase Ib/II single-arm trial evaluating the combination of everolimus, lapatinib and capecitabine for the treatment of HER2-positive breast cancer with brain metastases (TRIO-US B-09).

BACKGROUND: Improving outcomes for patients with human epidermal growth factor 2-positive (HER2+) central nervous system (CNS) metastases remains an unmet clinical need. This trial evaluated a novel combination of everolimus, lapatinib and capecitabine for this disease. METHODS: Patients with trastuzumab-pretreated, HER2+ breast cancer brain metastasis without prior therapy with a mammalian target of rapamycin (mTOR) inhibitor were eligible. Patients received lapatinib and everolimus daily (continuously) and capecitabine twice daily (d1-14) in 21-d cycles. The primary endpoint was the 12-week CNS objective response rate (ORR). Secondary endpoints included safety, progression-free survival (PFS), overall survival (OS), best CNS ORR and extra-CNS ORR. RESULTS: A total of 19 participants were enrolled and treated with ⩾1 dose of the study drug. The median age was 58.5 years, the median number of therapies for metastatic breast cancer was 2.5 (0-11). Pretrial, 74% of participants had received prior lapatinib, capecitabine or both. A total of 63% had received previous CNS radiation or surgical resection and CNS radiation. The maximum tolerated doses were lapatinib at 1000 mg, everolimus at 10 mg, and capecitabine at 1000 mg/m2. Phase II proceeded with capecitabine at 750 mg/m2 due to better tolerability. The most common grade 3/4 adverse events were mucositis (16%), diarrhea, fatigue, and hypokalemia (11% each). Of 11 participants evaluable for 12-week CNS ORR, 3 (27%) had partial response and 7 (64%) had stable disease. The best CNS ORR in eligible participants was 28% (5/18). The median PFS and OS were 6.2 and 24.2 months, respectively. CONCLUSIONS: This novel triplet combination of lapatinib, everolimus, and capecitabine is well tolerated and yielded a 27% response rate in the CNS at 12 weeks in heavily pretreated participants. Larger studies are warranted to further evaluate this regimen. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01783756. Registered 05 February 2013, https://clinicaltrials.gov/ct2/show/NCT01783756.

Phase II trial of everolimus in patients with refractory metastatic adenocarcinoma of the esophagus, gastroesophageal junction and stomach: possible role for predictive biomarkers.

PURPOSE: Our study was designed to evaluate the efficacy and safety of everolimus in patients with pre-treated metastatic gastric and esophagus cancers in a US-based population focusing on biomarker correlation. METHODS: Patients with advanced upper GI adenocarcinomas who progressed after 1-2 prior regimens received everolimus 10 mg PO daily. The primary endpoint was disease control rate (DCR). Secondary endpoints included progression-free survival (PFS), toxicity, overall survival (OS) and biomarker correlatives of the mTOR pathway. Target accrual was 50 patients based on one-sided type I error of 10 % and power of 90 %. RESULTS: Forty-five patients were evaluable, 21 gastric, 11 esophagus and 13 from the GEJ. The median age was 64 (range 38-73); all patients had an ECOG of 0 or 1; and 18 patients (40 %) had only 1 prior regimen. The most common grade 3-4 adverse events included fatigue (24 %) and thrombocytopenia (22 %). We observed 1 partial response with 39 % of evaluable patients having stable disease. Median OS was 3.4 months (95 % CI 2.7-5.6 months), and PFS was 1.8 months (95 % CI 1.7-2.2 months). There was a strong correlation between ≥2 + IHC staining for p-S6 in tumor samples with better PFS (p < 0.0001) and DCR (p = 0.0001). CONCLUSIONS: Our clinical outcomes were inferior to the Asian studies, which may be explained by disease heterogeneity. However, there was a similar strong correlation between clinical benefit and tumor high pS6. Testing this biomarker in patient samples from the randomized phase III Granite trial may lead to a positive predictive marker.