Phase 2 trial of afatinib, an ErbB family blocker, in solid tumors genetically screened for target activation

e15554 Background: HER2 is an emerging treatment target for colorectal cancer (CRC). Previous phase 2 trials have demonstrated the promising antitumor activity of dual HER2 inhibition with trastuzumab plus lapatinib or pertuzumab in HER2-positive metastatic CRC. Pyrotinib, a novel irreversible HER2/EGFR dual tyrosine kinase inhibitor, has been approved for breast cancer in 2018 in China. The antitumor effect of pyrotinib was also shown in other solid tumors, such as lung cancer and gastric cancer. The randomized phase 3 PHOEBE trial proved that the efficacy of pyrotinib was better than lapatinib when in combination with capecitabine in HER2-positive local relapsed or metastatic breast cancer. We reported preliminary results of pyrotinib plus trastuzumab in patients with HER2-positive advanced CRC from an ongoing multicenter phase 2 trial (NCT04380012). Methods: Patients with confirmed recurrent/metastatic CRC, HER2-positive disease, and ECOG performance status 0-2, received oral pyrotinib 400 mg once a day plus intravenous trastuzumab 8 mg/kg loading dose followed by 6 mg/kg once every 3 weeks. The primary endpoint was objective response rate (ORR), as assessed according to the Response Evaluation Criteria In Solid Tumors version 1.1. The data cutoff date was December 24, 2020. Results: From December 2019 to November 2020, a total of 11 patients were enrolled. The median age was 57 (range, 44-70) years and 73% (8/11) of patients were male. The number of prior therapy lines was 0, 1, and ≥2 in 1 (9%), 2 (18%), and 8 (73%) patients, respectively. One (9%) patient only showed HER2 overexpression, 7 (64%) showed HER2 amplification and overexpression, and 3 (27%) showed HER2 mutation and overexpression. The detection of co-mutations showed that 5 (45%) patients had KRAS mutations, 1 (9%) had NRAS mutation, and none had BRAF mutation. Three patients achieved partial response, with an ORR of 27% (3/11) in the total population, 50% (3/6) in KRAS wild-type patients, and 60% (3/5) in patients with wild type of both KRAS and NRAS, respectively. The disease control rate was 45% (5/11). The most common (occurring in at least 2 patients) grade ≥3 adverse event was diarrhea (73% [8/11]). Dose interruption owing to diarrhea occurred in 7 (64%) patients, and 5 (45%) patients reduced the dose to 320 mg due to diarrhea. No treatment-related death was observed. Conclusions: Pyrotinib combined with trastuzumab showed promising ORR with acceptable safety in patients with HER2-positive advanced CRC, suggesting a potential treatment option, especially in those without co-mutations. Clinical trial information: NCT04380012.

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Phase 2 trial of pemetrexed in children and adolescents with refractory solid tumors: A Children's Oncology Group study

Pediatric Blood & Cancer ◽

10.1002/pbc.24244 ◽

2012 ◽

Vol 60 (2) ◽

pp. 237-241 ◽

Cited By ~ 23

Author(s):

Anne B. Warwick ◽

Suman Malempati ◽

Mark Krailo ◽

Allen Melemed ◽

Richard Gorlick ◽

...

Keyword(s):

Children And Adolescents ◽

Solid Tumors ◽

Phase 2 ◽

Oncology Group ◽

Oncology Group Study ◽

Phase 2 Trial

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788 Pembrolizumab for patients with leptomeningeal metastasis from solid tumors: efficacy, safety and cerebrospinal fluid biomarkers

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0788 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A837-A837

Author(s):

Jarushka Naidoo ◽

Karisa Schreck ◽

Wei Fu ◽

Chen Hu ◽

Roisin Connolly ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Solid Tumors ◽

Checkpoint Inhibitors ◽

Squamous Carcinoma ◽

Leptomeningeal Metastasis ◽

Phase 2 ◽

Color Flow ◽

Phase 2 Trial ◽

Cytokine Analysis ◽

Dismal Prognosis

BackgroundImmune checkpoint inhibitors (ICI) have anti-cancer activity in selected patients with central nervous system (CNS) metastases. However, the benefit of ICIs in patients with leptomeningeal metastases (LMM) is unknown. We hypothesized that pembrolizumab would lead to CNS responses in patient with LMM from solid tumors, and that genomic and immunologic features of the cerebrospinal fluid (CSF) may identify biomarkers of LMM response.MethodsWe undertook a single-center investigator-initiated phase 2 trial of pembrolizumab in patients with LMM from solid tumors. Eligible patients had radiologic (>3mm on MRI) or cytologic (+CSF cells) LMM and ECOG PS 0-1. Pembrolizumab was administered IV at 200mg q3W until disease progression or unacceptable toxicity. The primary endpoint was CNS response (complete response=CR, partial response=PR or stable disease=SD) after 4 cycles, defined radiologically/cytologically/clinically. Radiologic response was assessed by RECIST v1.1 and irRC. Secondary endpoints were CNS-progression-free survival (PFS), overall survival (OS) and safety. Baseline and serial CSF samples were assessed by tumor-derived DNA aneuploidy assay (t-DNA), 16-color flow cytometry and multiplex cytokine analysis.ResultsThirteen of a planned 18 patients were treated between 04/2017-12/2019. The study closed early due to poor accrual. Median age was 57 years (range 22-79); 54% were female. The majority of patients had tumors not traditionally responsive to ICI (62%: hormone-receptor+ breast carcinoma=39%; high-grade glioma=23%), while 38% had ICI-responsive tumors (NSCLC=23%, head&neck carcinoma=8%, cutaneous squamous carcinoma=8%). CNS response was observed in 38% of patients (95% CI 13.9-68.4%). Two patients achieved durable CRs (cutaneous squamous carcinoma=1, OS 3+yrs; MET-exon14+ NSCLC=1, OS 9 mos.), 1 PR (7.7%, OS 6 mos), and 2 SDs (15.4%) in the CNS. Median CNS-PFS and OS were 2.9 mos (95% CI: 1.3-NR) and 4.9 mos (95% CI: 3.7-NR), respectively. There were no unacceptable safety signals. Sensitivity for LMM detection by t-DNA was 84.6% (95% CI: 54.6-98.1%), and 46.2% (95%CI: 19.2-74.9%) by cytopathology. Pre and on-therapy CSF cytokine analysis showed complete responders clustered together, while progressors clustered differently.ConclusionsPatients with LMM from solid tumors have a dismal prognosis and limited treatment options. In this phase 2 trial, we identified an impressive 38% CNS response rate for pembrolizumab in patients with LMM, deep and durable responses in selected patients with ICI-responsive tumors, and that pembrolizumab was well-tolerated. CSF t-DNA may be more sensitive for detection of LMM than cytopathology, and immunologic subsets of ICI-response based on cytokine profiles warrant further study. These data support investigation of pembrolizumab in larger populations with LMM.Trial RegistrationNCT03091478Ethics ApprovalThe study was approved by John’s Hopkins University’s Institututional Ethics Board, approval number J1655ConsentAll participants provided informed consent as per the study protocol

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A pediatric phase I trial and pharmacokinetic (PK) study of erlotinib (ERL) followed by the combination of ERL with temozolomide (TMZ): A Children’s Oncology Group Study

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.9015 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 9015-9015 ◽

Cited By ~ 1

Author(s):

R. I. Jakacki ◽

J. Tersak ◽

S. Blaney ◽

M. Krailo ◽

M. Hamilton ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Single Agent ◽

Phase 2 ◽

Dose Escalation Study ◽

Minor Response ◽

Pediatric Solid Tumors ◽

Phase 2 Trial ◽

Egfr Family ◽

A Minor

9015 Background: EGFR is potently inhibited by ERL. Aberrant cell signaling via the EGFR family has been implicated in the development of several human cancers, including certain pediatric solid tumors. Methods: A phase I dose escalation study in children with refractory solid tumors was conducted to define the maximal tolerated dose (MTD) and dose limiting toxicities (DLTs) of single agent ERL, determine the tolerability of the combination of ERL and TMZ, and to determine the PK of ERL. Pts received single agent ERL qd × 28 d followed by ERL qd continuously in combination with TMZ 180 mg/m2/day × 5d. Cycles were repeated q 28 d. ERL was initially administered using the IV formulation given orally. The tablet form was subsequently studied at the MTD to further evaluate PK. Results: 46 pts (36 fully evaluable for toxicity) median age 11.5 yrs (range 3–20 yrs), were enrolled in cohorts of 3–6 pts at ERL doses of 35, 50, 65, 85 and 110 mg/m2/d. At the 110 mg/m2/day dose level, 2/4 pts had DLT (1 rash, 1 hyperbilirubinemia). In the expanded cohort at the MTD of 85 mg/m2/d, (n=21), 3 pts had DLT (2 rash, 1 diarrhea). Non-DLTs observed during the single agent cycle included diarrhea (n=14), rash (n=9), hyperbilirubinemia (n=7), neutropenia and/or thrombocytopenia (n=5). 1 pt with a soft tissue sarcoma had a minor response after 28d of single agent ERL, continuing to a PR by cycle 4. 3 pts (2 neuroblastoma, 1 neurocytoma) had prolonged responses (13–20+ months) to the combination. Oral administration of the IV formulation resulted in a higher Cmax and a lower Cmin compared to the adult data using tablets. Median apparent clearance was 2.85 (range 1.61–6.37) L/hr/m2 with a terminal half of 8.45 (5.1–27.1) hr. No PK interaction was observed between ERL and TMZ and the combination was well tolerated. Conclusions: The pediatric recommended phase 2 dose of ERL of 85 mg/m2/day, either alone or in combination with TMZ, is well tolerated in children. A COG phase 2 trial is planned. [Table: see text]

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