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A multicenter phase II study of ganetespib monotherapy in patients with genotypically defined advanced non-small cell lung cancer.

ABSTRACT: Ganetespib is a novel inhibitor of the heat shock protein 90 (Hsp90), a chaperone protein critical to tumor growth and proliferation. In this phase II study, we evaluated the activity and tolerability of ganetespib in previously treated patients with non-small cell lung cancer (NSCLC).Patients were enrolled into cohort A (mutant EGFR), B (mutant KRAS), or C (no EGFR or KRAS mutations). Patients were treated with 200 mg/m(2) ganetespib by intravenous infusion once weekly for 3 weeks followed by 1 week of rest, until disease progression. The primary endpoint was progression-free survival (PFS) at 16 weeks. Secondary endpoints included objective response (ORR), duration of treatment, tolerability, median PFS, overall survival (OS), and correlative studies.Ninety-nine patients with a median of 2 prior systemic therapies were enrolled; 98 were assigned to cohort A (n = 15), B (n = 17), or C (n = 66), with PFS rates at 16 weeks of 13.3%, 5.9%, and 19.7%, respectively. Four patients (4%) achieved partial response (PR); all had disease that harbored anaplastic lymphoma kinase (ALK) gene rearrangement, retrospectively detected by FISH (n = 1) or PCR-based assays (n = 3), in crizotinib-naïve patients enrolled to cohort C. Eight patients (8.1%) experienced treatment-related serious adverse events (AE); 2 of these (cardiac arrest and renal failure) resulted in death. The most common AEs were diarrhea, fatigue, nausea, and anorexia.Ganetespib monotherapy showed a manageable side effect profile as well as clinical activity in heavily pretreated patients with advanced NSCLCs, particularly in patients with tumors harboring ALK gene rearrangement.

SUBMITTER: Socinski MA

PROVIDER: S-EPMC3874465 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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A multicenter phase II study of ganetespib monotherapy in patients with genotypically defined advanced non-small cell lung cancer.

Socinski Mark A MA Goldman Jonathan J El-Hariry Iman I Koczywas Marianna M Vukovic Vojo V Horn Leora L Paschold Eugene E Salgia Ravi R West Howard H Sequist Lecia V LV Bonomi Philip P Brahmer Julie J Chen Lin-Chi LC Sandler Alan A Belani Chandra P CP Webb Timothy T Harper Harry H Huberman Mark M Ramalingam Suresh S Wong Kwok-Kin KK Teofilovici Florentina F Guo Wei W Shapiro Geoffrey I GI

Clinical cancer research : an official journal of the American Association for Cancer Research 20130403 11

<h4>Purpose</h4>Ganetespib is a novel inhibitor of the heat shock protein 90 (Hsp90), a chaperone protein critical to tumor growth and proliferation. In this phase II study, we evaluated the activity and tolerability of ganetespib in previously treated patients with non-small cell lung cancer (NSCLC).<h4>Experimental design</h4>Patients were enrolled into cohort A (mutant EGFR), B (mutant KRAS), or C (no EGFR or KRAS mutations). Patients were treated with 200 mg/m(2) ganetespib by intravenous in ...[more]

PMID: 23553849

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Project description:BackgroundThe programmed death-ligand 1 inhibitor atezolizumab had shown clinical activity against several advanced malignancies.Patients and methodsThis phase II, open-label basket study (NCT02458638) was conducted in 16 main cohorts of patients aged ≥18 years with stage III or IV solid tumors. In stage I, 12 patients were enrolled into each cohort. Treatment was atezolizumab 1200 mg intravenously every 3 weeks until loss of clinical benefit or unacceptable toxicity. The primary efficacy endpoint was the non-progression rate (NPR) at 18 weeks in treated, assessable patients. NPR ≤20% was not of interest for development as monotherapy, and NPR ≥40% was defined as the threshold of benefit/success. If ≥3 patients had non-progressive disease in stage I (interim analysis), 13 additional patients could be enrolled into stage II (final analysis). Secondary efficacy and safety endpoints were also evaluated.ResultsOverall, 474 patients were enrolled and treated; 433 were included in the efficacy set. Due partly to slow recruitment because of competing trials and limited efficacy at interim analyses, enrollment was stopped early, including in cohorts that passed stage I boundaries of success. NPR was >20% in five cohorts: cervical cancer {n = 27; NPR 44.4% [95% confidence interval (CI) 25.5% to 64.7%]}; follicular/papillary thyroid cancer [n = 11; 54.5% (95% CI 23.4% to 83.3%)]; thymoma [n = 13; 76.9% (95% CI: 46.2% to 95.0%)]; gastroenteropancreatic (GEP) and lung neuroendocrine tumors [NETs; n = 24; 41.7% (95% CI 22.1% to 63.4%)], and low/intermediate grade carcinoid GEP and lung NETs [n = 12; 58.3% (95% CI 27.7% to 84.8%)]. Treatment-related adverse events occurred in 55.3% of patients overall, and at grade 3, 4, and 5 in 10.3%, 1.7%, and 0.4%, respectively.ConclusionsAtezolizumab monotherapy was effective in the cervical cancer cohort. The interim benefit threshold was crossed in patients with follicular/papillary thyroid cancer, thymoma, and GEP and lung NETs, but recruitment was stopped before these signals could be confirmed in stage II. Safety was consistent with previous findings.

Project description:BackgroundThere is currently a lack of effective treatments for non-small cell lung cancer (NSCLC) patients harboring HER2 mutations. We examined the efficacy and safety of, and potential resistance mechanism to, pyrotinib, a pan-HER inhibitor, in advanced NSCLC carrying HER2 mutations.MethodsIn this multicenter, single-arm, phase II trial, stage IIIB-IV NSCLC patients harboring HER2 mutations, as determined using next-generation sequencing, were enrolled and treated with pyrotinib at a dose of 400 mg/day. The primary endpoint was 6-month progression-free survival (PFS) rate, and secondary endpoints were objective response rate (ORR), PFS, overall survival (OS), disease control rate (DCR), and safety. The impact of different HER2 mutation types on sensitivity to pyrotinib and the potential of utilizing mutational profile derived from circulating tumor DNA (ctDNA) to predict disease progression were also explored.ResultsSeventy-eight patients were enrolled for efficacy and safety analysis. The 6-month PFS rate was 49.5% (95% confidence interval [CI], 39.2-60.8). Pyrotinib produced an ORR of 19.2% (95% CI, 11.2-30.0), with median PFS of 5.6 months (95% CI, 2.8-8.4), and median OS of 10.5 months (95% CI, 8.7-12.3). The median duration of response was 9.9 months (95% CI, 6.2-13.6). All treatment-related adverse events (TRAEs) were grade 1-3 (all, 91.0%; grade 3, 20.5%), and the most common TRAE was diarrhea (all, 85.9%; grade 3, 16.7%). Patients with exon 20 and non-exon 20 HER2 mutations had ORRs of 17.7% and 25.0%, respectively. Brain metastases at baseline and prior exposure to afatinib were not associated with ORR, PFS, or OS. Loss of HER2 mutations and appearance of amplification in HER2 and EGFR were detected upon disease progression.ConclusionsPyrotinib exhibited promising efficacy and acceptable safety in NSCLC patients carrying exon 20 and non-exon 20 HER2 mutations and is worth further investigation.Trial registrationChinese Clinical Trial Registry Identifier: ChiCTR1800020262.

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A multicenter phase II study of ganetespib monotherapy in patients with genotypically defined advanced non-small cell lung cancer.

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A multicenter phase II study of ganetespib monotherapy in patients with genotypically defined advanced non-small cell lung cancer.

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