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M.G. Zauderer
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MO09 - Mesothelioma I (ID 120)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track:
- Presentations: 1
- Moderators:K. Suzuki, S.G. Armato III
- Coordinates: 10/28/2013, 16:15 - 17:45, Bayside 204 A+B, Level 2
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MO09.01 - Evaluation of tolerability and anti-tumor activity of GDC-0980, an oral PI3K/mTOR inhibitor, administered to patients with advanced malignant pleural mesothelioma (MPM) (ID 1712)
16:15 - 16:20 | Author(s): M.G. Zauderer
- Abstract
- Presentation
Background
The PI3K-AKT-mTOR signaling pathway is dysregulated in a wide variety of cancers. Pathway activation in mesothelioma may occur through diverse cellular mechanisms, including activation of receptor tyrosine kinases that signal through Ras and PI3K/Akt/mTOR, and loss of PTEN expression. GDC-0980 is a potent and selective oral dual inhibitor of class I PI3K and mTOR kinases that has demonstrated broad activity in various xenograft cancer models.Methods
A phase I dose-escalation study was conducted in 2 Stages: Stage 1 evaluated oral, daily (QD) doses of 2-70 mg GDC-0980 given 21/28 or 28/28 days in a 3+3 dose escalation design. Stage 2 evaluated disease specific cohorts at the recommended phase 2 dose (RP2D), including a MPM cohort at 30 mg GDC-0980 QD 28/28 days. Safety and tolerability of GDC-0980 was assessed as well as pharmacokinetics (PK) and pharmacodynamics (PD) assessment of PI3K pathway inhibition by FDG-PET. Anti-tumor activity was assessed by modified RECIST; CT scans were centrally reviewed retrospectively by a radiologist with MPM expertise. Archival tumor tissue was evaluated for PIK3CA mutation by allele specific PCR or Sanger sequencing and PTEN expression was assessed by immunohistochemistry.Results
33 MPM patients were enrolled: 6 in Stage 1 at 8-70 mg and 27 in Stage 2 at 30mg GDC-0980. Safety and tolerability of GDC-0980 in Stage 1 was similar in MPM compared to other solid tumor patients, with the exception of a Grade 5 pneumonitis that occurred in a MPM patient at 40 mg GDC-0980 QD. Based on Stage 1 tolerability data, a RP2D of 30 mg QD was evaluated in Stage 2 for MPM patients. The most frequent Grade ≥3 drug-related adverse events (AEs) at 30 mg GDC-0980 were rash (19%), with one patient (4%) having to discontinue GDC-0980. Other AEs were fatigue (15%), and hyperglycemia, diarrhea, and colitis (7% each). Reversible Grade 2 pneumonitis was reported for 2 patients (7%). Population PK analysis was used to assess the behavior of GDC‑0980 in MPM patients. Additionally, PK/PD relationships will be discussed for efficacy and safety, including exposure‑response, where appropriate. Archival tissue was analyzed for 29 MPM patients. Two samples had PIK3CA mutations (R88Q and E545G) and one sample showed loss of PTEN expression. PI3K pathway inhibition by FDG-PET responses was observed in 8 of 24 MPM patients with available scans. Anti-tumor activity was observed in both stages. Two patients achieved a partial response (PR) in Stage 1, one patient at 50 mg and one patient with the PIK3CA mutation R88Q at 8 mg GDC-0980. Two PRs were observed at the RP2D of 30 mg in Stage 2. Eleven (41%) MPM patients at the RP2D remained on study for >6 months, and 2 (7%) patients remained on study >12 months.Conclusion
GDC-0980 was generally well tolerated in MPM patients at the RP2D. Anti-tumor activity, evidenced by tumor regression and prolonged disease control, has been observed. PIK3CA mutations and PTEN loss were uncommon.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO14 - Mesothelioma II - Surgery and Multimodality (ID 121)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Mesothelioma
- Presentations: 1
- Moderators:E. Lim, B. McCaughan
- Coordinates: 10/29/2013, 10:30 - 12:00, Bayside Gallery B, Level 1
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MO14.11 - Safety of hemithoracic pleural intensity-modulated radiation therapy (IMRT) for malignant pleural mesothelioma (MPM) in the multimodality setting: interim analysis of a phase II study. (ID 2802)
11:25 - 11:30 | Author(s): M.G. Zauderer
- Abstract
- Presentation
Background
Pleurectomy/decortication (P/D) is increasingly used for the surgical management of MPM. The presence of the remaining ipsilateral lung poses a challenge when delivering adjuvant radiation therapy, as the risk for radiation pneumonitis (RP) is high. We developed an IMRT technique targeting the entire pleura of the involved hemithorax, with promising early results. Here, we present the interim results of a prospective phase II study to determine the safety and toxicity profile of pleural IMRT following induction chemotherapy and P/D.Methods
Twenty-nine patients with locally advanced MPM have been enrolled to date. All patients received up to four cycles of pemetrexed/platinum chemotherapy. P/D was performed for all resectable patients. Sequential hemithoracic pleural IMRT was then administered with the intent of achieving a total planned dose of 50.4Gy in 28 fractions, as previously described (Rosenzweig et al., IJROBP 2012). All patients were simulated with a 4D-CT scan. A PET scan for image fusion and radiation planning was available for all patients. A Simon two-stage design was applied. A safety analysis after the first 9 patients led to the identification of only one case with ≥grade 3 RP in the first 3 months. The cohort was therefore expanded to 28 evaluable patients, defined as having initiated RT. The primary endpoint is the incidence of ≥grade 3 RP defined per Common Terminology Criteria for Adverse Events, v4.0. Steroids are typically initiated for ≥grade 2 RP.Results
To date, 21 out of 29 patients total are evaluable. The median follow-up is 10 months. The median age at diagnosis is 66 years (range 38-79). Median KPS was 90% (range 70-90%). Three patients had sarcomatoid, 3 had biphasic and 23 had epithelioid MPM. All patients received chemotherapy. Eight patients (28%) had a partial response, nine patients (38%) progressed, and all others had stable disease. Twenty-four patients (83%) underwent surgical exploration. Five patients underwent an extended P/D or P/D, 11 had a partial P/D, and 8 were found to be unresectable. Eight patients were removed from the study prior to receiving IMRT (7 due to disease progression and 1 due to grade 4 pulmonary embolism after one cycle of chemotherapy). To date, nineteen patients have completed IMRT [median dose 4680cGy (range 4500 to 5040cGy)]; one patient had distant disease progression after 16 fractions; one patient is currently on treatment. Five patients experienced grade 2 RP that was successfully controlled with steroids. One patient experienced grade 3 RP requiring supplemental oxygen, but quickly improved after steroid initiation. Other commonly observed ≥grade 2 radiation-related toxicities included fatigue (37%), dyspnea (47%), nausea (42%), esophagitis (26%), and cough (11%). No grade 4 or 5 radiation-related toxicities were observed.Conclusion
Hemithoracic pleural IMRT appears to have an acceptable toxicity profile in this ongoing phase II study. Early intervention with steroids is effective in controlling RP. This novel radiation technique has great promise as a component of lung-sparing multi-modality therapy in locally advanced MPM.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
