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Lyudmila A Bazhenova



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    MA 17 - Locally Advanced NSCLC (ID 671)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Locally Advanced NSCLC
    • Presentations: 1
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      MA 17.07 - Veliparib in Combination with Paclitaxel/Carboplatin (P/C)-Based Chemoradiotherapy (CRT) in Patients with Stage III NSCLC (ID 10210)

      15:45 - 17:30  |  Author(s): Lyudmila A Bazhenova

      • Abstract
      • Presentation
      • Slides

      Background:
      CRT is a standard for patients with Stage III non-small cell lung cancer (NSCLC). Veliparib (V) is a potent, orally bioavailable PARP1/2 inhibitor that can delay DNA repair following chemotherapy or radiation induced damage. A phase 2 study indicated favorable efficacy of V vs placebo when added to P/C in advanced NSCLC (Ramalingam et al. Clin Cancer Res. 2016). Based on these results, a phase 1/2 trial was initiated to study the safety and efficacy of V/P/C-based CRT in the treatment of Stage III NSCLC.

      Method:
      Patients without prior NSCLC therapy suitable for definitive CRT received V plus C AUC 2 + P 45 mg/m[2] weekly + 60 Gy over 6-9 weeks. V was escalated from 60 mg BID to a maximum planned dose based on prior studies of 240 mg BID via 3+3 design with over-enrollment allowed followed by consolidation therapy of V 120 mg BID + C AUC 6 + P 200 mg/m[2] for up to two 21-day cycles.

      Result:
      Thirty-nine patients (median age 66; 14 male) have been enrolled to date into dosing cohorts at 60 mg (7), 80 mg (9), 120 mg (7), 200 mg (8), and a maximum planned dose of 240 mg (8). Median tumor volume at screening was 81 cc (16-555 cc). PK of V was dose proportional. CRT or V required dose reduction for 0 or 1 patient, respectively. Four (10%) patients discontinued study during CRT. No DLTs were observed and an MTD has not been identified. The most common any-grade AEs were esophagitis (23), nausea (22), fatigue (20), neutropenia (19), and thrombocytopenia (19). 27 SAEs occurred including 12 SAEs with reasonable attribution to V but outside the DLT window including G3/4 febrile neutropenia (2), G3 dehydration (1), G3 vomiting (1), G3 esophagitis (1), G3 radiation esophagitis (1), G3 esophageal stricture (1), G3 intractable N/V (1), G3 aspiration pneumonia (1), G3 radiation pneumonitis (1), G4 sepsis (1), and G5 sepsis during consolidation (1). Of 29 patients evaluable for tumor assessment, best response was CR (2), PR (22), SD (3), and PD (2).

      Conclusion:
      V/P/C-based CRT followed by V/P/C consolidation therapy is a tolerable regimen for the treatment of Stage III NSCLC. The RPTD for V during CRT is 240mg BID. A randomized placebo-controlled phase 2 extension of this study is planned. Clinical trial information: NCT02412371

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    P1.01 - Advanced NSCLC (ID 757)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P1.01-004 - Hypertension With Brigatinib: Experience in ALTA, a Randomized Phase 2 Trial in Crizotinib-Refractory ALK+ NSCLC (ID 8346)

      09:30 - 16:00  |  Author(s): Lyudmila A Bazhenova

      • Abstract
      • Slides

      Background:
      The next-generation ALK inhibitor brigatinib received accelerated approval in the United States in April 2017 for the treatment of patients with metastatic ALK+ NSCLC who have progressed on or are intolerant to crizotinib. Hypertension has been identified as an adverse event of interest with brigatinib treatment based on prior clinical data; here, we report incidence, management, and outcomes of hypertension in ALTA (NCT02094573).

      Method:
      In ALTA, 222 patients were randomized 1:1 to receive brigatinib at 90 mg qd (arm A; n=112 randomized, n=109 treated) or 180 mg qd with a 7-day lead-in at 90 mg (arm B; n=110 randomized and treated). A medical history of hypertension was allowed, but patients with significant, uncontrolled, or active cardiovascular disease were excluded. Blood pressure (BP) was measured at screening, on days 1, 8, and 15 of the first 28-day cycle, and then every 4 weeks (starting on day 1 of cycle 2).

      Result:
      Median age was 50/57 years in treated patients in A/B; 22%/25% of treated patients in A/B had a history of hypertension at baseline. As of February 21, 2017, hypertension was reported as a treatment-emergent adverse event (TEAE; any grade) in 17%/27% of patients (A/B) and as a grade 3 TEAE in 6%/8%; no grade 4 hypertension was reported. Few patients had dose interruptions (1%/2%, A/B) or reductions (1%/1%) due to hypertension; no patients discontinued brigatinib due to hypertension. Among patients with hypertension, median time to onset of first hypertension TEAE was 5.8 months/2.1 months in A/B. Among patients with baseline systolic BP <120 mmHg (n=50/n=48, A/B), 20%/42% had a maximum shift to 140–159 mmHg postbaseline (6%/10%, <120 mmHg to ≥160 mmHg); among patients with baseline diastolic BP <80 mmHg (n=68/n=72, A/B), 29%/35% had a maximum shift to 90–99 mmHg postbaseline (10%/8%, <80 mmHg to ≥100 mmHg). Among patients with hypertension TEAEs (n=19/n=30, A/B), 84%/80% started a new antihypertensive medication during the study. Among patients with hypertension TEAEs and no medical history of hypertension (n=11/n=20, A/B), 73%/70% started a new antihypertensive medication during the study. Cardiovascular events in patients with hypertension TEAEs included: angina pectoris in 1 patient without a medical history of hypertension and, in patients with a medical history of hypertension, hypertensive retinopathy (n=1), intermittent claudication (n=1), and peripheral artery stenosis (n=1).

      Conclusion:
      Hypertension was observed frequently with brigatinib, and appeared dose-related, but was managed with antihypertensive therapy and rarely led to dose modification or discontinuation.

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    P2.03 - Chemotherapy/Targeted Therapy (ID 704)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Chemotherapy/Targeted Therapy
    • Presentations: 1
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      P2.03-058 - Tiger-3: A Phase 3 Randomized Study of Rociletinib Vs Chemotherapy in EGFR-mutated Non-small Cell Lung Cancer (NSCLC) (ID 8395)

      09:30 - 16:00  |  Author(s): Lyudmila A Bazhenova

      • Abstract

      Background:
      Rociletinib, an oral, irreversible tyrosine kinase inhibitor (TKI), selectively targets activating mutations in EGFR and the acquired resistance mutation T790M and demonstrated antitumor activity in the phase 1/2 TIGER-X study (NCT01526928). Initial results are reported from the TIGER-3 study (NCT02322281) of rociletinib vs chemotherapy in EGFR TKI-resistant patients with EGFR-mutated NSCLC.

      Method:
      Eligibility criteria included: metastatic or unresectable, locally advanced, EGFR-mutated NSCLC; radiological progression on most recent TKI therapy; ≥1 line of platinum doublet chemotherapy. Patients were not selected based on T790M status. Patients (N=900) were to be randomized (1:1:1) to rociletinib 500 or 625 mg BID or investigator’s choice of chemotherapy (pemetrexed, gemcitabine, docetaxel, or paclitaxel). The primary endpoint was investigator-assessed progression-free survival (PFS) (RECIST v1.1); objective response rate (ORR) was a secondary endpoint. The rociletinib dosing groups were combined and compared with chemotherapy in a step-down procedure (patients with a centrally confirmed T790M mutation, followed by all randomized patients).

      Result:
      TIGER-3 enrollment was halted upon discontinuation of rociletinib development in NSCLC in 2016; therefore, target enrollment was not achieved. TIGER-3 enrolled 75 patients in the rociletinib groups [500 mg BID, n=53; 625 mg BID, n=22] and 74 in the chemotherapy group. Median age was 62 years, 69.1% had ECOG Performance Status of 1, 39.6% were Asian, 58.4% were female, and median number of prior therapies was 3. PFS and ORR data are presented in the Table. The most common adverse events (all grade; grade ≥3) in the rociletinib group were diarrhea (62.7%; 2.7%), hyperglycemia (58.7%; 24.0%), nausea (37.3%; 4.0%), fatigue (37.3%; 8.0%), and decreased appetite (37.3%; 0%) and in the chemotherapy group were nausea (27.4%; 5.5%), anemia (24.7%; 2.7%), and fatigue (24.7%; 9.6%).

      Outcome Centrally Confirmed T790MPositive Centrally Confirmed T790MNegative Intent-to-Treat Population*
      Rociletinib[†] (n=25) Chemotherapy (n=20) Rociletinib[†] (n=36) Chemotherapy (n=41) Rociletinib[†] (n=75) Chemotherapy (n=73)
      Median PFS, mo (95% CI) 6.8 (3.7–12.2) 2.7 (1.3–7.0) 4.1 (2.5–4.6) 1.4 (1.3–2.7) 4.1 (2.8–5.5) 2.5 (1.4–2.9)
      HR (95% CI) 0.570 (0.285–1.140); P=0.105 0.532 (0.322–0.878); P=0.011 0.609 (0.423–0.875); P=0.006
      Confirmed ORR, n (%) [95% CI] 9 (36.0) [18.0%–57.5%] 3 (15.0) [3.2%–37.9%] 3 (8.3) [1.8%–22.5%] 2 (4.9) [0.6%–16.5%] 13 (17.3) [9.6%–27.8%] 6 (8.2) [3.1%–17.0%]
      *Includes patients with undetermined T790M mutation status. [†]Rociletinib 500 mg BID and 625 mg BID dose groups were pooled for the analysis. CI, confidence interval; HR, hazard ratio.


      Conclusion:
      Incomplete enrollment precluded hypothesis testing. However, the data show a trend toward longer PFS and higher ORR with rociletinib.

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    P3.01 - Advanced NSCLC (ID 621)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P3.01-048 - CBL Mutations as Potential Mediators of EGFR TKI Resistance Effectively Treated with Sitravatinib (ID 9560)

      09:30 - 16:00  |  Presenting Author(s): Lyudmila A Bazhenova

      • Abstract
      • Slides

      Background:
      Third generation EGFR inhibitors are efficacious in patients with NSCLC harboring EGFR sensitizing mutations. Acquired resistance includes alternative mechanisms of EGFR activation and activation of other signaling pathways. Here we report a patient with a CBL mutation as a potential mechanism of acquired resistance to 3[rd] generation EGFR TKI effectively treated with sitravatinib, a spectrum-selective RTK inhibitor of TAM receptors (comprised of TYRO3, AXL, and MER), PDGFRA, KIT, and MET.

      Method:
      In Study 516-001, a phase 1/1b study of sitravatinib in patients with advanced solid tumor malignancies, patients are selected based on mutations in targeted pathways. Eligible genetic alterations include inactivating mutations of CBL, which encodes an E3-ubiquitin ligase that regulates degradation of activated RTKs that include EGFR, TAM receptors, PDGFRA, KIT, and MET and which account for ~2-3% of NSCLC. Based on overlap of sitravatinib and CBL RTK targets and supporting cancer cell line and tumor model data, we hypothesize that inactivating CBL mutations predict response to sitravatinib.

      Result:
      After Phase 1, patients were enrolled by mutational profile, and here we report on a patient enrolled into the CBL mutation cohort. The patient is a 77 year-old female, lifelong non-smoker with metastatic lung adenocarcinoma characterized by EGFR exon19del initially treated with erlotinib with a partial response (PR) of 9 months. Upon disease progression (PD), a new EGFR T790M mutation led to treatment with rociletinib (an experimental inhibitor of EGFR T790M) with stable disease for 11 months. Upon PD she was treated with osimertinib without response. She then received carboplatin/pemetrexed with a PR. Brief erlotinib re-challenge resulted in PD, with post-progression NGS revealing loss of EGFR T790M, presence of the original EGFR exon19del, and a new CBL C384R, a mutation located in the RING domain and predicted to result in the loss of CBL ligase adaptor function resulting in sustained activation of relevant RTKs. The patient then started sitravatinib treatment in Study 516-001. After 36 days on-study, restaging demonstrated PR, which was later confirmed with a maximum decrease in unidimensional target lesion measurement of 77%. She remains on-study.

      Conclusion:
      Loss of function mutations in CBL represent a unique class of mutations that may be responsible for acquired resistance to 3[rd] generation EGFR TKI. Sitravatinib has demonstrated clinical activity in a patient with NSCLC characterized by EGFR exon19del and CBL C384R mutations. The clinical trial with sitravatinib is currently enrolling patients with CBL loss of function mutations. (NCT02219711).

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