August 2013 Vol 6, No 6 Special Issue - Incretin Therapies
Caroline Helwick
Wayne Kuznar

Chicago, IL—Targeted therapies and immune-focused agents with novel mechanisms of action yielded impressive outcomes in the early- and late-phase studies that were reported at ASCO 2013.

Melanoma
The MEK inhibitor selumetinib is the first drug to prove effective in patients with metastatic uveal (ocular) melanoma, according to phase 2 clinical trial results. In a study of 98 patients, 50% of those receiving selumetinib had tumor regression compared with 11% of the patients in the control group who received temozolomide (Temodar). The median progression-free survival (PFS) was 15.9 weeks and 7.0 weeks (P = .005), respectively, a 54% risk reduction. Lynn Mara Schuchter, MD, Program Leader, Melanoma Program, Abramson Cancer Center of the University of Pennsylvania, Philadelphia, noted that these findings “will ultimately be practice-changing.”

A new class of immunotherapy agents blocks programmed death-1 (PD-1) and its ligand (PD-L1) and helps T-cells attack the tumor. In an expanded phase 1 trial of the PD-1 inhibitor nivolumab in 107 heavily pretreated patients, the median overall survival (OS) approached 17 months. In combination with ipilimumab (Yervoy) in another phase 1 study, nivolumab led to deep, rapid, and durable responses. With concurrent treatment, 53% of patients responded and 17% achieved a complete response (CR); the estimated 1-year OS with this regimen was 82%.

Lambrolizumab is another anti–PD-1 antibody that recently received a Breakthrough Therapy designation from the US Food and Drug Administration (FDA). Lambrolizumab was evaluated in an open-label study of 135 patients; 52% of the patients receiving the optimal dose responded, with a median PFS exceeding 7 months. Lambrolizumab is currently being studied in patients with melanoma, non–small-cell lung cancer (NSCLC), breast cancer, head and neck cancer, and bladder cancer. A global phase 2 study of the drug in patients with ipilimumab-refractory advanced melanoma will enroll 510 patients.

Talimogene laherparepvec (T-VEC) was the first oncolytic virus to show benefit in patients with advanced melanoma in the phase 3 OPTiM trial. Of the 436 patients, those receiving T-VEC injections had more durable responses compared with patients receiving granulocyte-macrophage colony-stimulating factor and significantly longer time (8.2 months vs 2.9 months, respectively) to treatment failure. Melanoma experts suggested that the best use of this novel drug may be in combination with another immunomodulating agent. Whether the oncolytic virus will pan out remains to be seen, but melanoma experts are betting on the success of the anti–PD-1 and anti–PD-L1 agents. According to Walter J. Urba, MD, PhD, Providence Cancer Center, Portland, OR, these novel drugs “are certainly going to change the state of the care of patients with melanoma.”

Lung Cancer
Ganetespib. In a phase 2b/3 study, the novel second-generation heat shock protein (HSP) 90 inhibitor ganetespib improved survival as second-line therapy in patients with advanced-stage NSCLC, a benefit that was more apparent in patients who were diagnosed >6 months before treatment. Improvements in OS and PFS were seen when ganetespib was used in combination with docetaxel (Taxotere).

Lead investigator Suresh S. Ramalingam, MD, Winship Cancer Institute of Emory University, Atlanta, GA, said that HSP inhibitors are molecular chaperones for several key cellular oncogenic proteins, and that inhibiting HSP90 may stall tumor development and progression. In the trial known as GALAXY-1, 252 patients with adenocarcinoma were randomized to ganet­espib/docetaxel or to docetaxel alone.

The median PFS was 4.5 months in the combination arm and 3.2 months in the docetaxel monotherapy arm, with a hazard ratio (HR) of 0.84 (P = .038). OS was 9.8 months versus 7.4 months (HR, 0.82; P = .082). Patients who were enrolled >6 months from being diagnosed derived the most benefit—with PFS of 5.4 months with ganetespib/docetaxel versus 3.4 months with docetaxel alone (P = .041); OS was 10.7 months versus 6.4 months, respectively (P = .093). Improved survival with ganetespib was not related to endothelial growth factor receptor (EGFR) or to KRAS mutational status.

Ninteda­nib. A phase 3 study demonstrated an improvement in PFS when ninteda­nib, a triple angiokinase inhibitor, was added to docetaxel in the second-line setting compared with do-cetaxel alone in patients with NSCLC. Nintedanib targets 3 tyrosine kinases—fibroblast growth factor receptor, platelet-derived growth factor receptor, and vascular endothelial growth factor, according to Martin Reck, MD, PhD, of Grosshansdorf Hospital, Germany.

In the LUME-Lung 1 study, 1314 patients with NSCLC whose disease progressed after first-line chemotherapy were randomized to nintedanib/docetaxel or to docetaxel alone. The median PFS was 3.4 months in the combination arm and 2.7 months in the monotherapy arm (HR, 0.79; P = .019).

The median OS was 10.1 months in the nintedanib/docetaxel arm versus 9.1 months in the docetaxel arm, a nonsignificant difference. The greatest improvement in median OS was in patients with adenocarcinoma, whose time to study treatment was <9 months since the start of first-line treatment—10.9 months versus 7.9 months (HR, 0.75; P = .073). In patients with an adenocarcinoma histology, median OS was significantly improved with nintedanib/docetaxel versus docetaxel alone (12.6 months vs 10.3 months, respectively), a 17% reduction in risk (P = .035).

Ovarian Cancer
A retrospective analysis of a phase 2 study of olaparib, a poly ADP ribose polymerase (PARP) inhibitor, demonstrated an improvement in PFS as maintenance therapy for women with advanced platinum-sensitive ovarian cancer. The stratification of data by BRCA1 or BRCA2 mutation status showed that olaparib is most likely to benefit patients with BRCA1 or BRCA2 mutations, said Jonathan A. Lederman, MD, BSc, of University College, London. In women with BRCA mutation, PFS was 11.2 months with olaparib versus 4.3 months with placebo (P <.001). There was a “strong trend” for improvement in median OS with olaparib compared with placebo in patients with BRCA mutations (34.9 months vs 31.9 months, respectively; P <.208). A pivotal phase 3 trial is planned.

Renal-Cell Carcinoma
The anti–PD-L1 antibody MPDL3280A produced durable responses in a phase 1 study of patients with renal-cell carcinoma (RCC). PD-L1 is believed to be “abhorrently expressed in both primary and metastatic renal-cell carcinoma,” said lead investigator Daniel C. Cho, MD, Beth Israel Deaconess Medical Center, Boston, MA.

This dose-finding study of patients with multiple tumor types included 53 patients with RCC (mostly clear-cell histology). Patients received MPDL3280A intravenously 3 times weekly at various doses. No treatment-­­related deaths or dose-limiting toxicities were reported in the patients with RCC.

The overall response rate (ORR) among all tumor types was 21%, and an additional 16% of patients achieved stable disease for ≥24 weeks. The ORR was 13% in patients with RCC and 32% of patients achieved stable disease. The 24-week PFS in the patients with RCC was 53%. Responses were higher among patients expressing the PD-L1 receptor than in PD-L1–negative patients. CRs occurred only in the PD-L1–positive group.

Leukemia
The novel anti-CD20 agent obinutuzumab added to standard chemotherapy improved the response rate and the PFS of patients with chronic lymphocytic leukemia (CLL) and comorbidities compared with chlorambucil (Leukeran) alone in the phase 3 clinical trial CLL11, reported Valentin Goede, MD, of the University of Cologne, Germany. Based on these data, the FDA has granted obinutuzumab priority review status. Obinutuzumab is a type 2 antibody with stronger binding to the B-cell compared with rituximab, which increases direct cell death.

The CLL11 study enrolled 590 adults with treatment-naïve CLL and comorbidities and/or impaired kidney function. The median investigator-assessed PFS improved from 10.9 months with chlorambucil chemotherapy alone to 23 months with the addition of obinutuzumab to chemotherapy (P <.001). Obinutuzumab/chlorambucil resulted in an 86% reduction  in the risk of disease progression or death compared with chlorambucil alone (P <.001).

CRs were achieved by 22.2% of the combination arm and in none of the patients in the chlorambucil arm. A third arm—rituximab/chlorambucil —also had improved PFS (median, 16.7 months) compared with chemotherapy alone, and approximately 8% of patients in the rituximab plus chlor­ambucil group had a CR. The risk reduction of disease progression or death with rituximab/chlorambucil was 68% compared with chlorambucil alone. At 1 year, PFS was 84% with obinutuzumab, 63% with rituximab, and 27% with chlorambucil alone. OS data were not mature after 14 months of follow-up.

Lymphoma
Idelalisib. In early-phase trials of patients with non-Hodgkin lymphoma (NHL), this novel agent targeting the PI3K pathway (which fuels the growth and survival of B-cell and T- cell malignancies) turned in impressive results as a single agent and in combination with standard therapy. Idelalisib was combined with standard therapy in a phase 1 study of 78 previously treated patients with indolent NHL, producing response rates of 78%, with 26% CRs, reported John P. Leonard, MD, of Weill Cornell Medical College, New York. At the discretion of the treating physician, patients received idelalisib in combination with rituximab (Rituxan), bendamustine (Treanda), or rituximab/bendamustine. Patients were treated for 6 cycles, and responders could continue idelalisib therapy for a total of 48 weeks. The median PFS has not been reached; at 24 months, 62.5% of patients are still in remission.

Single-agent activity of idelalisib was confirmed in another phase 1 study, with a 48% response rate, rising to 67% among optimally dosed patients (≥100 mg twice daily).

In patients with mantle-cell lymphoma, single-agent idelalisib showed activity in phase 1 studies, but it appeared especially beneficial in combination with other agents. In a phase 1 study of 33 patients reported by Nina D. Wagner-Johnston, MD, of Washington University, St Louis, MO, the combination of idelalisib and everolimus (Afinitor), bortezomib (Velcade), or bendamustine/rituximab yielded an impressive 49% ORR, with 12% CRs. In the bendamustine/rituximab arm, 100% of patients responded, but this population was not heavily pretreated, unlike the other 2 arms, Dr Wagner-Johnston pointed out. The median PFS was 8 months and tolerability was good, although elevations in liver enzymes were seen. Phase 3 trials of this PI3K inhibitor are under way.

The Bruton’s tyrosine kinase inhibitor ibrutinib, which has received Breakthrough Therapy designation from the FDA, was evaluated in combination with rituximab plus chemotherapy (R-CHOP) in a small phase 1/2 study of 33 treatment-naïve patients with NHL, reported Anas Younes, MD, of the University of Texas M.D. Anderson Cancer Center, Houston. The combination produced an ORR of 100%, including 67% CRs. Although ibrutinib shows promising results in lymphoma, researchers are still debating whether it will best be used as a single agent or in combination with other drugs.

Multiple Myeloma
The final results of the phase 1 study of the oral proteasome inhibitor ixazomib, better known as MLN9708, were reported by Shaji K. Kumar, MD, Mayo Clinic, Rochester, MN. The study included 32 heavily pretreated patients in the dose-escalation phase, and 31 patients in the expansion cohort (who received the maximum tolerated dose). Of 50 evaluable patients, 18% responded to monotherapy, increasing to 26% among optimally dosed patients. “Some responses have been long-lasting, beyond 10 cycles of therapy,” Dr Kumar reported. The drug is known to be less neurotoxic than current therapies. The overall rate of peripheral neuropathy was 20%, with grade ≥3 in 1 patient only.

The data continue to accumulate for novel monoclonal antibodies in patients with myeloma. “For the first time, monoclonal antibodies are appearing to make a difference in the treatment of multiple myeloma patients,” said Mehdi Hamadani, MD, MBBS, of West Virginia University, Morgantown.

In a phase 1/2 study of elotuzumab plus lenalidomide (Revlimid)/dexamethasone (Decadron), the ORR among 98 heavily pretreated patients was 84%, rising to 92% in patients receiving elotuzumab 10 mg/kg. Median PFS was 33 months in this optimally dosed cohort. “Historically, treatment with lenalidomide plus high-dose dexamethasone (no elo­tuzumab) resulted in an objective response rate of about 60% and median time to progression of about 11 months in 2 randomized phase 3 studies with similar patient populations,” noted lead investigator Sagar Lonial, MD, of Emory University, Atlanta, GA. Elotuzumab is being studied in 2 phase 3 trials: in the frontline setting in the ELOQUENT-1 trial and in relapsed/refractory disease in the ELOQUENT-2 trial.

Daratumumab is being studied in a phase 1/2 study of 32 heavily pretreated patients with relapsed and/or refractory multiple myeloma that produced clinical benefit in nearly 70% of patients. At 18-week follow-up, median PFS has not been reached.

The histone deacetylase inhibitor quisinostat, given in combination with bortezomib and dexamethasone in patients with relapsed myeloma, produced an 87.5% ORR in a phase 1b dose-escalation study involving 18 patients.

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