Mechanism of Action: Key Advances in Hematology Oncology
Other Recent Key Presentations in Oncology
Humanized Monoclonal Antibody Shows Promise in Combination Therapy in Chronic Lymphocytic Leukemia with ComorbiditiesChemoimmunotherapy (CIT)—typically fludarabine, cyclophosphamide, and rituximab—is standard of care for young and physically-fit patients with chronic lymphocytic leukemia (CLL). There is no standard of care, however, for older and less fit patients with CLL. At the American Society of Clinical Oncology 2013 annual meeting, Valentin Goede, MD, German CLL Study Group, Cologne, Germany, reported final results for stage 1 of phase 3 trial CLL11, the largest trial to evaluate 3 treatment regimens in previously untreated patients with CLL and comorbidities. GA101, or obinutuzumab, is a third-generation humanized anti-CD20 monoclonal antibody under study in various B-cell malignancies, including CLL and non-Hodgkin lymphoma. Compared with rituximab, GA 101 binds with high affinity to CD20, resulting in the induction of antibody-dependent cytotoxicity that is 5- to 100-fold greater than observed with rituximab treatment. In a phase 1/2 trial, GA101 had a similar safety profile to rituximab, and exhibited promising efficacy in patients with relapsed and/or refractory CD20-positive lymphoid malignancies. The CLL11 trial was designed to compare the 3 treatments (chlorambucil alone [C; n=118], GA101 + chlorambucil [GC; n=238], and rituximab + chlorambucil [RC; n=233]) in 2 stages: stage 1a compares C with GC, stage 1b compares C with RC, and stage 2 compares GC and RC. The primary efficacy end point was investigator-assessed progression-free survival (PFS). Data from 589 patients in stage 1a and stage 1b show that CIT with either GC or RC significantly prolongs PFS compared with C alone. Safety data included grade 3 or 4 infusion-related reactions with GC that occurred during the first infusion only. Splitting the first dose over 2 days effectively managed this toxicity. These results demonstrate that both GC and RC are highly active in patients with newly diagnosed CLL and comorbidities, and are superior treatment options to C alone for these patients. The comparative analysis of GC and RC (stage 2 of CLL11) will be reported late this year or in 2014.
ReferenceGoede V, Fischer K, Humphrey K, et al. Obinutuzumab (GA101) plus chlorambucil (Clb) or rituximab (R) plus Clb versus Clb alone in patients with chronic lymphocytic leukemia (CLL) and preexisting medical conditions (comorbidities): final stage 1 results of the CLL11 (BO21004) phase III trial. J Clin Oncol. 2013;31(suppl). Abstract 7004.
Engineered PD-L1 Antibody Encouraging in Locally Advanced or Metastatic Solid TumorsIn cancer cells, programmed death ligand 1 (PD-L1) protein acts as a disguise, hiding these cells from the immune system. However, when MPDL3280A, an engineered PD-L1 antibody, attaches to this protein, cancer cells are “unmasked” and tumor-specific T-cell immunity is restored. MPDL3280A, a human monoclonal antibody, blocks PD-L1 from binding to its receptors. Roy S. Herbst, MD, PhD, a professor of medicine at Yale Cancer Center and chief of medical oncology at Smilow Cancer Hospital at Yale-New Haven in Connecticut, and colleagues conducted a large phase 1 study in which 171 patients were assigned to MPDL3280A administered intravenously 3 times a week, including 3+3 dose-escalation and expansion cohorts. MPDL3280A was given for a median of 127 days. During the American Society of Clinical Oncology 2013 presentation, Herbst stated that patients in the dose-escalation cohorts did not experience dose-limiting toxicities, and no maximum tolerated dose was identified. During the study period, 13% of patients reported a treatment-related grade 3 or 4 adverse event (AE). No grade 3 to 5 pneumonitis was observed, and no treatment-related deaths occurred. AEs of special interest included hepatitis, rash, and colitis. Of the 140 patients evaluated for clinical efficacy, there was an overall response rate of 21%. Patients with melanoma had a 29% response rate, patients with non–small-cell lung cancer had a 22% response rate, and patients with renal cell carcinoma had a 13% response rate. Responses to MPDL3280A were durable, with the time on study for responders ranging from 3 to 15 months. The 24-week progression-free survival was 45%. Dr Herbst also pointed out that some patients had a gradual response to MPDL3280A over multiple cycles. In fact, some patients who progressed but stayed on the trial for clinical benefit responded to MPDL3280A later in time. When a diagnostic test was used to examine archival tumor samples from 33 patients in the MPDL3280A trial, patients with tumors positive for PD-L1 had a response rate of 36% compared with 13% in PD-L1–negative patients. Because the diagnostic test to detect PD-L1 is still evolving, a negative result does not necessarily mean that a patient will not respond to MPDL3280A. “This drug is generally well tolerated, with no significant side effects,” Herbst said during a press conference. “Tumor PD-L1 expression appears to be associated with response to the agent, and further studies of monotherapy and other combination studies are planned.”
ReferenceHerbst RS, Gordon MS, Fine GD, et al. A study of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumors. J Clin Oncol. 2013;31(suppl). Abstract 3000.
Nintedanib Combined With Chemotherapy Shows Survival Benefit in Some Lung CancersNintedanib (BIBF 1120) is an oral, triple angiokinase inhibitor that targets the vascular endothelial growth factor, platelet-derived growth factor, and fibroblast growth factor pathways. These pathways are key regulators of angiogenesis, which is essential for tumor growth and metastasis. In clinical trials, nintedanib appears to be effective and well tolerated in various tumor types, including lung, colorectal, hepatocellular, and prostate. The single-agent efficacy of nintedanib as second- and third-line therapy in recurrent advanced non–small-cell lung cancer (NSCLC) was demonstrated in a phase 2 trial. Martin Reck, MD, head of department of thoracic oncology, Hospital Grosshansdorf, Grosshansdorf, Germany, and colleagues presented results of a large placebo-controlled phase 3 trial of nintedanib and docetaxel in patients with locally advanced or recurrent NSCLC that progressed after first-line therapy. Known as the LUME-Lung 1 study, this trial enrolled more than 1300 patients with stage IIIB/IV or recurrent NSCLC. These patients were stratified by histology, Eastern Cooperative Oncology Group performance status, prior bevacizumab, and brain metastases, and then randomized to receive nintedanib (200 mg orally twice daily) plus docetaxel (75 mg/m2 every 21 days) (n=655) or placebo plus docetaxel (n=659). Patient characteristics were balanced between the arms. The study’s primary end point was centrally reviewed progression-free survival (PFS) after 713 events. Key secondary end points included overall survival (OS). Reck and colleagues reported that nintedanib plus docetaxel (ND) significantly prolonged PFS compared with placebo plus docetaxel (PD). The median PFS for ND was 3.4 months, and 2.7 months for PD. The hazard ratio (HR) was 0.79 (confidence interval 0.68-0.92; P=0.002). PFS was unaffected by NSCLC histology (squamous vs adenocarcinoma). OS was significantly prolonged in all patients with adenocarcinoma (medians: 12.6 months [ND] vs 10.3 months [PD]) with the greatest improvement seen in those who relapsed within 9 months after starting their first-line NSCLC therapy (medians: 10.9 months [ND] vs 7.9 months [PD]). While a trend toward improved OS was seen in all NSCLC patients (medians: 10.1 [ND] vs 9.1 [PD]), this difference did not reach statistical significance. The incidence of grade ≥3 adverse events (AEs) was 71.3% for ND, and 64.3% for PD. The most common AEs associated with ND included diarrhea and alanine aminotransferase elevations. Rates of study withdrawal due to AEs were similar in both arms, as were rates of AEs typically seen with angiogenesis inhibitors, including grade ≥3 hypertension, bleeding, and thrombosis. Reck and colleagues concluded that, independent of histology, combination use of triple angiokinase inhibitor nintedanib with docetaxel significantly improved PFS for patients with NSCLC, locally advanced or metastatic, that progressed after first-line therapy. The ND combination prolonged OS for patients with adenocarcinoma, but not those with squamous cell carcinoma. AEs associated with ND were generally manageable with dose reductions and symptomatic management. Further assessments of nintedanib in NSCLC and other solid tumors continue.
ReferenceReck M, Kaiser R, Mellemgaard A, et al. Nintedanib (BIBF 1120) plus docetaxel in NSCLC patients progressing after first-line chemotherapy: LUME Lung 1, a randomized, double-blind phase III trial. J Clin Oncol. 2013;31(suppl). Abstract LBA 8011.
Alpha Emitter Approved for Castration-Resistant Prostate Cancer with Bone MetastasesIn May 2013, the US Food and Drug Administration approved radium (Ra)-223 dichloride, a first-in-class alpha emitter. Ra-223, formerly known as Alpharadin, is indicated for the treatment of patients with castrationresistant prostate cancer (CRPC), symptomatic bone metastases, and no known visceral metastatic disease. The approval of Ra-223 was based on a phase 3, double-blind trial of more than 800 patients with CRPC and symptomatic bone metastases. In the Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial, eligible patients had progressive, symptomatic CRPC with 2 or more bone metastases, no known visceral metastases, were receiving best standard of care (BSC), and had received prior docetaxel or were unfit for or declined docetaxel. Patients with CRPC were stratified by baseline alkaline phosphatase level, bisphosphonate use, and prior docetaxel exposure. Patients in ALSYMPCA were randomly allocated (2:1) to receive Ra-223 50 kBq/kg intravenously at 4-week intervals for 6 cycles (n=541) plus BSC or matching placebo plus BSC (n=268). Study results showed that Ra-223 significantly improved median overall survival (OS) by 3.6 months compared with placebo in patients with CRPC with bone metastases receiving BSC. Ra-223 had a highly favorable safety profile in the most recent ALSYMPCA analysis. At the American Society of Clinical Oncology 2013 annual meeting, Nicholas J. Vogelzang, Comprehensive Cancer Centers of Nevada, Las Vegas, and colleagues reported results of a predefined subgroup analysis that assessed the efficacy and safety of Ra-223 in patients with CRPC and bone metastases who did or did not receive prior docetaxel. Among the 921 randomized patients in ALSYMPCA, 395 (43%) had no prior docetaxel, while the balance (526 [57%]) had received prior docetaxel. In this analysis, the improvement in median OS for patients with no prior docetaxel who received Ra-223 was 4.6 months compared with placebo. In patients who had received docetaxel, Ra-223 improved median OS by 3.1 months compared with placebo. The incidence of myelosuppression was low. Incidence rates of neutropenia and thrombocytopenia with Ra-223 were higher in patients with prior docetaxel compared with those who had not received docetaxel. In summary, Ra-223 significantly prolonged OS with a highly favorable safety profile in patients with CRPC and bone metastases, regardless of whether or not they had received prior docetaxel. Patients who received docetaxel had a slightly increased rate of grade 3 or 4 bone marrow suppression with Ra-223. Vogelzang and colleagues concluded that this bone-targeting radiopharmaceutical is a viable alternative for men with CRPC who have received, who are ineligible for, or who prefer to delay or avoid use of cytotoxic chemotherapy. Combination studies of Ra-223 and hormonal agents, immunomodulatory agents, and docetaxel are pending or under way to further elucidate the role of Ra-223 as a part of oncology care providers’ armamentarium.
ReferenceVogelzang NJ, Helle SI, Johannessen DC, et al. Efficacy and safety of radium-223 dichloride (Ra-223) in castration-resistant prostate cancer (CRPC) patients with bone metastases who did or did not receive prior docetaxel (D) in the phase III ALSYMPCA trial. J Clin Oncol. 2013;31(suppl). Abstract 5068.
Following the advent of molecularly targeted agents, and more recently, immunotherapy, over the past few decades, we have witnessed dramatic changes in the treatment paradigms for many types of cancer.
According to data from a preliminary phase 1b clinical trial, a novel approach using the investigational toll-like receptor 9 (TLR-9) agonist CMP-001 in combination with pembrolizumab may have the potential to reverse resistance to anti–PD-1 therapy.