2015 Oncology Drugs in the Pipeline

Ipilimumab

Ipilimumab (Yervoy, Bristol-Myers Squibb) is one systemic therapy that may have an impact on the standard of care for men with metastatic castration resistant prostate cancer (CRPC) in the coming year.

Ipilimumab is an immune checkpoint inhibitor, specifically a CTLA-4 blocker. Immune checkpoint inhibition has led to tremendous changes in the way we treat patients with other malignancies, particularly melanoma. Other immune checkpoint inhibitors, such as PD-1 or PDL-1 inhibitors, are having a tremendous impact on the care for other solid tumors. However, no immune checkpoint inhibitor currently is available or approved for use in men with prostate cancer.

Two phase 3 trials of ipilimumab have been completed in metastatic CRPC. The first was performed post-chemotherapy (Kwon ED. Lancet Oncol. 2014;doi:10.1016/S1470-2045(14)70189-5). Patients received a dose of radiation designed to release antigen and stimulate the immune system. They then were randomly assigned to ipilimumab or placebo. It narrowly missed meeting a positive primary endpoint for improving OS (HR = 0.85; P = .053).

Some patients — particularly the better-prognosis patients, such as those without liver (visceral) metastases — demonstrated a more profound improvement in survival.  This suggested that men with a better long-term prognosis may have a greater survival benefit with immunotherapy, a finding that has also been observed with sipuleucel-T (Provenge, Dendreon), a commonly used immunotherapy approved in this setting.

Bristol-Myers Squibb conducted another phase 3 randomized, placebo-controlled trial performed pre-chemotherapy in men with metastatic CRPC. That trial completed more than a year ago, and I’d expect results to be reported within the next 6 to 12 months. A positive study for OS — given the challenges in meeting this endpoint with the current landscape of multiple approved and active agents — would generate a lot of optimism and hope for immunotherapy in this disease, and the concept of immune checkpoint blockade in prostate cancer would be then validated. This would help in the development of other immune checkpoint inhibitors in this disease, some of which remain in very early stages of development.

Ipilimumab has some serious side effects. Autoimmune disorders are common, and some  can be life-threatening, so there is a potential for risk. However, ipilimumab is a distinct immunotherapy. It is possible it could be used in conjunction with — or before or after — other currently approved therapies and would be preferred in the pre-taxane setting in appropriately selected men without major comorbidities. If the results of the second phase 3 study demonstrate a positive impact on OS, it could fundamentally change our treatment algorithm. Based on the already nearly positive phase 3 trial in prostate cancer and the positive results observed in melanoma — and with the successes seen with immune checkpoint inhibition in general across multiple oncology indications — I believe there is a reason for optimism.

Daratumumab

The multiple myeloma community has with great interest watched the development of daratumumab (Janssen). Daratumumab is a human monoclonal antibody directed against CD38, an antigen highly expressed on myeloma cells. Preclinical studies have demonstrated complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis and inhibition of CD38 ADP-ribosyl cyclase activity. The initial phase 1/phase 2 dose-escalation study has shown single-agent activity in very heavily pretreated patients, with an overall response rate of approximately 40%. Notably, activity has been observed in patients who are dual refractory to immunomodulatory agents and proteasome inhibitors, a subgroup of patients who historically have had a dismal prognosis. The side-effect profile has thus far been shown to be quite manageable, with the primary toxicity being related to infusion reactions. Currently, daratumumab is being investigated in a variety of other drug combinations, including in both the upfront and relapsed/refractory settings. Preliminary reports have indicated very high response rates when used in combination with standard agents. For example, the combination of daratumumab with lenalidomide (Revlimid, Celgene) and dexamethasone in relapsed/refractory patients yielded a 100% overall response, with a 31% complete response rate in the dose-escalation phase. Thus, not only does this drug provide hope for patients refractory to standard therapies, but if it is used with standard therapies in the upfront setting, this could result in significantly deeper responses that in turn could translate to improved long-term survival.

Pacritinib

Pacritinib (CTI Biopharma/Baxter International), previously known as SB1518, is an oral JAK2 and FLT3 inhibitor. Phase 1 and phase 2 testing in the United States and Australia demonstrated the agent was efficacious in improving the splenomegaly and symptoms of patients with myelofibrosis (Komrokji RS, et al. Blood. 2015;Published online ahead of print March 11), with manageable gastrointestinal toxicities but minimal hematological toxicities, a limiter of FDA-approved ruxolitinib (Jakafi, Incyte).

These latter results led to the PERSIST-1 trial (NCT01773187), a randomized phase 3 trial of pacritinib vs. best alternative therapy in JAK inhibitor-naive patients. The trial had the unique aspect of not excluding patients based on thrombocytopenia. Top-line results of PERSIST-1, announced March 9, showed the study met its primary endpoint of superior improvement in splenomegaly at 24 weeks in the pacritinib arm, along with improvement in myelofibrosis-associated symptoms, and improvements in anemia in many erythrocyte transfusion-dependent patients. In parallel, a second phase 3 trial — PERSIST-2 (NCT02055781) is enrolling for patients with myelofibrosis who have baseline thrombocytopenia (<100 x 109/L) who may have had prior JAK inhibitor exposure.

Several areas of further investigation of pacritinib are ongoing given its favorable safety profile and activity. These include pre-allogeneic transplant in myelofibrosis (NCT02410551) and acute myeloid leukemia with FLT3 mutations (NCT02323607). Exploratory trials of pacritinib in patients with myelodysplastic syndrome and in patients with solid tumors are planned, including those with non–small cell lung cancer who have EGFR-mutant disease and failed one prior tyrosine kinase inhibitor (NCT02342353), as well as for those with refractory colorectal cancer (NCT02277093).

Pacritinib seems to represent an incrementally important addition to therapeutic options for patients with myelofibrosis with cytopenias, and this combination of efficacy without hematological toxicity might prove beneficial in other hematologic and solid tumor indications.

Ado-trastuzumab emtansine

Ado-trastuzumab emtansine (Kadcyla, Genentech) has been shown to be a very efficacious drug in treatment of trastuzumab (Herceptin, Genentech)-resistant HER-2–positive breast cancer. It is a drug–antibody conjugate (ADC), which is a class of drugs that combine the benefits of targeted treatment with a monoclonal antibody with a highly potent chemotherapy drug. ADC works by binding to the target antigen on cancer cells, causing the whole molecule to be internalized, leading to release of the chemotherapy moiety and cell death. This method of delivery increases the therapeutic window for the chemotherapy drugs by decreasing systemic release but increasing intratumoral concentration of the active chemotherapy agent. Expression of the target antigen on normal cells and nonspecific antibody bindings leads to systemic release of the chemotherapy agent and induces any toxicities. Two pivotal phase 3 trials of T-DM1 — TH3RESA and EMILIA — have shown that ado-trastuzumab emtansine is very active in patients with HER-2–positive breast cancer resistant to trastuzumab therapy. Ado-trastuzumab emtansine not only has been shown to be superior to other second-line therapies, but it also has a much better toxicity profile marked by low levels of thrombocytopenia, elevated alanine and aspartate aminotransferases, fatigue, diarrhea and nausea/vomiting. It is currently being evaluated in both HER-2–positive breast cancer and HER-2–positive gastric cancers in multiple clinical trials in the neoadjuvant, adjuvant and metastatic settings, alone or in combination with various targeted, endocrine and chemotherapy agents. There are currently 34 open clinical trials with this agent listed on clinicaltrials.gov, which indicates the great interest and promise of this drug.

Defactinib

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that mediates signaling through integrins associated with extracellular matrix attachment as well as other growth factors. Enhanced FAK signaling has been shown to promote cell survival through resistance to apoptotic stimuli, cell migration and epithelial-mesenchymal transition, making FAK an attractive therapeutic target in oncology.

FAK is important in the maintenance of cancer stem cell populations; in a mesothelioma xenograft model, FAK inhibition was shown to eliminate stem cells that were enriched following treatment with pemetrexed (Alimta, Eli Lilly) and cisplatin (Shapiro IM, et al. Sci Transl Med. 2014;doi:10.1126/scitranslmed.3008639). FAK also has been linked to mesothelioma in other ways; the tumor suppressor merlin, the gene product of the neurofibromatosis 2 gene (NF2), is frequently inactivated in mesothelioma and has been shown to be a negative regulator of FAK activity (Poulikakos PI, et al. Oncogene. 2006;25:5960-5968).

Defactinib (VS-6063, Verastem) is a potent and selective orally available FAK inhibitor that is active against human mesothelioma cell lines and xenograft models, and displays greater activity against merlin-negative tumors (Shapiro IM, et al. Mol Cancer Ther. 2013;doi:10.1158/1535-7163.TARG-13-C262). A phase 1 trial in patients with solid tumors demonstrated good tolerability at doses above the minimal efficacious concentration.

Defactinib is now being studied in the COMMAND trial (NCT01870609), an international phase 2 study of oral defactinib vs. placebo as maintenance therapy following front-line pemetrexed/platinum chemotherapy for patients with malignant pleural mesothelioma who have shown disease stability/response. Patients are stratified by high vs. low merlin expression status, which will allow the assessment of merlin as a predictive biomarker. Other trials of defactinib in mesothelioma include a phase 2 neoadjuvant trial of single-agent therapy prior to extrapleural pneumonectomy or pleurectomy (NCT02004028), and a phase 2 trial of defactinib in combination with the PI3K/mTOR inhibitor VS-5584 in patients with relapsed pleural mesothelioma who have received at least one line of prior chemotherapy (NCT02372227).

Defactinib is also being studied as a single agent in previously treated KRAS-mutant non–small cell lung cancer (NCT01951690), and in combination with paclitaxel in ovarian cancer (NCT01778803). Positive data from these trials would provide validation of this unique target, as well as the promise of cancer stem cell therapeutics.

Nivolumab

Over the past few years, we have seen the clinical development of an exciting new class of drugs called immune checkpoint inhibitors. One of the most actively studied immune checkpoint pathways is the programmed death-1 (PD-1) axis. PD-1 is a negative regulator of T cells, and tumors express PD-L1, the ligand for PD-1 that binds to PD-1 on T cells to inactivate the anti-tumor immune response by the T cells. Nivolumab (Opdivo, Bristol-Myers Squibb) is a fully human IgG4 anti–PD-1 monoclonal antibody.

In a recently published update from a multicenter dose escalation phase 1 study with nivolumab, encouraging OS rates were observed in patients with non–small cell lung cancer who had been heavily pretreated (Gettinger SN, et al. J Clin Oncol. 2015;published online ahead of print April 20). The analysis included 129 patients who received nivolumab at three different doses: 1 mg/kg, 3 mg/kg and 10 mg/kg. The overall response rate was 17.1% (95% CI, 11-24.7) and median OS was 9.9 months. Researchers reported survival of 42% at 1 year, 24% at 2 years and 18% at 3 years. With the caveats of this being a phase 1 study, these findings represent a significant advance in treatment of patients with previously treated NSCLC.

These findings were further supported by a subsequent single-arm multicenter phase 2 trial, CheckMate 063 (Rizvi NA, et al. Lancet Oncol. 2015;doi:10.1016/S1470-2045(15)70054-9). In this trial, nivolumab was administered 3 mg/kg every 2 weeks to previously treated squamous NSCLC (≥2 prior lines of therapy) until progression or unacceptable toxic effects. Seventeen (14.5%) of 117 patients had an objective response, median OS was 8.2 months and 1-year survival was 41%.

A randomized phase 3 trial that compared docetaxel to nivolumab in previously treated advanced squamous NSCLC (CheckMate 017) was stopped early due to efficacy, but the clinical data have not yet been published or presented at a meeting. However, in a somewhat unprecedented manner, FDA had expeditiously approved nivolumab (3 months ahead of schedule) for patients with metastatic squamous NSCLC that progressed after platinum-based chemotherapy.

Another phase 3 randomized trial (CheckMate 057) of docetaxel vs. nivolumab in non-squamous NSCLC was stopped early due to efficacy, and data are under FDA review for consideration of expansion of nivolumab’s indication to non-squamous NSCLC histology.

Data from these trials and other similar drugs that target the PD-1 axis have induced a new wave of excitement and hope for patients with lung cancer. Even though the lure of long-term survival with the PD-1 inhibitors is appealing, the response rates in unselected patients are only modestly better than those of cytotoxic chemotherapy. Further studies will need to focus on evaluating potential predictive biomarkers for these drugs.