Clinicians offer insights into promising drugs in the pipeline

Patrick C. Ma, MD, MS

Following the initial discovery of BEZ235 (Novartis) as a dual pan-PI3K/mTOR clinical compound, further effort was invested by the drug development industry to develop additional phosphoinositide 3-kinase (PI3K) inhibitors from different chemical classes with different selectivity profiles. More recently, a novel pan-PI3K inhibitor, BKM120 (Novartis), was identified and characterized. It is an orally available 2-morpholino pyrimidine derivative kinase inhibitor.

BKM120 inhibits all four class I PI3K isoforms (α, β, , ) in biochemical assays with high selectivity. The compound also is active against the most common somatic PI3Kα mutations. Somatic mutations in PIK3CA, the gene encoding the p110α subunit of PI3K, were frequently found in various human cancers, with the initial hotspots mutations H1047R and E545K shown to be oncogenic in activating the lipid kinase activity.

Because PI3K signaling cascade is believed to be a very important central oncogenic signaling path in many human malignancies, targeted inhibition of PI3K could play a major role in personalized cancer therapy in many cancer types. Cancer mutational and genomic profiling has identified high frequency of mutations of PIK3CA and PTEN in a variety of tumor types. Furthermore, many somatic cancer mutations have been found in other cancer genes involved in the PIK3CA signaling pathway, such as in the downstream signaling molecules PDK1, AKT and p21-actived kinase 4 (PAK4).

Synergistic activities of this compound also have been identified with either targeted agents (eg, HER-2 or MEK inhibitors) or with cytotoxic chemotherapeutics (eg, docetaxel, temozolomide). It is now being tested in phase 2 and phase 3 trials in a variety of human cancer types, including breast and lung cancers.

Bassam N. Estfan, MD

Pancreas cancer continues to be a highly fatal disease, even after surgical resection. Despite adjuvant chemotherapy, median OS is usually less than 2 years. Immunotherapy showed promise in prostate cancer and melanoma treatment. Algenpantucel-L (HyperAcute Pancreas, NewLink Genetics) exploits the role of the host’s immune system in treating pancreas cancer through hyperacute rejection, and it may show promise where other targeted agents did not.

Algenpantucel-L is a vaccine made of two pancreatic cancer cell lines that are genetically modified to express the murine αGal protein, a mammalian protein not present on human cells. One percent of circulating human antibodies target this protein.

This vaccine is given intradermally with adjuvant chemotherapy. The expected result with repeated vaccination is to allow the host’s immune system to attack microscopic pancreas cell after surgery.

A phase 2 study on 69 patients showed the drug to be well tolerated, with 1-year DFS of 62% and 1-year OS of 86%, both of which were higher than those reported in RTOG 9704 [<50% and 69%, respectively (Hardacre JM. J Gastrointest Surg. 2013;17:94-101)]. The benefit was greater with a higher cell dose of 300 million (DFS, 81%; OS, 96%).

These results are exciting and are being investigated in a multicenter phase 3 trial comparing chemotherapy with/without radiation to the same with the addition of algenpantucel-L vaccination.

Nathan Pennell, MD, PhD

Non–small cell lung cancer (NSCLC) has historically been considered a poorly immunogenic malignancy, and numerous attempts to target NSCLC with immune-stimulating therapies such as vaccines have failed to show clinical benefit. More recently, however, immune checkpoint blockade of the programmed death-1 pathway (PD-1) has renewed hope for this strategy. Programmed death ligand-1 (PDL-1) is overexpressed on many human malignancies, including NSCLC, and may represent a major pathway by which cancers escape destruction by the immune system.

In a phase 1 trial that included multiple tumor types, including NSCLC, nivolumab (BMS-936558, Bristol-Myers Squibb) — the fully human blocking antibody to PD-1 — induced objective responses in 18% of patients with NSCLC, including 33% of patients with squamous cell carcinoma (Topalian S. N Engl J Med. 2012;366:2443-2454). Some of these responses were durable, lasting more than 1 year from initiation of therapy. Serious treatment-related side effects were seen in 14% of patients on the trial. Three percent of patients developed pneumonitis, and three of those cases were fatal.

Perhaps most importantly, researchers have identified a potential biomarker for benefit from anti-PD–1 therapy, namely the presence of PDL-1 on the tumor cells. PDL-1–expressing tumors responded to anti-PD–1 36% of the time, while none of the tumors lacking PDL-1 expression had an objective response. A validated biomarker would allow investigators to select for patients who would be most likely to benefit from the therapy while minimizing risk to those unlikely to benefit. Registration trials in NSCLC are under way.

Brian Hill, MD, PhD

Dale R. Shepard, MD, PhD

Manmeet Ahluwalia, MD, FACP

Jason Valent, MD

Daratumumab (Genmab) is a human IgG1 CD38 monoclonal antibody developed for the treatment of multiple myeloma.

In pre-clinical studies, daratumumab induced multiple myeloma cell death through complement mediated and antibody dependent cellular cytotoxicity (DeWeers M. J Immunol. 2011;186:1840-1848). This prompted an international phase 1/2 study in patients with relapsed and refractory multiple myeloma with no established therapeutic options remaining. 

The phase 1 portion of the daratumumab study was presented at the ASH Annual Meeting and Exposition in 2012 (Plesner T. Blood. 2012;120:Abstract 73). Once-weekly doses up to 24 mg/kg were tolerated, and this was the maximum planned dose. Prednisolone or methylprednisolone was permitted up to a dose equivalent of 27 mg of dexamethasone per week to prevent infusion-related events.

Significant adverse events reported included one patient with grade 3 anemia and grade 4 thrombocytopenia at a dose level of 0.1 mg/kg. Two patients experienced bronchospasm at the 2 mg/kg and 24 mg/kg dose level. Grade 3 AST elevation occurred in one patient at 1 mg/kg dose level. Cytokine release syndrome grade 2 was reported in one patient at 0.1 mg/kg dose level. Infusion-related events were minimized with utilization of corticosteroid premedication at dose levels at or above 4 mg/kg.  Based on the data from 32 patients presented, daratumumab seemed to be well tolerated.

The most interesting finding in this study was that daratumumab exhibited significant single-agent activity in relapsed and refractory multiple myeloma patients. This has not been demonstrated with other monoclonal antibody therapies in development for multiple myeloma treatment. At doses greater than or equal to 4 mg/kg, eight of 12 patients had minor response or better. By IMWG criteria, four patients (13%) achieved partial response or better.

Daratumumab combination therapy trials are moving forward. Relapsed and refractory multiple myeloma studies with lenalidomide (Revlimid, Celgene), dexamethasone and daratumumab — as well as bortezomib (Velcade, Millennium Pharmaceuticals), dexamethasone and daratumumab — are in early stages of recruitment. In addition, the CD38 target provides potential therapeutic options in other hematologic malignancies.

Notably, the FDA on May 1 granted daratumumab a breakthrough therapy designation. This will guide and speed the process of approval for use in multiple myeloma.

Robert H.I. Andtbacka, MD, CM, FACS, FRCSC

Talimogene laherparepvec (Amgen) is a herpes simplex virus type-1–derived oncolytic immunotherapy virus. T-VEC is administered by direct injection into tumors, where it selectively infects and replicates in tumor cells. Virus replication leads to tumor cell lysis and exposure of tumor-specific antigens to the patient’s immune system, resulting in a local and systemic immune activation and an immune-mediated destruction of tumor cells throughout the body. To enhance the local and systemic antitumor immune response, T-VEC is engineered to express granulocyte macrophage colony-stimulating factor (GM-CSF).

A phase 2 study evaluated the safety and effect of T-VEC in 50 patients with stage IIIC or IV melanoma. T-VEC was well tolerated, with adverse effects limited primarily to grade 1 or 2. The most common adverse effects observed were transient flulike symptoms.  The overall response rate to T-VEC was 26%. Responses were seen in injected and noninjected lesions. Similar to other immunotherapies, it may take several months for patients to respond to T-VEC, and it is not uncommon for new metastatic lesions to develop before a response is seen. The results of phase 2 study led to the OPTiM phase 3 randomized trial in which 436 patients with unresected stage IIIB, IIIC or IV melanoma were randomly assigned 2:1 to receive T-VEC injected intralesionally or GM-CSF subcutaneously. The treatment could last for up to 18 months, and patients with stable or responding disease could get additional treatment on an extension protocol. The primary endpoint was durable response rate (DRR), defined as a partial or complete response lasting continuously for at least 6 months.

T-VEC had a statistically significant greater DRR compared with GM-CSF (16% vs. 2%). A pre-planned interim analysis indicated a trend toward improved OS in patients treated with T-VEC. Since OS is an event-driven endpoint, a final analysis will be conducted when sufficient events have occurred. This is anticipated late this year.

One advantage of T-VEC compared with many other immune- and chemotherapies is the low adverse effect profile. This may render T-VEC especially useful in patients with a poorer performance status. One disadvantage of T-VEC compared with systemic agents is the need to directly inject T-VEC into palpable skin/subcutaneous tumors or palpable lymph nodes. Patients with tumor metastases available for direct injection represent a relatively small portion of all patients with metastatic melanoma.

The role of T-VEC as a single agent or in combination with other agents also needs to be established. A current study is evaluating T-VEC in combination with ipilimumab (Yervoy, Bristol-Myers Squibb) and will provide valuable insight into the combined use of two different immunomodulating agents in patients with metastatic melanoma.

Maurie Markman, MD

Although not yet approved by the FDA for routine use in the gynecologic malignancies, the administration of bevacizumab (Avastin, Genentech) in combination with cytotoxic chemotherapy has been shown to improve survival outcomes in cancers of the ovary and cervix. In ovarian cancer, phase 3 randomized trials have revealed a statistically significant favorable impact on PFS when the anti-angiogenic agent is added to carboplatin/paclitaxel in the primary setting (Burger RA. N Engl J Med. 2011;365:2473-2483. Perren TJ. N Engl J Med. 2011;365:2484-2496); with carboplatin/gemcitabine in potentially platinum-sensitive recurrent disease (Aghajanian C. J Clin Oncol. 2012;30:2039-2045); and with either weekly paclitaxel, topotecan or pegylated liposomal doxorubicin in platinum-resistant tumors (Pujade-Lauraine E. J Clin Oncol. 2012;30:327s).

In one of the two reported phase 3 primary chemotherapy trials, data suggest that patients with the most advanced disease may experience an OS benefit when bevacizumab is added to the carboplatin/paclitaxel program. In cervix cancer, a recently reported phase 3 trial by Tewari and colleagues — results of which are scheduled to be presented at the 2013 ASCO Annual Meeting — has revealed that adding the anti-angiogenic drug to cisplatin/paclitaxel or topotecan/paclitaxel improves both PFS and OS in the setting of metastatic, persistent or recurrent disease.

Tobenna Nwizu, MD

The epidermal growth factor receptor (EGFR) is upregulated in more than 90% of patients with head and neck squamous cell carcinoma (HNSCC), making EGFR an attractive therapeutic target.

Afatinib (Boehringer Ingelheim) is a next-generation, oral, irreversible EGFR tyrosine kinase inhibitor that has been shown to have activity in a wide variety of malignancies. It works by covalently binding and irreversibly inhibiting all kinase-competent ErbB family members, including human epidermal growth factor receptor 2 (HER-2) and EGFR.  Resistance to first-generation TKIs like erlotinib (Tarceva, Genentech), gefitinib (Iressa, AstraZeneca) and lapatinib (Tykerb, GlaxoSmithKline) typically occurs through molecular plasticity of the ErbB pathway axis, leading to increased expression of other ErbB family members and cognate ligands. Afatinib overcomes this resistance by inhibiting multiple members of the ErbB family, thereby improving efficacy. The most common side effects are diarrhea and skin rash.

A recent phase 2 trial by Seiwert and colleagues compared afatinib to cetuximab (Seiwert TY. 2012. Ann Oncol. 23[suppl 11]:xi35-xi36). The analysis included 124 patients with recurrent or metastatic HNSCC who had failed platinum-based therapy. They were randomly assigned to receive afatinib 50 mg/day or cetuximab weekly until disease progression. Crossover was allowed. The results were equivalent, with a PFS of 15.9 weeks for the afatinib-treated patients and 15.1 weeks for the cetuximab group (P=.78).

An improved overall response rate was seen in the afatinib arm (16.1% vs. 6.5%), although this did not prove statistically significant. Patients who progressed on cetuximab and then crossed over to afatinib had a disease control rate of 38.9%, for a median 20.2 weeks. The results of this trial have generated considerable interest. Afatinib is the first EGFR TKI to show activity in HNSCC that is comparable to cetuximab in platinum-refractory patients. Afatinib also appears to be effective in patients who have failed cetuximab. Larger phase 3 trials are needed to confirm these findings and are currently under way.

Mitchell Smith, MD, PhD

We are on the verge of a seismic shift in our therapeutic approach to B-cell lymphoma of a magnitude similar to that of the introduction of rituximab (Rituxan, Genentech/Idec Pharmaceuticals). Both malignant and normal B cells express immunoglobulin on their surface as part of the B-cell receptor (BCR) complex. Intra-cellular signals transmitted downstream from the BCR are critical to B-cell growth and survival and present an attractive B-cell–specific therapeutic  target.

Among inhibitors in this pathway, farthest along in clinical development is the orally available ibrutinib (Janssen/Pharmacyclics), which irreversibly inhibits Bruton’s tyrosine kinase (BTK). Ibrutinib has demonstrated response rates in the range of 80% in relapsed chronic lymphocytic leukemia, and these responses are often durable on continued therapy. Response evaluation has been complicated by an on-target effect of BCR inhibition that affects stromal interaction, resulting in a lymphocytosis that can raise concern about progressive disease even as lymph nodes regress.

Data from the recent AACR meeting demonstrated activity in CLL with deletion 17p. A randomized trial in relapsed CLL comparing ibrutinib with ofatumumab (Arzerra, GlaxoSmithKline) has completed accrual. Ibrutinib also has shown impressive activity in relapsed mantle cell lymphoma. Of interest from a mechanistic standpoint is that ibrutinib has activity in a subset of relapsed diffuse large B-cell lymphomas driven by BCR signaling, but not in those driven by other signaling pathways.

Other agents in development that affect BCR signals include fostamatinib (AstraZeneca/Rigel Pharmaceuticals), which inhibits spleen tyrosine kinase, and PI3 kinase inhibitors such as idelalisib (GS-1101, Gilead Sciences), which inhibits the PI3K delta-isoform specific for lymphoid cells. Although these can be tolerably combined with chemotherapy, important questions are whether BCR inhibitors can replace chemotherapy, perhaps even as initial therapy, and how to rationally combine them with other biologically targeted agents. 

Douglas Yee, MD

A decline in Ki67 in response to an endocrine therapy has served as a predictive biomarker for clinical benefit. As a surrogate marker for proliferation, tumors with high Ki67 have proliferative rates that do not appear to be affected by estrogen receptor (ER) alpha-targeted therapies alone. It has long been known that control of the progression through the cell cycle is mediated by the cyclin proteins and their interactions with the cyclin dependent kinases (CDK). The serine-threonine kinases CDK 4 and 6 interact with cyclin D1 to hyperphosphorylate the retinoblastoma protein and allow cell cycle progression into S-phase. Thus, inhibition of cell proliferation through disruption of CDK4/6 function could be useful in highly proliferative tumors.

Palbociclib (PD-0332991, Pfizer) is an oral CDK4/6 inhibitor and was tested in ER-positive, HER-2–negative metastatic breast cancer in the TRIO-18 trial. This randomized phase 2 study demonstrated that the addition of palbociclib to letrozole enhanced objective response, clinical benefit rate and PFS (Finn RS. Abstract #S1-6. Presented at: San Antonio Breast Cancer Symposium; Dec. 4-8, 2012; San Antonio). Based on these data, palbociclib received designation as a “breakthrough therapy” by the FDA. The designation is intended to speed up the review and development of this drug. A randomized phase 3 study of letrozole with or without palbociclib (NCT01740427) in first-line treatment of advanced breast cancer is currently open to accrual. Palbociclib is also undergoing testing in other cancer cell types, including sarcoma, ovarian cancer, myeloma and glioblastoma).

James P. Stevenson, MD

The phosphoinositide-3 kinase (PI3K)/Akt signaling pathway is frequently activated in cancer and is associated with increased downstream signaling through the mammalian target of rapamycin kinase (mTOR). Dysregulation of this pathway has been shown to promote key steps in tumor initiation, growth, invasion and metastasis.

GDC-0980 (Genentech) is a potent, orally bioavailable dual PI3K/mTOR inhibitor. A first-in-human phase 1 trial of GDC-0980 revealed antitumor activity in three of six mesothelioma patients enrolled in the study (Wagner AJ. Abstract #3020. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago).

How to explain this? Further elucidation of molecular abnormalities in malignant mesothelioma has shown frequent alterations in the tumor suppressor gene NF2, leading to loss of expression of its gene product Merlin. Merlin loss is linked to activation of signaling through PI3K/mTOR, making these kinases an attractive target for inhibition in Merlin null mesotheliomas. Once-daily GDC-0980 was subsequently studied in an expansion cohort of 24 patients with pleural mesothelioma (Kindler HL. Abstract #IVB2. Presented at: International Conference of the International Mesothelioma Interest Group; Sept. 11-14, 2012; Boston). The majority of patients treated showed some degree of tumor shrinkage, and three patients had partial responses. Molecular characterization of patients treated in this cohort is awaited.

Trials of targeted therapies in mesothelioma have otherwise proven disappointing, including a 660-patient randomized trial of the HDAC inhibitor vorinostat (Zolinza, Merck). The results of GDC-0980 described above are grounds for optimism in the search for another active agent in this disease: It has been nearly 10 years since the initial FDA approval of pemetrexed (Alimta, Eli Lilly) for mesothelioma, and to date it remains the only drug to have that designation.

Tanios Bekaii-Saab, MD

Ramucirumab (IMC-1121B, Eli Lilly) is a fully human monoclonal antibody (IgG1) directed against the vascular endothelial growth factor receptor 2 (VEGFR2), a receptor that is responsible for the majority of VEGF-mediated effects in angiogenesis. There is currently no standard second-line therapy for advanced cancers of the esophagus and stomach and, following initial disappointment with agents targeting VEGF, ramucirumab will have the potential to fill this treatment gap. Findings from the international REGARD trial — a phase 3 trial of second-line therapy for advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma — demonstrate that ramucirumab is tolerable and significantly improves median OS and PFS following progression on first-line chemotherapy (Fuchs C. Abstract #LBA5. Presented at: Gastrointestinal Cancers Symposium; Jan. 14-16, 2013; San Francisco).

The magnitude of this improvement is similar to those observed with cytotoxic agents such as paclitaxel in this setting. An ongoing randomized clinical trial (RAINBOW) is further assessing the role of ramucirumab in combination with paclitaxel in second-line treatment compared with paclitaxel alone in patients with advanced GEJ adenocarcinoma. Given the initial enthusiasm with ramucirumab, including its likelihood to be approved for the treatment of refractory GEJ cancer, this study may well push the survival benefit even further in this desperate disease.