BY RAMASWAMY GOVINDAN, MD
The recently concluded American Association for Cancer Research (AACR) Annual Meeting featured several insightful presentations relevant to novel therapeutics. Due to space constraints, I have selected only a few for discussion here.
Palbociclib, an inhibitor of cyclin dependent kinases (CDK) 4 and 6 improved progression-free survival (PFS) in patients with previously untreated ER+, HER2- metastatic breast cancer (Abstract CT101). Preclinical studies with palbociclib have shown decreases in cell proliferation and cellular DNA synthesis due to inhibition of Rb phosphorylation resulting in cell cycle arrest in G1 phase. Moreover, palbociclib preferentially inhibited proliferation of luminal estrogen receptor positive human breast cancer cell lines.
PALOMA-1 is a Phase II study that randomized 165 postmenopausal patients with metastatic breast cancer to receive palbociclib and letrozole or letrozole alone. The median progression-free survival with the combination therapy was 20.2 months versus 10.2 months with letrozole alone (HR-0.488, p=0.0004). Overall survival favored the combination therapy, although the differences were not statistically significant (37.5 months vs. 33.3 months, HR- 0.813, p=0.2105).
The most common adverse events included neutropenia, leukopenia, fatigue, and anemia. Alterations in cyclin D1 and/or p16 did not identify a subgroup of patients who had greater benefit with palbociclib.
Two large ongoing Phase III studies are evaluating the role of palbociclib in patients with breast cancer--one in advanced-stage (PALOMA-3) and another in early-stage disease (PENELOPE-B).
Results from a Phase I study of another inhibitor of CDK 4 and 6, LY2835219, were also presented at this meeting (Abstract CT232). Patients with five different tumor types (glioblastoma, melanoma, and cancers of the lung, colon/rectum, and breast) were enrolled. The activity of the agent in 47 patients with heavily pretreated metastatic breast cancer (the median number of previous treatments was seven) was impressive, with the partial response rate of 19 percent and disease-control rate of 51 percent. The disease control rate was 81 percent for patients with HR+ disease.
The median progression-free survival time was 5.8 months for all patients with breast cancer and 9.1 months for HR+ patients. If additional studies confirm these early promising results, CDK4/6 inhibitors may play a key role in breast cancer and hopefully in other malignancies as well. We should make every effort to identify biomarkers to select rationally for this class of compounds.
An investigational agent, DEDN6525A, an antibody-drug conjugate, showed some early signs of activity in patients with malignant melanoma in a Phase I study (Abstract CT233). DEDN6525A is a conjugate of antibody against the endothelin B receptor (ETBR) and chemotherapy monomethyl auristatin (MMAE). Nearly 50 percent of melanoma cells express ETBR.
In this Phase I study, 12 of the 19 patients who received 1.8 mg/kg of DEDN6526A had either a partial response or stable disease for six or more months. The most common side effects were infusion-related reactions, fatigue, neutropenia, and neuropathy.
The recommended Phase II dose for this agent is 2.4 mg/kg administered every three weeks. Data analysis from the expansion cohort is ongoing.
Results from another Phase I study reported at the meeting highlighted the potential of a new form of immunotherapy. IMCgp100 is a novel agent with an affinity-enhanced T cell receptor (TCR) specific for the HLA-A2 restricted melanoma gp100 peptide (YLEPGPVTA) fused to an anti-CD3 antibody.
IMCgp100 seems to direct T cell cytotoxicity even in the face of significant levels of PD-1 and PDL-1. Patients with advanced melanoma who are HLA A2 positive and not ideal candidates for vemurafenib were enrolled in this Phase I study (Abstract CT329). Four partial responses were observed so far, including three lasting for more than nine months in this very early analysis. Toxicities included skin rash, pyrexia, and hypotension.
These studies raise the hope that options for patients with malignant melanoma (and possibly other cancers) would continue to increase in the coming years.
Several studies have reported activity of PD-1 and PDL-1 inhibitors in patients with melanoma and lung cancer over the past few years. Efforts are ongoing to identify patients who are likely to respond to the drugs that inhibit immune checkpoint.
In a study presented at the AACR meeting, patients with advanced malignant melanoma who received MK-3475 whose tumor cells were “positive” for PDL-1 had a 49 percent response rate compared with only 13 percent in those who were “negative” for PDL-1 (Abstract CT104). These data were derived from 195 patients enrolled in the Phase I study of MK-3475 at three different doses.
Tumor samples were considered positive if at least one out of 100 cells had expression of PDL-1 protein. Of 125 evaluable tumor samples 71 percent were positive for PDL-1. The response to MK-3475 in the PDL-1 positive group was the same regardless of whether patients were treated with ipilimumab or not.
In a related presentation, response rates in patients with advanced NSCLC with MK-3475 were higher in those with PDL-1 positive tumors than in those with PDL-1 negative tumors (37% vs. 11%) (Abstract CT105). By using a stringent criterion of requiring 50 percent of the cells stained for PDL-1 to define the “high score” group, the response rate (by RECIST) was 37 percent in the “high” score group compared with only 11 percent in the low score (or negative) group. The differences in the response rates were reflected predictably in six month PFS (41% vs. 17%, HR- 0.53, 95% CI: 0.33-0.83, p=0.004).
Data from two ongoing studies will be used to validate these findings in patients with NSCLC.
Mutations involving isocitrate dehydrogenase (IDH) 2 have now been reported in acute myeloid leukemia (AML), myelodysplastic syndrome, and other malignancies. Cancer-associated IDH2 mutants produce 2-hydroxyglutarate (2-HG), which blocks normal cellular differentiation.
AG-221 is a first-in-class compound that blocks the activity of mutated IDH2 enzyme and decreases the level of 2-HG. In this Phase I trial, patients with AML and MDS with IDH2 mutation received AG-221 (Abstract CT103).
It is remarkable that six of the seven evaluable patients had objective responses, with significant decrease in the levels of 2-HG (90% decline in patients with R140Q mutation). In addition, the investigators found evidence of maturation in the bone marrow consistent with pre-clinical studies. AG-221 is well tolerated.
Although these results are preliminary, targeting IDH2-mutant leukemia may soon become possible in the clinic.
In summary, it is heartening to see that a number of novel therapies are being developed to treat patients with a wide variety of malignancies, moving findings from the laboratory to the clinic at an impressive pace. I would encourage readers to visit the AACR webcast website (webcast.aacr.org) to hear some (or most) of these inspiring and instructive presentations.