November 2013, Vol 2, No 7
Personalized Cancer Treatment: Combination Therapies May Be Key to Hitting Tumor Heterogeneity
Combinations of targeted therapies will be key to overcome resistance that occurs in tumor cells that leads to eventual failure of a single targeted agent, said Alex Adjei, MD, PhD, at the second annual Global Biomarkers Consortium conference.
“Tumor heterogeneity is the predominant reason for therapeutic failure in cancer,” he said.
The 2 types of resistance that occur in tumor cells are 1) initial resistance to treatment, and 2) an initial response to treatment followed by resistance (secondary resistance). Secondary resistance may occur as the result of the formation of a resistance mechanism or a secondary mutation.
Personalized medicine has 3 principles: treat those who will benefit, avoid treatment of those who will not benefit, and avoid unnecessary toxicity. Even targeted agents produce toxicities. Identifying those patients who have the highest likelihood of benefit and the lowest likelihood of toxicity will require the use of genomics-driven therapies made possible by detecting genome alterations through techniques such as next-generation sequencing, said Adjei, professor and chair, department of medicine, Katherine Anne Gioia Chair in Cancer Medicine, senior vice president of clinical research, Roswell Park Cancer Institute, Buffalo, New York.
Actionable Targets in NSCLC
“The good news is that we are finding actionable targets, and there are drugs in the clinic to target them,” he said. He discussed some of the targets in non–small cell lung cancer (NSCLC).
A translocation of EML4 and ALK is a potent oncogenic driver, responsible for both initiation and maintenance of certain cancers. It has been identified in a small subset of patients with NSCLC who respond to ALK inhibitors.
Inhibiting ALK signaling with agents such as crizotinib has proven to be effective therapy against diseases with ALK-driven pathways. In a phase 1 study of patients with ALK-positive refractory NSCLC, median progression-free survival with crizotinib was 10 months.
ROS1 rearrangements occur in about 1% of patients with NSCLC. The ROS1 and the ALK tyrosine kinase domains are similar; “they share about 77% of sequence homology,” said Adjei. As such, crizotinib has also been shown to have antitumor activity in advanced ROS1-positive NSCLC, with overall response rates approaching 60%.
RET kinase has also recently been identified as a potential new oncogenic driver in a subset of patients with NSCLC. Cabozantinib has activity in NSCLC with rearrangements in RET, with clinical studies in patients with RET-translocated tumors starting soon, he said.
In NSCLC, activating BRAF V600E mutations occur in 2% or less of tumors, primarily adenocarcinoma, and is a therapeutic target. Dabrafenib is a reversible, small-molecule inhibitor of BRAF V600E kinase. It has been studied in a single-arm open-label study of patients with NSCLC and the BRAF V600E mutation whose disease had progressed on prior chemotherapy. In the first 20 patients treated, the overall response rate was 40%, and the disease control rate was 60%. There was no difference in outcome by smoking status.
Targeting Resistance With Combinations
The not-so-good news with the targeted drugs, Adjei said, “is that we don’t cure anybody.” Forty percent or more of patients do not experience tumor regression with the targeted drugs. In NSCLC, most patients will develop resistance to crizotinib within 2 years. These mechanisms of resistance are diverse, from development of ALK resistance mutations to alternative signaling pathways.
“When it comes to ALK, we have second-generation compounds that appear to be very active,” he said. For example, alectinib has shown activity in patients in whom crizotinib has stopped working. LDK378 is an investigational selective inhibitor of ALK that appears to have activity both in crizotinib-naive patients and those with molecularly defined crizotinib-resistant tumors.
In solid tumors, the critical question in personalizing therapy is whether primary resistance mechanisms (tumor heterogeneity) or acquired resistance is at play. The first convincing evidence of tumor heterogeneity came from Gerlinger et al in 2012 (N Engl J Med. 2012;366:883-892). In presurgical and postsurgical biopsies of renal cell tumors, they found that 66% of mutations detected in single biopsies were not uniformly present in multiple tumor biopsies. A “favorable prognosis” and “unfavorable prognosis” gene profile were present in different regions of the same tumor, and different inactivating PTEN mutations were present in different portions of the tumor.
With the discovery of different molecular profiles within tumors, “combination therapy will be key,” said Adjei. Combination therapies have been difficult to execute because of overlapping toxicities, such as erythematous rash and stomatitis with MEK and AKT inhibitors. Drug combinations should employ agents that have nonoverlapping dose-limiting toxicities and the ability to be administered at the full dose of each agent. True cytotoxic synergy is important in the combination, as is dose schedule and sequence.
An example is the response obtained with the addition of a MEK inhibitor to continued treatment with the BRAF inhibitor vemurafenib in patients whose cancers progress on single-agent vemurafenib. Inhibiting MEK downstream from BRAF is an indirect attack on RAS proteins that activate the MEK and other signaling pathways that lead to cell proliferation and survival, he explained.
Vemurafenib blocks the mutated BRAF protein in melanoma cells but also activates the MEK pathways driven by the formation of RAF dimers that lead to signaling through CRAF. MEK pathway hyperactivation induces secondary cutaneous squamous cell cancers. Blocking this pathway activation with a MEK inhibitor is a strategy that can induce improvement of hyperproliferative skin lesions in patients treated with a BRAF inhibitor.
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Incorporating personalized medicine into everyday oncology clinical practice will require new paradigms in an effort to match cancer patients with the best therapies and attempts to treat solid tumors at an earlier stage with targeted agents, said Razelle Kurzrock, MD, at the second annual Global Biomarkers Consortium conference. “In a [ Read More ]