The Lynx Group

Personalized Cancer Care: Combination Therapies May Be Key to Hitting Tumor Heterogeneity

April 2014, Vol 5, No 3

Boston, MA—Combinations of targeted therapies will be key to overcoming resistance that occurs in tumor cells and leads to eventual failure of a single targeted agent, said Alex Adjei, MD, PhD, the Katherine Anne Gioia Chair in Cancer Medicine, Roswell Park Cancer Institute, Buffalo, NY, at the Second Global Biomarkers Consortium annual conference.

“Tumor heterogeneity is the predominant reason for therapeutic failure in cancer,” Dr Adjei 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 (ie, secondary resistance). Secondary resistance may occur as the result of the formation of a resistance mechanism or a secondary mutation.

Personalized medicine includes 3 principles:

  • Treat those who will benefit
  • Avoid treatment of those who will not benefit
  • Avoid unnecessary toxicity.

Even targeted agents produce toxicities. Identifying the 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 genetic alterations through techniques such as next-generation sequencing, said Dr Adjei.

Actionable Targets in NSCLC
“The good news is that we are finding actionable targets, and there are drugs in the clinic to target them,” Dr Adjei said. He discussed some of the targets in non–small-cell lung cancer (NSCLC).

A translocation of echinoderm microtubule-associated protein-like 4 and the anaplastic lymphoma kinase (ALK) tyrosine kinase receptor is a potent oncogenic driver, responsible for 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 (Xalkori) has proved to be effective against cancers with ALK-driven pathways. In a phase 1 study of crizotinib in patients with ALK-positive refractory NSCLC, median progression-free survival was 10 months, with response rates as high as 60%.

ROS1 rearrangements occur in approximately 1% of patients with NSCLC. The ROS1 and the ALK tyrosine kinase domains are similar; “they share about 77% of sequence homology,” said Dr Adjei. Crizotinib has also been shown to have antitumor activity in advanced ROS1-positive NSCLC, with overall response rates approaching 60%.

The rearranged during transfection (RET) kinase has also recently been identified as a potential new oncogenic driver in a subset of patients with NSCLC. Cabozantinib (Cometriq) has activity in NSCLC with rearrangements in RET, with clinical studies in patients with RET-translocated tumors starting soon, Dr Adjei said.

In NSCLC, activating BRAF V600E mutations occur in ?2% of tumors, primarily adenocarcinoma, and is a therapeutic target. Dabrafenib (Tafinlar) is a reversible small molecule that has been studied in a single-arm open-label study of patients with NSCLC and BRAF V600E mutation whose disease had progressed with 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, Dr Adjei said, “is that we don’t cure anybody.” At least 40% of patients do not experience tumor regression with the targeted drugs. Most patients with NSCLC will develop resistance to crizotinib within 2 years. These mechanisms of resistance are diverse, from the 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,” Dr Adjei 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 in crizotinib-naïve patients and in 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 are at play. The first convincing evidence of tumor heterogeneity came from Gerlinger and colleagues in 2012 (N Engl J Med. 2012;366:883-892), who took pre- and postsurgical biopsies of renal-cell tumors. They found that approximately 66% of mutations detected in single biopsies were not uniformly present in multiple tumor biopsies. “Favorable prognosis” and “unfavorable prognosis” genetic profiles were present in different regions of the same tumor, and different inactivating PTEN mutations were present in various portions of the tumor.

With the current understanding of different molecular profiles within tumors, “combination therapy will be key,” said Dr Adjei. Combination therapies have been difficult to execute because of overlapping toxicities, such as erythematous rash and stomatitis, with mitogen-activated protein kinase (MEK) and protein kinase B (AKT) inhibitors.

Drug combinations should use agents that have nonoverlapping dose-limiting toxicities and have the ability to administer full doses 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 an MEK inhibitor to continued treatment with the BRAF inhibitor vemurafenib (Zelboraf) in patients whose melanoma progresses with the single-agent vemurafenib. Inhibiting MEK downstream from BRAF is an indirect attack on the RAS proteins that activate the MEK and other signaling pathways that lead to cell proliferation and survival, Dr Adjei explained.

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