Therapies that target lung cancer at the molecular level are proliferating — and so are the biomarkers for guiding their use.
Precision is a virtue in most things and cancer treatment is no exception. Rather than attacking all dividing cells in hopes of cutting down the cancerous ones, many treatments today home in on and disable genetic and other anomalies that allow cancer cells to run rampant, metastasize and kill.
Lung cancer treatment has become especially targeted partly because there is such a need. The American Cancer Society estimates that about 228,000 people in the U.S. will be diagnosed with lung cancer this year, an incidence total second only to breast cancer. Moreover, lung cancer is far and away the deadliest cancer in the U.S. as measured by the total number of deaths. The American Cancer Society estimates that there will be 135,000 lung cancer deaths this year in this country, more than deaths than caused by colon, breast and prostate cancer combined.
Targeted therapy for lung cancer became possible because researchers have characterized in greater and greater detail an increasing number of the genetic and other molecular-level events that trigger the initiation and growth of lung cancer tumors. Along with the lengthening roster of targeted therapies are a growing number of biomarkers that clinicians need to test for to help them decide which, if any, of those targeted therapies to prescribe. The National Comprehensive Cancer Network’s 2020 clinical practice guidelines for non-small-cell lung cancer (NSCLC), which comprises 90% of all lung cancers, now includes seven biomarkers.
Shayma Kazmi, M.D., RPh, a medical oncologist and hematologist at the Cancer Treatment Centers of America in Philadelphia, notes that lung cancer has more identified biomarkers than any other solid tumor cancer. These activating mutations and genetic aberrations have multiple treatment modalities that are effective and can spare patients harsh chemotherapy, she adds.
“It is imperative to test all lung cancers for biomarkers and genomic aberrations as targeted therapies and immunotherapies have shown to be highly effective initial therapies in this group,” Kazmi says. She mentions a patient who was diagnosed with metastatic lung cancer in 2014. “Due to the patient’s EGFR mutations and targeted therapies, chemotherapy has not yet been necessary and the patient continues to function in full capacity with oral medications that are not toxic.”
Kim Norris, co-founder and president of the Lung Cancer Foundation of America, an industry-sponsored group that advocates for lung cancer patients and research, says the rapid pace of discovery in lung cancer research is giving patients more treatment options than ever. “I am confident we will continue to see a dramatic increase in the five-year survival rate for lung cancer.”
However, advances in lung cancer treatment and the growing number of biomarkers guiding treatment choices are presenting clinicians and patients with a number of difficult of issues. Many biomarker tests are performed as a series of tests, which can be a costly and time-consuming process. Some experts argue that next-generation sequencing, which can test for many genetic markers at once, would be more efficient and less costly.
“As more and more gene targets have emerged it would be beneficial to switch to broader NGS (next-generation sequencing)-based assays that can evaluate all proven and emerging biomarkers in a single test,” wrote Nathan Pennell, M.D., Ph.D., and his co-authors in an article on biomarkers in last year’s American Society of Clinical Oncology’s (ASCO) Education Book.
Pennell is a medical oncologist at Cleveland Clinic. He and his co-authors say NGS tests can be grouped into two basic categories: amplicon-based tests that cover smaller “hot spots” of the genome and don’t detect certain types of mutations, and targeted hybridization capture tests that are more encompassing but also more complex. The turnaround time on an NGS targeted hybridization test is 15 to 20 days, according to Pennell and his colleagues.
So-called liquid biopsies that detect tumor DNA in blood plasma are another testing option for clinicians and patients to consider. In August, the FDA approved Guardant360 CDx, which the agency said was the first liquid biopsy that also uses next-generation sequencing. The test is approved to find mutations in the epidermal growth factor receptor (EGFR) gene.
One pitfall in the current enthusiasm for biomarker-guided, targeted lung cancer treatment is overusing the expensive treatments. Pennell and his colleagues touch on the subject in their ASCO article. “For the majority of patients, standard treatments will offer more compelling evidence of clinical benefit than those based on molecular alterations, particularly if suggested targeted options are predicated only on preclinical or very limited evidence thus far,” they wrote.
They also warned that targeted treatment might be detrimental if it’s used instead of standard treatments that are more effective.
Important lung cancer biomarkers
The number of possible lung cancer biomarkers seems to grow almost daily. The Wolters Kluwer UpToDate article on personalized therapy for advanced NSCLC by Lecia Sequist, M.D., M.P.H., and Joel Neal, M.D., M.P.H., provides a rundown on many of the most clinically relevant mutations. Here are three of them:
Mutations in the EGFR gene occur in about 15% of NSCLC adenocarcinomas diagnosed in the U.S. and the mutations occur most commonly in nonsmokers. (Adenocarcinoma of the lung arises from the mucosal glands and accounts for about 40% of all lung cancers.) The incidence of EGFR mutations is higher in Asian populations. The College of American Pathologists and two other groups issued guidance for testing for EGFR mutations in 2013 and ASCO endorsed the guidance a year later. In advanced NSCLC, EGFR mutations are associated with a more favorable prognosis. Lung cancers with EGFR mutations can be treated with a number of EGFR tyrosine kinase inhibitors, such as Tarceva (erlotinib), Iressa (gefitinib), Gilotrif (afatinib), Vizimpro (dacomitinib) and Tagrisso (osimertinib).
Rearrangements of the anaplastic lymphoma kinase (ALK) gene occur in about 4% of NSCLC adenocarcinomas. The rearrangements are more common in the lung cancers of young patients and among those who haven’t smoked. Most NGS tests can identify the ALK rearrangements. ALK-positive lung cancers are sensitive to the cancer-fighting effects of ALK tyrosine kinase inhibitors, such as Xalfoni (crizotinib), Zykadia (ceritinib), Alecensa (alectinib) and Alunbrig (brigatinib).
c-ROS oncogene 1 (ROS1) is the causative factor in 1% to 2% of cases of NSCLC. In ROS1 rearrangements, part of the gene is out of place, or “translocated,” and inserted in another gene in the genome. ROS1-positive lung cancers are more commonly seen in adenocarcinomas than not, in younger people, and in those who haven’t smoked. Xalkori (crizotinib) and Rozlytrek (entrectinib) are FDA-approved for patients with ROS1 translocation.
In the future
The search for additional targeted therapies and the biomarkers that can guide their use is continuing. Researchers have discovered, for example, that some NSCLC tumors have mutations in the human epidermal growth factor receptor 2 (HER2) gene that has been a breast cancer biomarker for more than 20 years.
Keith Orford, M.D., Ph.D., chief medical officer of Calithera Biosciences, speaks of the recently emerging science that suggests that the KEAP1/NRF2 molecular pathway may identify a unique vulnerability in the subset of NSCLC patients.
“Mutations in the KEAP1/NRF2 pathway, which occur in an estimated 20% of NSCLC patients, are associated with aggressive tumor growth,” Orford says. “Recently presented clinical data demonstrate that activation of this pathway, either through the loss of KEAP1 function or activation of NRF2, is associated with poor clinical outcomes among patients with NSCLC receiving front-line standard-of-care chemoimmunotherapy.”
“Interestingly,” Orford continues, “we are also observing in preclinical research that the activation of the KEAP1/NRF2 pathway makes tumors dependent on glutaminase activity for growth and survival, making these tumors exquisitely sensitive to inhibition of glutaminase activity.”
His company is currently developing the first-in-clinic glutaminase inhibitor telaglenastat, which is being evaluated in the phase 2 KEAPSAKE trial for the treatment of NSCLC in combination with standard-of-care chemoimmunotherapy.
Keith Loria, a regular contributor to Managed Healthcare Executive®, is a freelance writer in the Washington, D.C., area.