Monday, January 16, 2017

Targeting Mutations in Lung Cancer: EGFR

As I’ve previously written, the most useful biomarkers for predicting the efficacy of targeted therapy in advanced NSCLC are genomic alterations known as "driver mutations." These mutations occur in cancer cells within genes encoding for proteins critical to cell growth and survival. Through the use of molecular testing, the discovery of genetic mutations that drive NSCLC is rapidly improving the outlook for some patients in stage 4 disease. This is significant because almost 40% of lung cancer diagnoses are stage 4 patients. One of the first breakthroughs was the discovery of the EGFR (epidermal growth factor receptor) mutation, which is present in about 10 percent of patients who are diagnosed with lung cancer in the United States (interestingly more common in patients with adenocarcinomas and no prior history of smoking, as well as in women and those of Asian descent).

I remember being at the American Society of Clinical Oncology (ASCO) conference in 2004 and the buzz surrounding a drug called Gefitinib (Iressa). The FDA had approved Iressa in May of 2003 for treatment of Non-Small Cell Lung Cancer (NSCLC) and it was notable that in clinical trials the drug worked spectacularly well in about 10% of lung cancers patients but failed to help the rest. No one could figure out why. Then researchers figured out that most people who responded to Iressa had similar genetic mutations in their tumors. A later study extended the findings in EGFR research to a related drug, Tarceva, which was awaiting approval by the FDA.
The two groups of Harvard researchers, one at Massachusetts General Hospital (MGH) and one at Dana Farber Cancer Institute did a deep dive into the data regarding lung tumors from patients who responded to Iressa and those who did not. Most responders had the EGFR mutations. Non-responders did not. The laboratories began offering a test to detect the mutations and scientists speculated they could become widely available in the near future. MGH had a clinical trial that was testing patients for the mutations as a predictor of their response to Iressa as an initial treatment. Iressa wasn’t usually the first option; it was typically given to lung cancer patients who didn’t respond to chemotherapy. Now that scientists could explain the drug’s effectiveness in some cases, there was hope that they could better predict who would respond to them in the future and that lessons from Iressa and Tarceva could be applied to other cancers. This is when targeted therapy began to become a reality.
Iressa and Tarceva are part of a relatively new class of drugs known as targeted drugs, which are different from traditional chemotherapy drugs because they are designed to specifically hit cancer cells. Unlike chemotherapy drugs which kill healthy and cancerous cells, targeted drugs are supposed to kill only cancer cells. Until the mid-2000’s, treatment options for lung cancer were mostly limited to surgery, chemotherapy and radiation. Now, people diagnosed with lung cancer have newer, more personalized treatment options. The goal of targeted therapy is to accurately target your individual tumor, which hopefully leads to more effective treatments and less side effects.
Thankfully screening has become an increasingly standard part of the diagnostic work-up for NSCLC, and is useful in choosing between standard chemotherapy and targeted therapies. EGFR-targeting drugs — which include Tarceva (erlotinib), Iressa (gefitinib) and Gilotrif (afatinib) — are now used in the first-line treatment for metastatic lung cancer patients. Patients are able to get a treatment that matches the mutation that has been identified through a molecular test of their tumor. While most lung cancer patients with EGFR mutations who respond well to targeted treatments ultimately develop resistance to the drugs after a year or so as the cancer finds other ways to grow, newer drugs are being evaluated to be used as second-line treatments. This is why it’s important to have tumors continuously tested during treatment to detect different mutations that evolve during treatment. For example, Tagrisso (osimertinib) is approved for patients with a specific EGFR mutation called T790M who relapse after being treated with a different EGFR drug. A similar drug called rociletinib (CO-1686) is in late-stage trials in patients with the T790M resistance mutation.
I saw first-hand this process of genetic testing, and the resulting treatment when a good friend of mine was diagnosed with stage 4 lung cancer. He went to the hospital and started chemotherapy treatment. Within 24 hours he was on a ventilator fighting for his life and not responding to the chemo. Test results showed that he had the EGFR exon 19 mutation and his regimen was immediately changed from chemo to Tarceva. He started responding and was off the ventilator breathing on his own within 2 days. We were all blown away with how quickly he responded to the targeted treatment. While unfortunately in his case it was too late to save his life, it did show me how remarkable the response was to a targeted therapy. It also convinced me that every cancer patient deserves to get molecular testing to identify the best course of treatment, which may be a targeted therapy such as Tarceva.

Friday, January 6, 2017

What's Next for the CancerMoonshot?

Vice President Joe Biden will be leaving office in 2 weeks. This has me thinking about what role he will play in the cancer community moving forward.
I’ve been optimistic about increased cancer research funding and advances in targeted treatments since President Obama announced his Precision Medicine Initiative (PMI) in early 2015, a research effort focusing on bringing precision medicine to many aspects of healthcare. The mission statement of the PMI is “To enable a new era of medicine through research, technology, and policies that empower patients, researchers and providers to work together toward development of individualized care”. In his budget for fiscal 2016 he included $216 million in funding for the initiative for the NIH, the National Cancer Institute (NCI) and the FDA.  I was even more enthusiastic when in his 2016 State of the Union, Obama called on Vice President Biden to lead a new, national “Moonshot” initiative to eliminate cancer as we know it. He launched the National #CancerMoonshot asking for, among other things, $1 billion to provide funding necessary for researchers to accelerate the development of new cancer detection and treatments, with the ultimate goal “to make a decade’s worth of advances in cancer prevention, diagnosis and treatment in 5 years”.
And since the launch of the initiative, Biden, the Cancer Moonshot Task Force and a Blue Ribbon Panel of experts have engaged thousands of cancer patients, caregivers, clinicians, healthcare organizations, advocacy groups, researchers, technologists, and industry leaders in support of the bold mission. In October Biden presented the Blue Ribbon Panel Report, describing 10 transformative recommendations for achieving this ambitious goal. Among the 10 recommendations are support for cancer research including immunotherapy, childhood cancers and a better understanding of tumors – how their cellular and genetic makeup shapes a patient’s response to drugs and how tumors evolve to develop resistance. The report also included announcement of new commitments from both public and private sectors. For example, the NCI, Microsoft and Amazon Web Services announced a collaboration to build a model for maintaining cancer genomic data in the cloud to be available for researchers. And Uber and Lyft offered to expand support of affordable and reliable transportation for cancer patients to address the issue of patients missing appointments. In all, over 70 public-private partnerships were formed, committed to the Cancer Moonshot. And the passage of the 21st Century Cures Act in December of 2016 provided for $1.8 billion reserved for the initiative – very encouraging news.
Fast forward to January, 2017 – what’s next for the #CancerMoonshot program and for cancer research and treatment overall? There is so much uncertainty with a new administration taking over in a couple weeks. I have concerns about the commitment to cancer research, and to affordable care – the cost of cancer treatment. Oncologists are already worried about the cost of treatment. Newly approved cancer drugs cost an average of $10,000 per month, some over $30,000 per month. Patients typically pay 20 to 30 percent out of pocket for drugs, so an average year's worth of new drugs would cost $24,000 to $36,000 in addition to health insurance premiums. This has to be addressed. I understand the pharmaceutical companies invest billions and need to recoup their costs. But there needs to be concerted effort between pharma, insurers, providers and the government to help patients afford these breakthrough treatments. With Republicans now controlling the White House and Congress, it’s unclear what direction the government will go to address any of this. What role will Joe Biden play once he leaves office, and how can we keep the momentum and spirit of collaboration moving forward? Because, as Douglas Lowy, MD, acting director of the NCI said, “the vice president has galvanized the community to move forward so we can greatly increase our ability to prevent, diagnose, and treat cancer”.
I believe one thing is clear. Joe Biden will remain committed to cancer and there is no greater ally to the cancer community. He is said to be forming a nonprofit, currently being called the Biden Cancer Initiative, but the final name could be different. Biden recently said his nonprofit group will focus on many important Moonshot issues including the need to break down the “silos” in cancer research and sharing research data and medical records more widely. He also has talked about boosting participation in clinical trials and the racial disparities that exist in diagnosis and treatment. Biden has been steadfast in his commitment, even in the face of critics who claim beating cancer is far more complicated than putting a man on the moon. He assembled a “Who’s Who” list in cancer for his task force and Blue Ribbon Panel. He brought together all stakeholders, including patients. He has pressed ahead, meeting with researchers and clinicians, repeatedly calling for greater data sharing and collaboration. He lost his son Beau to brain cancer in May 2015. I met him in September 2015. He was very thoughtful and he spoke so eloquently about his losing his son and his determination to lead the way.
We need someone to be the driving force and I have every reason to believe that Joe Biden is the right man to lead this effort to increase collaboration in the cancer community. Whatever direction the new administration may take, I hope Joe Biden will remain the beacon of hope that we can make true precision medicine a reality someday. And let’s hope he also helps energize the philanthropic community to support cancer research.