GRACE :: Lung Cancer

erlotinib

What’s the Status and Potential Utility of Cabozantinib in Lung Cancer?

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Dr. Heather Wakelee of Stanford University Medical Center discusses whether or not cabozantinib – a drug already approved for thyroid cancer – can help patients with lung cancer. February 2014.


What is the value of maintenance therapy in advanced NSCLC, and who should get it?

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We’ve covered the question of maintenance therapy for lung cancer in many posts over the past 5-6 years as it has evolved from a concept with little evidence to a standard of care, but it is difficult to get a good summary of the big picture. This presentation is my attempt to distill the field into the most important principles.

 

What is the value of maintenance therapy in advanced NSCLC, and who should get it? from H. Jack West

And for those who want to download the slides in an easily printable form, here’s the slide set as a pdf file: Maintenance therapy primer

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Targeted Therapy as Adjuvant Treatment: Should We Extrapolate from Advanced NSCLC to Earlier Stage?

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This past week, I saw a new patient who had just moved from another part of the country and needed long-term management of her high risk lung cancer.  A never-smoking Asian woman, she was found to have a stage IIIA lung cancer with “N2″ mediastinal lymph nodes involving cancer in her mid-chest. As is typically done, she received chemotherapy with a cisplatin/Alimta (pemetrexed), a very strong treatment option for her lung adenocarcinoma, and she then proceeded to surgery.  There, she was found to have a small amount of residual cancer in her mediastinal lymph nodes, which suggests a high risk of recurrence. Her oncologist recommended post-operative radiation to treat this area.

Though radiation to the mid-chest is commonly and I think appropriately favored for patients with residual N2 nodal disease after surgery, especially if they hadn’t received it before surgery, this woman declined the radiation. She was far more receptive to more systemic therapy, especially in the form of targeted therapy once it was discovered that her tumor has a ROS1 rearrangement. This is rare (only about 1-1.5% of lung cancers, disproportionately in younger never-smokers with an adenocarcinoma) and has been found to very often respond well to XALKORI (crizotinib), the same agent used for the 4-5% of patients in the US (more in Asia) who have an ALK rearrangement, for whom XALKORI is approved. XALKORI isn’t technically FDA approved for people with a ROS-1 rearrangement, but it’s often covered by insurers when they are made to understand the profound value of this agent for these rare patients. 

But when we talk about XALKORI for patients with an ALK or ROS1 rearrangement, or an EGFR tyrosine kinase inhibitor (TKI) like Tarceva (erlotinib), Iressa (gefitinib), or Gilotrif (afatinib) for those with an EGFR mutation, we’re focusing on the overwhelmingly favorable data obtained in patients with metastatic cancer.  It’s an entirely different situation with curable and potentially cured lung cancer. When someone has undergone surgery or chemo/radiation or some other combination for stage I-III NSCLC, we know that some of these people are already going to be cured without adding any other treatment. When we give targeted therapies for lung cancer who may already be cured, we often presume we can only be helping them.  However, that wasn’t true when adding Iressa after chemo/radiation for patients with stage III NSCLC — in fact, Iressa was significantly harmful and shortened survival. We decided, with the benefit of hindsight, that this was because the patients on that trial were not molecularly selected as having an EGFR mutation; they didn’t check for or require EGFR mutations, so we presume that 90% didn’t have an EGFR mutation, and we know such patients typically benefit modestly at best from EGFR TKIs.  However, when we saw the results of a trial of post-operative (adjuvant) Iressa in early stage NSCLC patients, we saw that not only was there a trend toward worse outcomes for the recipients of Iressa in the overall, molecularly unselected population, but the trend of worse outcomes was especially pronounced in patients with an EGFR mutation. If there was ever an observation that was humbling in highlighting how wrong we could be in our presumptions, it was that one.

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Squamous Lung Cancer Part 5, Q and A Session by Dr. David Spigel

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Title slide from Squamous Lung Cancer Webinar Q&A SessionDr. David Spigel, Sarah Cannon Cancer Center, answers audience questions about squamous lung cancer.

 

Squamous Lung Cancer Part 5, Q and A Session Audio Podcast


Squamous Lung Cancer, Part 3: Treatment by Dr. David Spigel

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Picture of lungsDr. David Spigel, Sarah Cannon Cancer Center, outlines treatment options for squamous lung cancer.

 

Squamous Lung Cancer, Part 3: Treatment Audio Podcast

 

What you’ll hear in Part 3

  • Treatment options for squamous lung cancer

 

Glossary of some terms you’ll hear in Part 3:

Find more cancer definitions at the National Cancer Institute’s Dictionary of Cancer Terms

  • Adenomcarcinoma – Cancer that begins in glandular (secretory) cells. Glandular cells are found in tissue that lines certain internal organs and makes and releases substances in the body, such as mucus, digestive juices, or other fluids. Most cancers of the breast, pancreas, lung, prostate, and colon are adenocarcinomas.
  • Histology – The study of tissues and cells under a microscope.
  • Platinum – A metal that is an important component of some anticancer drugs, such as cisplatin and carboplatin.
  • Radiation therapy – The use of high-energy radiation from x-rays, gamma rays, neutrons, protons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy), or it may come from radioactive material placed in the body near cancer cells (internal radiation therapy). Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that travels in the blood to tissues throughout the body. Also called irradiation and radiotherapy.
  • Squamous lung cancer – One of the three sub-types of lung cancer.
  • Toxicity – The extent to which something is poisonous or harmful. 
  • Unresectable – Unable to be removed by surgery.

 


MARQUEE Trial of MET Inhibitor Tivantinib (ARQ-197) Negative for Survival Benefit, But OS Benefit Seen in MET-Positive Patients

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Almost exactly a year ago, I reported that the large MARQUEE trial of EGFR inhibitor Tarceva (erlotinib) plus either the MET inhibitor tivantinib (ARQ-197) or placebo as second or third line treatment for advanced NSCLC had been discontinued after a planned interim analysis revealed that it wouldn’t be statistically significantly superior for overall survival (OS), the primary endpoint of the trial.  A year later, the results have just been presented by Dr. Giorgio Scagliotti of Turin, Italy at the European Society for Medical Oncology conference (abstract E17-1821), and they suggest that characterizing the trial as “negative” may be misleading, as there are certainly elements of the findings that lead me to think tivantinib is an active agent, at least in the subset of patients whose tumors express significant amounts of MET protein.

The concept of MET inhibition is summarized in other posts, but what is notable is that two different agents that have looked very promising in phase II research have moved forward in phase III testing.  Tivantinib is an oral small molecule inhibitor of MET, while MET-MAb (onartuzumab) is a monoclonal antibody against the same target. What is especially interesting is that while both agents appeared to improve outcomes in broad populations of patients with previously treated advanced NSCLC, the two trials suggested different things with regard to the need for significant expression of MET protein on the tumor cells. Specifically, there wasn’t a clear signal in the work with tivantinib that MET expression was needed, while in the early trial with MET-MAb actually showed a striking finding that it seemed very beneficial when combined with Tarceva, but only in the approximately half of patients whose tumors expressed significant MET protein.  In fact, it appeared to be detrimental when combined with Tarceva in the half of patients whose tumors don’t express significant amounts of MET protein.

This led to the development of the two drugs along divergent pathways.  Tivantinib’s MARQUEE trial was a phase III randomized trial for previously treated patients regardless of MET expression, while MET-MAb’s phase III trial, a little further behind, was limited to the half of patients with MET-positive NSCLC (by immunohistochemistry, with a dedicated diagnostic “immunohistochemistry” (IHC) test to be done by pathologists).   We still await results from the MET-MAb trial, while the tivantinib trial was closed early for showing no significant OS benefit, though it actually did demonstrate a significant improvement in progression-free survival (PFS).

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ASCO Lung Cancer Highlights, Part 6: Predicting Benefit of Chemotherapy vs. EGFR Inhibitor Therapy in Second Line by Dr. David Gerber

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Dramatic benefit from EGFR inhibition in lung cancer with EGFR mutationsDr. David Gerber, University of Texas-Southwestern, reviews the results of the PROSE study of the Veristrat serum proteomics test to predict benefit of chemo or EGFR inhibitor for second line treatment of advanced lung cancer.

 

ASCO Lung Cancer Highlights, Part 6: Predicting Benefit of Chemotherapy vs. EGFR Inhibitor Therapy in Second Line Audio Podcast


Dr. Philip Bonomi: Gefitinib and Later Generations of EGFR Inhibitors

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Dr. Phil Bonomi, from Rush University, describes the generations of EGFR inhibitors beginning with Gefitinib (Iressa).


Now that Afatinib’s Approved, How Should We Use It? Newer Isn’t Necessarily Better.

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Afatinib, newly christened Gilotrif, is the newest EGFR tyrosine kinase inhibitor (TKI) approved by the FDA, specifically for patients with an EGFR mutation as first line therapy.  As an irreversible inhibitor of the family of receptors in which EGFR is a member, there’s a theoretical appeal that it may be more effective than reversible EGFR inhibitors (which attach to and then come off of the EGFR receptor) that are currently available, namely Tarceva (erlotinib) and/or Iressa (gefitinib), depending on where you are in the world. But what role does it play in the current lung cancer landscape?  Sadly, I must confess that I don’t think it has demonstrated any incremental benefit over the EGFR inhibitors we’ve had available for years.  The best evidence I can see is that Gilotrif is a more toxic version of these already available agents.

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How do we approach acquired resistance to targeted therapies in lung cancer?

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Drs. Jack West, Mary Pinder, and Nate Pennell discuss options for managing acquired resistance to EGFR TKIs and ALK inhibitors in patients with advanced NSCLC and a driver mutation.


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