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Expert Round Table with Drs. Hensing & Jackman: Molecular Markers & Sequence of Therapy for Stage IV Lung Adenocarcinoma
The second part of my conversation with Drs. Tom Hensing from North Shore Health System in Chicago and David Jackman from Dana Farber Cancer Institute in Boston covered a case of a relatively young, generally healthy woman diagnosed with a lung adenocarcinoma that turned out to be stage IV.
Here, we discuss our priorities for molecular testing and how the results of EGFR, KRAS, and EML4-ALK testing would alter our clinical recommendations. We then discuss the options for this patient, with special focus on how long to continue first line therapy and when and how to transition off of first line treatment into either observation or maintenance therapy.
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Can An Early PET Scan Predict Response to Tarceva?
Over three and a half years ago, I wrote a post about about early work looking at the possibility that a PET scan done anywhere from three days to a month out from the start of a new systemic therapy (chemo or EGFR inhibitor) for advanced NSCLC could be predictive of a good outcome or not. Despite the increasing use of PET scans not only for staging but also for follow-up to assess response in patients with NSCLC, there hasn’t been a lot of new information since then. However, a study presented at ASCO 2010, coming from several Australian hospitals in collaboration with a couple in southern California, compared PET scans done after two weeks and then two months of Tarceva (erlotinib) therapy with the more established standard measure of response assessment, CT scans after two months of therapy.
Introduction to Locally Advanced, Unresectable Stage III NSCLC
When I was a medical student, the question about lung cancer that was always asked on “the Boards” had to do with the difference between stage IIIA and stage IIIB non-small cell lung cancer (NSCLC). The reason this question was always asked is because patients with stage IIIA NSCLC might be considered for surgery, whereas patients with stage IIIB NSCLC would not be considered for surgery and instead would be treated with chemotherapy and radiation. The idea is that young doctors should be able to make that distinction and to direct patients to the appropriate specialist/treatment. While I guess it makes a good test question, this distinction is too simplistic and doesn’t really give anyone a good understanding of the complexities of managing stage III lung cancer. And, in reality, all patients with suspected stage III lung cancer should be evaluated by a multidisciplinary team that includes thoracic surgeons, radiation oncologists, pulmonologists and medical oncologists. If the Medical Board would write a test question aimed at getting across this important principle, I’d breathe a big sigh of relief for lung cancer patients.
Expert Case Discussion with Drs. Hensing and Jackman, Molecular Markers and Sequencing Therapy for Advanced Squamous Cell NSCLC
Several weeks ago, my colleagues Dr. Tom Hensing from North Shore Health System in Chicago, affiliated with the University of Chicago, and Dr. David Jackman from Dana Farber Cancer Institute in Boston, were kind enough to take the time to go over a series of cases in a webinar format. We reviewed the time line of several patients with advanced NSCLC, focusing on two central questions:
1) For various clinical situations, which molecular markers would you be inclined to recommend?
2) How would you be most inclined to have a patient approach an end to first line therapy and either continue ongoing maintenance therapy (continuation maintenance), transition to a new maintenance therapy (switch maintenance), or just hold off on treatment until there is evidence of progression and a clear reason to restart treatment.
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Zactima (Vandetanib) Trial vs. Placebo Negative (for Survival): Details from ASCO
The negative trials don’t get a lot of discussion, but the ZEPHYR trial, a phase III study that directly compared Zactima (vandetanib), an oral inhibitor of EGFR and angiogenesis, vs. placebo, was one that merits some follow-up after my reporting that it failed to show a survival benefit, which was essentially the only thing we learned about the trial prior to ASCO this year. A more complete report of the ZEPHYR trial was presented at ASCO, and though it suffered the indignity of being the rare phase III trial that didn’t get presented during an oral session, I think the results are important enough in trying to assess the real value of Zactima that the results merit being reviewed.
ZEPHYR was the last of four major lung cancer trials with Zactima to be completed and reported. The others are summarized in a prior post, and they showed at best equivocal results. The others are discussed in a point-counterpoint fashion by GRACE member and moderator Neil Berch (arguing that the Zactima glass is half full) and me (taking the less beloved view that the benefits are extremely marginal and probably not enough) — let the record show that, at the present time, his post has been more favored by the people who have added a rating.
PF299804 vs. Tarceva: Added Benefit Over a Current Standard?
In my last post, I described the novel oral agent PF299804 (PF299), an irreversible “pan-HER” inhibitor not only of the epidermal growth factor receptor but of other members of the human epithelial growth factor receptor (HER) family. We covered some small studies in patients previously treated with chemotherapy and an EGFR inhibitor, with these studies demonstrating that this new agent clearly has activity, shrinking a minority of tumors, with many other patients demonstrating prolonged stable disease even after several lines of prior therapy. This suggests that this agent can provide some additional benefit beyond that conferred by a reversible EGFR inhibitor that we already have available, namely Tarceva (erlotinib) or Iressa (gefitinib).
But another way to ask about how much PF299 offers over a currently available standard oral EGFR inhibitor is to compare them directly in patients who have never received prior therapy against EGFR. That study has been done and was presented at ASCO 2010.
PF299804: Irreversible Pan-HER Tyrosine Kinase Inhibitor Showing Great Promise in Advanced NSCLC
We’ve received several questions about agents that might be helpful for patients who have already responded to inhibitors of the epidermal growth factor receptor (EGFR) like Tarceva (erlotinib) and Iressa (gefitinib) and then demonstrate progression. These latter agents are reversible inhibitors of of the tyrosine kinase domain (signalling portion inside the cell) of the EGFR molecule, meaning that they attach to and periodically detach from the receptor. Other inhibitors, like the novel Pfizer agent PF299804, bind to EGFR irreversibly, never coming off of the receptor, and requiring the cell to make new EGFR molecules without an inhibitor on them. Such agents can kill many kinds of cancer cells in a lab-based model, and appear that they may do so more effectively than currently agents like Tarceva and Iressa, but how well they work in real patients has remained an open question.
Another unresolved issue is whether PF299804, an inhibitor of not only EGFR but of other members of the human epidermal growth factor receptor (HER) family, of which EGFR (also known as HER1) is just one type, are more effective in patients than agents that inhibit EGFR alone. Such agents that block multiple members of the HER family are sometimes referred to as “pan-HER” inhibitors (as in “across the HER family“), but they’re still in clinical studies to determine whether such agents provide incremental benefit beyond what we see with the EGFR-specific agents we already use.
Though results with the orally available irreversible pan-HER inhibitor PF299804 weren’t a lead story at ASCO 2010, I think several of these trials were quite encouraging, both for patients with an EGFR mutation who might seek something after they become resistant to an EGFR inhibitor that previously was very beneficial, and also for people who don’t have an EGFR mutation and hope to do better than they might expect to do with an agent like Tarceva or Iressa.
Jack West, TV Personality?
People have said to me that a name like Jack West sounds like a good TV name, so I suppose it was only a matter of time before I found my way to the small screen. Yikes!
(click on image to enlarge)
This coming Saturday (August 14th), I’ll be part of a team of three on an expert panel covering many aspects of lung cancer on a program on Discovery Channel called Discovery Channel CME: Individualized Therapy for Non-Small Cell Lung Cancer. It airs at 8 AM and repeats again at 8 AM on August 21st and 28th.
Treatment of Small Cell Lung Cancer
This is the second of two parts in the Reference Library by Dr. Gadgeel on small cell lung cancer.
Patients with Limited Stage Small Cell Lung Cancer
As stated in the prior chapter from the reference library on basic principles and workup of small cell lung cancer (SCLC), in patients with limited disease (LD)-SCLC, the cancer is only detected in the lung, or the lung and the lymph nodes. But even if it is only detected in these sites it is known, based on prior studies, we remain concerned that the cancer has spread to other parts of the body but that it has not yet grown in these other sites for it to be seen on the scans.
It is for this reason chemotherapy is always included in the treatment of LD-SCLC . Chemotherapy goes throughout the body and therefore will not only attack the cancer visible in the primary lung tumor and the lymph nodes, but also the SCLC cells in the other parts of the body that may exist but remain invisible on the scans.
ARQ197: Encouraging Results from ASCO 2010
Continuing with the webinar discussion I had with Dr. Pennell, here is a summary I did of a randomized phase II trial of the novel agent ARQ-197 combined with the EGFR inhibitor Tarceva (erlotinib):
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Dr. West: We’re going to shift gears and move into the metastatic setting, and this is a new agent called ARQ197 that is orally available, which was tested in combination with erlotinib(Tarceva) compared with Tarceva alone. And this was actually in the patients who had received one or more prior lines of chemo and could not have received prior Tarceva or another EGFR inhibitor, directly comparing these two groups that randomized one-to-one. Also, patients who had been assigned to placebo could actually go on the combination at the time of progression, and we did get some interesting information from that.
(click on image to enlarge)
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