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Molecular Markers, Part 5: Dr. David Spigel on Integrating Markers into Clinical Trials
Here’s part 5 of our Santa Monica program on Molecular Markers in Advanced NSCLC, closing in on the end of the activity. In this podcast, my friend Dr. David Spigel from Sarah Cannon Cancer Center in Nashville, TN presents on the benefits as well as the challenges of new models of clinical trials in lung cancer that move away from “all comers” to smaller, more limited populations defined by molecular markers. Following his presentation, we continued our panel discussion, covering how much the transition into molecular oncology has disrupted how we do clinical research, as well as how our growing experience with molecular testing is leading us to question some of our previously held beliefs.
Below are the audio and video versions of this podcast, along with the transcript and figures for it.
Molecular Markers SM Pt 5 Spigel on Markers in Clinical Trials Audio Podcast
Molecular Markers SM Pt 5 Spigel on Markers in Clinical Trials Transcript
Molecular Markers SM Pt 5 Spigel on Markers in Clinical Trials Figs
Podcast: Play in new window | Download (Duration: 24:30 — 57.3MB) | Embed
Ongoing Great Panel Discussion from the Santa Monica Molecular Markers Webinar: Part 4
Here’s the next installment of the panel discussion on molecular markers from the webinar in Santa Monica with Drs. Charlie Rudin, Alice Shaw, David Spigel, and Glen Goss. We continued our animated discussion on the promise as well as the pitfalls of broadening the use of molecular markers in routine practice of managing patients with advanced NSCLC.
Below you’ll find the audio and video versions of the podcast, along with the transcript (no real figures to go with this one).
Molecular Markers SM Pt 4 Panel Discussion Audio Podcast
Molecular Markers SM Pt 4 Panel Discussion Transcript
We’ll continue with a presentation by Dr. Spigel on the value and challenges of incorporating molecular markers into the design of clinical trials in lung cancer.
Podcast: Play in new window | Download (Duration: 16:57 — 32.1MB) | Embed
Molecular Markers Webinar Part 3: Panel Discussion Debating Who to Test and What to Test For:
Here is the next portion of our special webinar on molecular markers in advanced NSCLC, featuring Drs. Charlie Rudin from Johns Hopkins, Dr. Alice Shaw from Massachusetts General Hospital, Dr. David Spigel from Sarah Cannon Cancer Center, and Dr. Glen Goss from the University of Ottawa and NCI-Canada’s Lung Cancer Committee.
In this continuing portion of the program, we have a debate on the merits of uniform vs. more selective testing of “druggable” mutations and consider whether it is more attractive to test for multiple markers simultaneous or perhaps sequentially, since they are typically mutually exclusive. We also discuss the challenge of the delays in treatment that may become a real clinical problem for some patients if testing may require a few weeks of downtime.
Below you’ll find the audio and video versions of the podcast, along with the transcript and figures for this activity.
Molecular Markers SM Pt 3 Panel Discussion Audio Podcast
Molecular Markers SM Pt 3 Panel Discussion Transcript
Molecular Markers SM Pt 3 Panel Discussion Figs
Podcast: Play in new window | Download (Duration: 17:28 — 38.3MB) | Embed
Dr. Alice Shaw on Clinical Factors Associated with Molecular Markers
I’m happy to bring you now the second part of the Santa Monica webinar, developed with the LUNGevity Foundation, on “Molecular Markers in Advanced NSCLC: Who to Test and What to Test For?“, in which I was joined by Drs. Charles Rudin (Johns Hopkins University in Balimore, MD), Alice Shaw (Massachusetts General Hospital in Boston, MA), David Spigel (Sarah Cannon Cancer Center in Nashville, TN), and Glen Gloss (University of Ottawa in Ontario, Canada).
In this short podcast, Dr. Alice Shaw reviewed the frequencies of different molecular markers in advanced NSCLC as a function of patient sex, smoking status, race, and tumor histology. This work is very interesting, of course, because if we only do molecular marker studies of people with an adenocarcinoma or never-smokers, we not only won’t ever find potentially relevant mutations in people with other histologies and those with a smoking history, but we won’t have any good idea of the probabilities of finding them either.
Here is the podcast in audio and video formats, as well as the transcript and figures.
Molecular Markers SM Pt 2 Shaw on Markers by Clin Factors Audio Podcast
Molecular Markers SM Pt 2 Shaw on Markers by Clin Factors Transcript
Molecular Markers SM Pt 2 Shaw on Markers by Clin Factors Figs
Podcast: Play in new window | Download (Duration: 10:48 — 24.9MB) | Embed
Molecular Markers in Lung Cancer: Dr. Charlie Rudin on the Lung Cancer Mutation Consortium
This is the first of a series of podcasts from the two hour special webinar we did in partnership with the LUNGevity Foundation at the Santa Monica “Targeted Therapies in Lung Cancer” meeting several weeks ago. There, I was privileged to be joined by four excellent guest faculty members — Dr. Charles Rudin from Johns Hopkins University in Baltimore, Dr. Alice Shaw from Massachusetts General Hospital in Boston, Dr. David Spigel from Sarah Cannon Cancer Center in Nashville, and Dr. Glen Goss from the University of Ottawa. They each brought their rich experience and some differing perspectives on the complex and evolving topic of how to apply new work on molecular markers in lung cancer to clinical practice.
Below you’ll find links to the audio and video versions of the podcast, along with the transcript and figures.
Molecular Markers SM Pt 1 Rudin on LCMC Audio Podcast
Molecular Markers SM Pt 1 Rudin on LCMC Transcript
Molecular Markers SM Pt 1 Rudin on LCMC Figures
Podcast: Play in new window | Download (Duration: 17:36 — 40.6MB) | Embed
Dr. Ben Solomon on ALK Inhibition: From Science to Effective Treatment for ALK-Positive NSCLC
Several weeks ago, we were fortunate enough to be joined by not one but two international stars in lung cancer research that is being translated directly from lab bench to bedside of the patient. I don’t think there’s a more clear and inspiring example of good science leading to effective therapy, albeit for a limited patient population, than the story of the anaplastic lymphoma kinase (ALK) inhibitor crizotinib (recently FDA approved and commercially launched as XALKORI) for patients with an EML4-ALK rearrangement (approximately 4% of the broader NSCLC population). Drs. Ben Solomon from Peter MacCallum Cancer Centre in Melbourne, Australia, and Ross Camidge from University of Colorado, in Denver, collaborated with a handful of other international researchers from all over the world to study crizotinib and conduct the critical trials, shepherding its development into a treatment now available to help a targeted subset of patients with this targeted therapy.
Dr. Ben Solomon spoke first, providing an overview of the (short) history of the EML4-ALK translocation and how crizotinib began to be studied in the first patients. He then took us on a tour of the highlights of both the efficacy data for this new agent and the side effect profile. Here’s the audio and video podcast versions of his presentation, along with pdf files of the accompanying transcript and figures:
dr-solomon-alk-inhibition-science-to-approved-therapy-audio-podcast
dr-solomon-alk-inhibition-science-to-approved-therapy-transcript
dr-solomon-alk-inhibition-science-to-approved-therapy-figures
Podcast: Play in new window | Download (0.0KB) | Embed
EGFR Mutations Demystified
It has become a common topic of conversation on this site (and in the lung cancer community at large) to discuss mutations in the epidermal growth factor receptor (EGFR). However, since we frequently throw out the terms “deletion 19 mutation”, “L858R”, and “T790M”, I thought would be worthwhile to explain a little bit about the different EGFR mutations and what we know about their clinical significance.
The history and significance of EGFR mutations has been covered quite well in previous posts here, but I’ll provide my own quick synopsis, from the perspective of someone working in Boston during the time this work was being done. In the early 2000s the EGFR tyrosine kinase inhibitors (TKIs) Iressa (gefitinib) and Tarceva (erlotinib) were tested in large numbers of patients with non-small cell lung cancer. It was known the EGFR was an important target in lung cancer, since most NSCLC tumors express it and high levels of expression were associated with a worse prognosis, and the results of numerous trials testing these drugs in unselected patients were modestly positive. In a phase III trial, Iressa did not improve overall survival compared to placebo treatment in previously treated NSCLC patients (leading to the death of this drug in the USA), but the similar BR.21 trial (testing Tarceva rather than Iressa) did show a modest (~2 month) improvement in overall survival in previously treated NSCLC patients. This led to the approval of Tarceva in all NSCLC patients who had failed one or two prior chemotherapy regimens.
However, what was immediately evident from these and earlier trials, was that about 10% of Western patients treated with either of these drugs had dramatic and sometimes long-lasting responses. When they looked at who these people were, they found that most were women, all had adenocarcinoma (or BAC, a type of adenocarcinoma), many were Asian ethnicity, and most had either never smoked or smoked very little compared to average NSCLC patients. In 2004, investigators at the Dana Farber Cancer Institute and at Massachusetts General Hospital in Boston, and also at Memorial Sloan Kettering Cancer Center in NYC, simultaneously published results showing that most of these “dramatic responders” had specific mutations in the tyrosine kinase (TK) domain of the EGFR gene. The EGFR protein sits in the cell membrane and straddles the inside and outside of the cell.
(Click to enlarge)
EGFR Tyrosine Kinase Inhibitors for Patients with EGFR Mutations
Back when I first started doing this, one of my earliest posts (see here) was on the question of whether EGFR tyrosine kinase inhibitors (TKIs) (see introduction to this work in prior post). My point, which is still true, is that EGFR TKIs aren’t only effective in a narrow population of patients, whether identified based on molecular or clinical variables. But in the more limited number of patients who have the “activating mutation” in the actual receptor, who might be expected to do especially well with an EGFR TKI, how do they do? How does a targeted therapy do in a precisely targeted population?
There are several studies that have now tested this by identifying patients who have an EGFR mutation and received an EGFR TKI. As shown in the table below, the results are very clear and consistent.
(Click to enlarge)
The Subtleties of Progressive Disease: Why Some Oncologists Continue EGFR Inhibitors (or Other Agents) after Progression
One of the basic concepts of oncology is that you treat patients with different drugs once they’ve shown progression on a treatment, rather than continue that a patient has presumably become resistant to. However, there are some exceptions to this: many or most women with breast cancer continue the antibody herceptin (trastuzumab) even after progression, adding it to one chemo and then the next, and the same is often done with avastin in colon cancer and sometimes lung cancer as well. In the past few years, there has been interest in whether the patients who respond well to an EGFR inhibitor like tarceva (erlotinib) or iressa (gefitinib) should continue on it for a while or even forever after showing the first evidence of progression on an EGFR inhibitor.
It may help for us all to take a step back and remember that the goal of improving survival and slowing the progression of a tumor may occur not only if the cancer is shrinking or even if it’s holding steady. If the cancer might potentially be growing quickly, even slowing the progression may translate to an improvement in how a patient does. In the lab, basic scientists examine the growth of a cancer in lab animals and consider it beneficial if the cancer progression is slower over time when a new treatment is added, compared with a placebo or some alternative approach. But in the grading system oncologists use, we don’t discriminate between slow progression and faster progression — it’s just considered a disappointment and time to move on.
(Click to enlarge)
The point is that imperfect brakes is better than no brakes. In fact, in some settings of especially effective treatments for other cancers, some investigators noticed that patients who were progressing slowly on a previously very effective treatment showed a rapid rebound progression when they stopped the treatment (as if they jumped from the blue line to the yellow line in the figure above). So a few years ago, the folks at Memorial Sloan Kettering Cancer Center (MSKCC)studied a small number of patients with either EGFR mutations or a prolonged response to EGFR inhibitors who were showing some progression (abstract here). They did CT scans and PET scans right before and right after patients took a planned three week break from their EGFR inhibitors, and they also assessed how these patients were feeling. After restarting their EGFR inhibitors and repeating scans and checking patient symptoms, they added another novel agent called everolimus, an mTor inhibitor (see prior post for discussion of the novel agent approach of mTor inhibitors alone and combined with EGFR inhibitors). For the more visually oriented, this is the overall design of the complicated trial:
EGFR and K-Ras Mutations in Patients with Early Stage NSCLC
We’ve seen clear evidence that patients who have tumors with certain mutations in the EGFR gene are highly likely to respond to oral EGFR inhibitors like tarceva (erlotinib) or iressa (gefitinib) — with response rates that are in the 70% range and often last for many months or even a few years (see prior post). On the other hand, K-Ras mutations are associated with a very low probability of responding to EGFR mutations (see prior post).
But the overall favorable or unfavorable results of these mutations may not be limited to their associations with how patients respond to EGFR inhibitors and/or other systemic therapies. I’ve noted how patients with advanced NSCLC and EGFR mutations have a superior survival even if they don’t receive an EGFR inhibitor. Another approach to assessing the prognostic value of mutations is to look at survival of patients with resected earlier stage NSCLC tumors.
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