|
|
|
ASCO vs. NCCN: Very Different Views on Molecular Testing in Advanced NSCLC
A couple of weeks ago, the American Society of Clinical Oncology (ASCO) released a set of revised guidelines for stage IV NSCLC. While grounded in good evidence, they are striking for the contrast they offer with the recommended strategy from the National Comprehensive Cancer Network (NCCN) guidelines for this population. Most notably, the difference is related to molecular testing and subsequent individualized treatment based on this. As many of you who follow the discussions here have observed, the question of who to test and what to test for is currently among the most timely, evolving, and still somewhat controversial questions in the practice of lung cancer today. This is especially true in the setting of the approval of the ALK inhibitor XALKORI (crizotinib) by the FDA just a few weeks ago, since this agent is only going to be made commercially available to the 4-5% of patients with NSCLC who test positive for an ALK rearrangement at the one designated central lab approved along by the FDA along with the drug. So here, the approval of the drug is actually predicated on molecular testing for patients who would hope to receive this agent.
Who to Test for an EGFR Mutation or ALK Rearrangement: Filtering Based on TTF-1 Status
Thyroid transcription factor-1 (TTF-1) is a protein seen on the surface of thyroid cells, but also on about 70-75% lung adenocarcinomas and only a small minority (~10%) of squamous cell NSCLC tumors. In fact, the presence of TTF-1 on a NSCLC tumor provides a good hint for the pathologist that this is an adenocarcinoma. It’s an immunohistochemical (IHC) test that is done on the vast majority of lung cancers, and there’s some new information that suggests it may also be useful for predicting which patients are especially unlikely to have an EGFR mutation or ALK rearrangement. This is especially important as we are now faced with a question of whose tissue to send for these particular tests, especially if this decision involves obtaining another biopsy.
A few months ago, a group from Seoul, Korea published their results on the correlation between ALK positivity in a series of 221 patients with lung adenocarcinoma and other clinical and pathologic features. In this somewhat selected group of Asian patients with an adenocarcinoma, 45 (20% had an ALK rearrangement, and this population skewed toward being younger than other patients (49 vs. 61), but didn’t differ in smoking status (about half were never-smokers in both groups for this population) or gender distribution, but they did have two striking features. ALK rearrangements were mutually exclusive with an EGFR mutation (they were never seen in the same patient), and there were no patients with an ALK rearrangement who tested negative for TTF-1 expression.
Beyond XALKORI for ALK-Positive NSCLC: More Evidence of Alimta’s Activity
The marker known as an anaplastic lymphoma kinase (ALK) translocation has been all over the lung cancer news in recent weeks, most notably in the setting of being the marker in about 4% of patients with non-small cell lung cancer (NSCLC) that is correlated with a high probability of response to the ALK inhibitor crizotinib, which was just approved by the FDA for patients whose tumors demonstrate this marker on a test in a central reference laboratory. But this marker may also be correlated with responsiveness to Alimta (pemetrexed), providing a readily available treatment option before or after these patients start crizotinib.
If this sounds familiar, it’s because I actually described such an association of particular benefit in ALK-positive NSCLC with Alimta back in February, when our friend, Dr. Ross Camidge, from the University of Colorado, published a retrospective review of patient outcomes with Alimta at the University of Colorado. They evaluated the outcomes of 89 patients tested for an EGFR mutation, KRAS mutation, or ALK translocation and also found that the median progression-free survival of their 19 ALK positive patients was significantly higher, at 9.0 months, than that seen in 37 who were wild type (WT, or “no mutation) for all three markers (4.0 months), and that neither patients with EGFR nor KRAS mutations demonstrated a significant difference compared with triple negative patients.
Though Dr. Camidge and I both noted that these results can only be taken so far, as a retrospective analysis from a single institution, these conclusions were corroborated by a remarkably similar retrospective review that comes out of Korea by Lee and colleagues, who evaluated 95 patients with advanced NSCLC and who had received Alimta as a second line or later therapy between March, 2007 and April, 2010. Specifically, they assessed outcomes as a function of whether these patients had an EGFR mutation (N = 43, or 45%), an ALK translocation (N = 15, or 16%), or WT for both (N = 37, or 39%), finding that patients with an ALK translocation had a more favorable outcome with Alimta across several endpoints. These included a significantly higher objective response rate compared to those with an EGFR mutation or WT for both (47% vs. 5% and 16%, respectively; p = 0.001), as well as disease control rate (87% vs. 26% and 57%, respectively; p < 0.001) and median time to progression (TTP) (9.2 vs. 1.5 and 2.8 months, respectively; p = 0.001).
(click on image to enlarge)
ALK inhibitor XALKORI (Crizotinib) FDA-Approved: New Era, with New Challenges
Yesterday afternoon, the FDA approved the ALK inhibitor crizotinib, newly christened as XALKORI, for patients with locally advanced or metastatic NSCLC who have an ALK rearrangement as identified by a particular central lab (test co-developed by Abbott and Pfizer, the makers of XALKORI). We’ve discussed the significant efficacy of XALKORI for this subset of NSCLC patients, with the frequency of an ALK rearrangement being somewhere in the range of 4-5%, and about 2/3 of ALK-positive patients showing significant tumor shrinkage on XALKORI, and more than 90% showing stable disease or tumor shrinkage. Moreover, these responses are of a duration typical of those we see with targeted EGFR-based therapies for patients with an EGFR mutation — in the range of a year, in contrast with more typical chemotherapy-based responses for advanced NSCLC, which more commonly last for several months, at most. The fact that XALKORI is an orally available anti-cancer treatment with very mild side effects also adds to the appeal.
The biggest limitation, of course, is that 4-5% frequency of an ALK rearrangement, far more commonly seen in patients with an adenocarcinoma, little or no smoking history, and also apparently more prevalent in younger patients, men a little more commonly than women, and especially seen in patients with the unusual (and often more aggressive) NSCLC subtype of signet cell adenocarcinoma.
ASCO Highlights in Lung Cancer Q&A Session
ALERT: The links for the podcasts are now fixed.
Here’s the question and answer session with Drs. Mary Pinder and Nasser Hanna following their presentations on the lung cancer highlights from the ASCO 2011 annual meeting (Dr. Pinder’s on SCLC, early stage NSCLC, and mesothelioma here, and Dr. Hanna’s on advanced NSCLC here), covering a lot of ground on timely issues raised from the conference. The program and podcast were developed in partnership with LUNGevity Foundation.
Below is the audio and video versions of the podcast, as well as the transcript and figures.
asco-2011-highlights-in-lung-cancer-qa-audio-podcast
asco-2011-highlights-in-lung-cancer-qa-session-transcript
asco-2011-highlights-in-lung-cancer-qa-session-figures
Podcast: Play in new window | Download (65.0MB) | Embed
Sacrilegious Thoughts on Adjuvant Therapy for Resected Early Stage NSCLC
There’s a problem in our discussions of standard treatment for patients with higher risk resected early stage NSCLC, and that is that there is a pretty clearly defined standard of care of giving typically around 4 cycles of cisplatin-based chemotherapy to reduce the risk of recurrence, but in truth, the majority of people in the real world don’t get it. Still, I wouldn’t want to imply that the problem is definitely that doctors aren’t giving the right treatment to people who should definitely be getting it. I’m concerned that the problem may be that the well defined, trial-defined standard of care may truly not be the ideal choice for the majority of patients.
The median age of patients in all of the trials that give adjuvant chemotherapy is 59-63, which is a decade younger than the median age of a patient newly diagnosed with lung cancer in the US. Even looking at younger patients, a very substantial fraction have other medical problems or aren’t doing and feeling very well 4-7 weeks after a big lung surgery, which is when we’d usually want to give it. Many have kidney function that isn’t great, hearing loss, or some other good reason to not get cisplatin. So when we actually look at the treatments early stage NSCLC patients actually get, a huge fraction get no chemotherapy even if they would otherwise technically be a candidate based on the pathology findings, and the most commonly used regimen in the US is carboplatin/Taxol (paclitaxel), a regimen that has been tested as a post-operative therapy and failed to show a survival benefit, relegating carboplatin-based adjuvant chemotherapy to second tier status, below cisplatin-based chemo.
Last weekend, I gave a summary of some ASCO Highlights in lung cancer at a meeting for oncologists, and I was charged with reviewing some of the adjuvant therapy results from this year, including a trial called TREAT that Dr. Pinder covered in our own webinar on ASCO Highlights in Lung Cancer, and which asked the question of whether cisplatin/Alimta (pemetrexed) might be a regimen more feasible to administer than the most data-supported option of cisplatin/Navelbine (vinorelbine). The background of that trial is that the existing trials with the cisplatin/Navelbine regimen show that in some studies, more than half of the people came off of treatment before getting through it, and huge proportions of patients need to delay or stop treatment due to prohibitive drops in blood counts or some other toxicities, or they simply refuse to continue with more treatment. I’ve certainly seen this in many of my own patients, on or off of a clinical trial — even if they know that there is a potential survival benefit to be gained, some express that they’d rather be dead than to continue on cisplatin-based chemo. The trial actually confirmed that the cisplatin/Navelbine regimen as best studied is quite difficult to administer on any kind of regular schedule, at least without it being a soul-crushing experience; cisplatin/Alimta was more feasible, though not a cake walk itself either.
More concerning to me is the fact that, if you pool many of these older trials together, around 1% of patients die as a result of adjuvant therapy. Let me remind you that these are people who already have a significant chance of being cured. There is also some work from longer term follow-up in adjuvant therapy trials that suggests that the survival benefit from adjuvant chemotherapy in the first few years may be compromised by higher death rates in recipients of chemotherapy more than 5 years out, compared with observed patients. Also of concern are the preliminary findings of the ongoing 1505 trial of cisplatin-based chemo with or without Avastin (bevacizumab) reveal that while there isn’t a statistically significant increase in serious side effects with addition of Avastin, the rate of treatment-related deaths on the two arms is 2.5% with chemo alone, and 3.8% with Avastin. [NOTE: Since writing this, I have learned from Dr. Suzanne Dahlberg, statistician for ECOG, that these numbers are not specifically attributed to treatment but could be from other causes, such as treatment-related recurrences. This is quite reassuring, as the quoted numbers were higher than I'd expect or hope to see for treatment-related deaths a multicenter North American experience.] Continue reading
PF-299804 Shows Trend Toward Survival Benefit vs. Tarceva
I’ve previously described the novel “pan-HER inhibitor” PF-299804 and even the randomized phase II trial of PF-299 vs. the EGFR tyrosine kinase inhibitor Tarceva that showed a higher response rate (RR) and longer progression-free survival (PFS) with PF-299. At the World Conference on Lung Cancer in Amsterdam, the investigators also presented updated results from this trial that showed a trend toward a survival benefit with PF-299 as well.
This was a trial of 188 patients with previously treated advanced NSCLC, not selected for having an EGFR mutation, being never smokers, or any other specific subset. The prior post describes many of the results, including the modestly greater side effects with PF-299 that accompanied the improvement in RR and PFS. In the update of the results, PFS is still significantly better with PF-299, and they also specifically focused on the 2/3 of patients who were KRAS “wild type” (no mutation), who are shown in the curves on the right in the figure below:
(click on image to enlarge)
XGEVA (Denosumab) for Lung Cancer: Survival Benefit Suggested by Retrospective Subset Analysis of Key Trial
Late last year, I reviewed the approval of the agent XGEVA (denosumab) for patients with skeletal metastases from solid tumors after a randomized phase III trial demonstrated a significant reduction in the rate of development of skeletal-related events compared with the pre-existing standard of Zometa (zoledronic acid) for bone metastases. Importantly, there was no difference in overall survival in the trial as a whole, which included patients with multiple myeloma or solid tumors other than breast cancer and prostate cancer (which were each studied in separate trials). A few months later, the publication of the phase III trial came out, and I actually wrote the accompanying editorial, in which I argued that while the results showing improvement in the endpoint of skeletal-related events, no improvement in survival, marginally better side effect profile, but considerably higher cost made XGEVA a very compelling option but not necessarily an iron-clad unchallanged standard of care when the cost vs. benefit of the agent over Zometa is taken into consideration.
Though I suggested that the results were provocative but not overwhelming from the bird’s eye view, I raised the point that if overall survival (OS) were to be improved in a subset of patients, the argument favoring XGEVA would be more compelling, as was noted in a very limited way for patients with NSCLC in the randomized trial:
It is therefore notable that, in a post hoc analysis of OS in the Henry et al11 trial, the HR for NSCLC was statistically superior with denosumab for patients with advanced NSCLC.
Among the many interesting presentations from the World Conference on Lung Cancer in Amsterdam was one by Dr. Giorgio Scagliotti that provides far more detail on the post hoc (retrospective) analysis of patients with lung cancer from this trial. Dr. Weiss provided a summary of the presentation in his great review of that day, but here I’ll provide a little more information (primarily just the “picture’s worth a thousand words” synopsis).
The overall trial enrolled 1776 patients with a range of cancer types, of which 40% had NSCLC and 9% had SCLC: this large subset of 811 patients with lung cancer served as the basis for this presentation. Looking at the entire group with lung cancer, there was a statistically significant 20% improvement in OS that translated to a 1.2 month prolongation in median OS, as illustrated in the figure below:
(click on image to enlarge)
World Lung Conference Day 4, 7/7/2011
Good morning, GRACErs.
Plenary
The first talk was by Dr. Hisao Asamura of Tokyo, Japan who discussed a surgeon’s view on adjuvant chemotherapy.He started with a 2010 meta-analysis, which included some older regimens yet still showed a 4% increase in survival at 5 years. Another analysis restricted to more modern regimens showed 9% benefit and some oncologists claim even higher numbers with yet more modern regimens.
World Lung Conference Day 3, 7/6/2011
Last night I had the good fortune to attend the fun young lung dinner. I had a lot of fun seeing old friends, and greatly enjoyed making a few new ones:
| Follow us on... |    |
||
Copyright ©2012 GRACE |
|||