GRACE :: Lung Cancer

Survey for Lung Cancer Chemo Patients Seeks to Improve Care

Cancer researchers need to hear from lung cancer patients who have gone through chemotherapy and experienced various side effects.

As part of that effort, GRACE is supporting the Research Advocacy Network, a non-profit organization, as it searches for lung cancer chemo patients willing to complete its online survey about their experiences and needs. Your responses will be completely anonymous. An incentive for your participation will be described and offered for taking the full survey – which will take about 20 minutes of your time. Your participation will help doctors and nurses improve patient care.  

Access the survey here and make your voice heard.

 

 


Lung Cancer Leaps Expected at Scientific Meeting

Dr. Thomas John is a thoracic oncologist at the Olivia Newton-John Cancer and Wellness Centre in Australia.

The American Society of Clinical Oncology’s (ASCO) Annual Meeting brings together 30,000 oncology professionals from around the world. Educational sessions feature world-renowned faculty discussing state-of-the-art treatment modalities, new therapies, and ongoing controversies in the field. The meeting will take place May 29 – June  2, 2015. 

ASCO 2015 promises to advance our knowledge of lung cancer. There are some positive studies that will impact treatments. In particular, it has been a big year for treatment advances for non-small cell lung cancer (NSCLC) which will provide insight into future diagnostic and therapeutic directions.

Immunotherapy

In lung cancer, as expected, several immunotherapy trials will be reported. The Checkmate 017 study, which investigated Opdivo (nivolumab) compared to Taxotere (docetaxel) in patients with squamous cell lung cancer in the second line setting, has already been reported as a press release. Nivolumab was associated with a three month improvement in overall survival compared to chemotherapy, with less toxicity. PD-L1 expression was not prognostic or predictive. These data are from a Phase III study and clearly indicate that immunotherapy is superior to Taxotere from both an efficacy and toxicity perspective.

Similarly the POPLAR study, which investigated Roche’s PD-L1 inhibitor MPDL3280A, was designed to investigate superiority against Taxotere. This study included both adeno- and squamous cell carcinomas, and the interim analysis showed a survival and response benefit restricted to tumours with high PD-L1 expression. For MPDL3280A, the rates of PD-L1 positivity appear to be lower than other assays. The assay measures PD-L1 expression in “tumour infiltrating lymphocytes” (immune cells invading the tumour) rather than tumour cells directly. The correlation between PD-L1 expression and response from this study appears striking, with no response in PD-L1 negative tumours.

There are many other abstracts pertaining to the immune checkpoint inhibitors being presented at ASCO this year. The Checkmate 017 study is practice-changing and suggests that Opdivo should be given to all squamous cell patients, regardless of PD-L1 status. Combinations of CTLA4 blockade (another means of activating the immune system by removing the brakes)/PD-L1 and pathological assessment of PD-L1 in molecularly subtyped tumours will also be reported.

It appears that PD-L1 expression certainly enriches for a group likely to derive maximum benefit, however depending on the assay, up to 20% of PD-L1 negative patients also respond, and indeed compared to chemotherapy these negative patients who respond also derive clinically meaningful survival benefits. There are further issues with tumour heterogeneity (differences in molecular characteristics of cancer cells even within the same tumour), and sampling making the companion biomarker a topic we will be talking about for many years to come.

Immune checkpoint inhibitors will be one of the most talked about treatments at this ASCO, as there are emerging data in small cell lung cancer, mesothelioma and in various permutations and combinations in molecularly driven NSCLC.

Targeted Therapies in Lung Cancer

Recently, AZD9291 was reported to result in significant response and survival benefit in patients with an acquired resistance mutation (T790M) that had developed after using an EGFR TKI for their EGFR mutant NSCLC. In a subset of patients from the Phase I study, a first line cohort was recruited. AZD9291 appears to be a highly effective drug in the first line setting, with an objective response rate of 70%, a disease control rate of 97% and a toxicity profile that is a lot better than Iressa (gefitinib) or Tarceva (erlotinib). The main question, however, is whether AZD9291 prolong progression free survival. These data are not mature enough, and median progression free survival has not been reached to date. Subsequent studies have already begun recruiting patients that compare AZD9291 to both chemotherapy and an oral TKI.

Other interesting studies show that the combination of BRAF and MEK inhibition (Tafinlar (dabrafenib)) plus Mekinist (trametinib) in BRAF mutant NSCLC is more effective than Tafinlar alone. It will be interesting to see how many patients were screened to discover this subset of patients. It is notable to see similar response data to that seen in melanoma. We still need to determine whether using immune checkpoint inhibitors in this subset is also as effective as it is in melanoma.

Gilotrif compared to Tarceva in squamous cell cancers (Lux Lung 8) will be reported as showing a survival benefit. However, the clinical utility of the one month improvement is likely to be questioned especially given the toxicity of this agent, the widely recognized minimal to modest efficacy of Tarceva in this setting, and the other agents becoming available.

Brain Mets

Finally, the plenary session will include a study where patients with 1-3 brain metastases were randomised to either receive stereotactic body radiation therapy (SBRT) plus whole brain radiation therapy (WBRT) or SBRT alone. Over 60% of patients in this study had lung cancer. The addition of WBRT controlled the disease but was associated with significantly greater cognitive decline and no survival advantage. This study suggests that WBRT should not be added to SBRT. By extrapolation, should we be using WBRT at all for 1-3 brain mets? We do not know the details here, so the question of surgery also comes to mind, but that would be contingent on having disease control extracranially.

Mesothelioma

For mesothelioma, data from the Keynote 028 study, which investigated Keytruda (pembrolizumab) after failure of initial chemotherapy has already been reported at the AACR Annual Meeting in April. It showed that for around one quarter of patients, the disease actually shrank, and the disease remained stable in about 50%. These data are encouraging and are launching several larger Phase II/III studies.

ASCO will showcase several abstracts pertaining to mesothelioma, including one that it is practice changing. The MAPS trial was initially a Phase II French study whose interim analysis was recently reported, and a decision to continue the trial was made. Here the Phase III part of this study is reported. Patients were randomised to receive standard cisplatin/pemetrexed chemotherapy +/- Avastin (bevacizumab/bev) 15mg/kg. This was a large trial with 448 patients. The addition of Avastin prolonged progression-free and overall survival by two months with minimal increase in toxicity. This is the first time an addition to overall survival has been reported in a Phase III trial in mesothelioma since the paper that established the value of cisplatin and Alimta for mesothelioma, 12 years ago!

In mesothelioma, it is good to see some positive results with Avastin, although there will likely be some debate about whether the cost is justified for a survival advantage of only 2 months.

Follow all of the ASCO happenings on Twitter at #ASCO15, @cancerGRACE, and @jackwestmd.


PFS vs. pfs: Why Progression-Free Survival Remains Controversial in Lung Cancer

Last year, an article came out in the Journal of Clinical Oncology that noted a gradual shift away from the “hard endpoint” of overall survival (OS) for lung cancer trials toward progression-free survival (PFS), a “softer endpoint” that is much more subject to interpretation.  The analysis also noted that many of the trials that were technically negative for the primary endpoint, the prospectively defined emphasis of the trial, were written up as if they were positive, highlighting a secondary endpoint that looked favorable, or a subset of patients who demonstrated a more favorable result than was seen in the overall trial population.

The accompanying editorial implied that this shift represented a regrettable relaxing of appropriate standards, but I actually didn’t and don’t see it that way.  First, we’ve seen that some trials haven’t reported on survival because patients were responding and continuing without progression for so long that it was self-obvious that survival was improving.  For instance, the US FDA approved XALKORI (crizotinib) back in August, 2011 for ALK rearrangement-positive patients, based on the terrific results in a single-arm, phase I/II trial that showed that nearly two thirds of patients had significant tumor shrinkage and that the median PFS was in the range of 8-10 months. Both of these results were about twice what we would expect from standard chemotherapy regimens.  It wasn’t until several years later that we saw the definitive evidence that XALKORI was superior to chemotherapy in terms of OS. How many ALK-positive patients would have been denied this clearly beneficial therapy over the additional 3 years just so that we could run a randomized trial that is the equivalent of running a trial to confirm the value of parachutes for people falling out of an airplane (technical term — “gravitationally challenged”)?  Most of the lung cancer community rightly considered XALKORI the clear standard of care in the first line setting without waiting for the subsequent trial to prove a survival benefit, because the conclusion was already self-evident based on a profound PFS benefit.  The FDA has actually just put out a new document noting that they will continue to consider approving drugs for lung cancer based on secondary endpoints like PFS.

Back in 2000-2005, there was much more reason to question the value of PFS as an independent and predictive endpoint.  Before trials with targeted therapies, the magnitude of PFS differences that you’d see between two arms of a trial was usually only up to 1.5-2 months. If that isn’t accommodated by at least as much of an improvement in OS, it’s hard to get excited about that. Yes, patients can argue that a few extra weeks before being told that their scan looks worse is valuable, and while that’s justifiable for drugs that don’t cost $5000-10,000/month or more, it’s fair for society to expect much more compelling value for cancer drugs when everyone ends up sharing the cost burden by paying taxes or rising insurance premiums.  On the other hand, I have firmly believe that seeing a PFS of more than 6 months in a randomized trial of Tarceva (erlotinib) with or without Avastin (bevacizumab) in favor of the combination is very clinically meaningful and predicts for a high probability of a survival benefit with additional follow up.   Imagine having two homes for sale that are next door to each other, very comparable, but one is in a color you clearly prefer and one is a less preferred color. Does color matter? Yes, and if they cost the same, you should jump at this minor factor. But if the home in your preferred color costs 25% more, it’s absolutely not worth it. It’s a very minor factor. On the other hand, if the color of the home also correlated with something that really matters, such as if the home in the color you prefer was also bigger and much nicer, it’s clearly worth paying the 25% premium.  

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The Immunotherapy Cola Wars

It’s been a big week for immunotherapy for lung cancer. Right on the heels of a press release that the PD-1 inhibitor Opdivo (nivolumab) significantly improved survival for patients with advanced non-squamous NSCLC, my friend Dr. Garon from UCLA presented results at the American Association for Cancer Research conference with another PD-1 inhibitor, Keytruda (pembrolizumab). These results are from phase I trial of this agent given at different doses and schedules to patients with advanced NSCLC, either squamous or non-squamous, most but not all patients having received prior chemotherapy, coincident with the online publication of the results in the New England Journal of Medicine.  Taken together, the entire population demonstrated an objective response rate of 19.4% and median overall survival (OS) of 12 months, median progression-free survival (PFS) of 3.7 months. These numbers are not especially impressive, though the median duration of response (DOR) in responders was a little over a year (12.4 months). 

What was most impressive here were the results in a subset of a little more than a third of the patients with tissue testing that showed a high proportion of the protein PD-L1, which is a key mediator of immune system activation vs. suppression. In that subpopulation with at least 50% of their tumor cells staining for PD-L1, the response rate was 45.2%, compared with 16.5% for patients with lower but detectable PD-L1 expression (on 1-49% of tumor cells) and 10.7% for patients <1% of tumor cells positive for PD-L1 expression. OS and PFS also appear to be higher for the high PD-L1 expression subgroup. 

These are very encouraging results, to be sure. But as we are now clearly entering an era where we have multiple immunotherapies for overlapping clinical settings, it’s time to ask whether these agents really provide meaningful differences if given to the same patients, or are the differences truly marketing differences of segmenting markets for remarkably similar treatments. Are we really just seeing results for Coke and Pepsi, perhaps with a newly created “Pepsi Generation”? 

Soda choices

 

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Immunotherapy Opdivo (Nivolumab) Non-Squamous NSCLC Trial Stopped, Reported as Positive

In January, 2015, the CheckMate 017 trial of the immune checkpoint inhibitor Opdivo (nivolumab) versus the standard chemo agent Taxotere (docetaxel) as second line therapy for patients with advanced squamous NSCLC was reported in a press release to be positive for a significant improvement in overall survival. No further details were offered at that time, but additional data were submitted to the FDA just days before the FDA approved Opdivo on March 4, 2015 and made it commercially available for these patients (with the FDA deserving credit for seemingly waiting in a conference room to go through an immediate approval process once the full data was supplied). We have since learned that Opdivo was associated with a significant, 3.2 month improvement in median overall survival, 9.2 vs. 6.0 months, but additional data await presentation at the annual ASCO meeting in Chicago in late May/early June.

Bristol-Myers-Squibb  (BMS) ran a parallel trial called CheckMate 057, also directly comparing Opdivo to docetaxel as second line therapy for patients with non-squamous NSCLC, which comprises about 75-80% of NSCLC patients in North America.  That trial completed enrollment around the same time as the squamous trial, but no results were forthcoming until this week, when a press release from BMS noted that an interim data review from this trial has demonstrated a significant survival benefit again for Opdivo — with no additional data offered yet. 

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