GRACE :: Lung Cancer

squamous cell NSCLC

Rare Mutation? Submit to Your Master (Protocol): It May Well Revolutionize Clinical Trials for the Molecular Era

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Over the past 10 years we’ve come to recognize that what is lumped together as “lung cancer” is actually a wide range of different cancers that behave in their own patterns and respond very differently to different treatments. Some of our greatest advances in the field have come from the recognition of the complex patterns, but it has also become more challenging to do trials for small groups that represent just 1 or 2% of the larger whole. How can oncologists all over have access to the most interesting new trials and drugs if they only see 1 patient with a particular mutation every year or two? How can patients with rare mutations get treated for their specific cancer subtype without getting on a plane to travel to one of the 3 places in the country or world running a trial on that small group? And how can we practically begin to implement genomic sequencing, the screening of cancers for dozens or even hundreds of mutations all at one time, on a large scale to channel a large population of patients into the right trial and drug for them?

I’m optimistic about a new mechanism of clinical trial for the era of molecular oncology, called a “master protocol“, that is being developed with a target of launching in 2014.  I think it has the potential to accelerate molecular testing, detection of different markers, and research in a wide range subgroups.  By doing so, it also has the promise of getting new drugs approved and available to the potential beneficiaries of these drugs much sooner than we might have envisioned with the old, sclerotic model of trials that has trudged along up to now but has become obsolete in a new era of targeted medicine and small subgroups.

Here’s how it works: a group of patients within a big category, in this case advanced squamous cell NSCLC after prior chemotherapy, will have their tumor tested by Foundation Medicine in Boston for a series of potentially “actionable” mutations that have a drug for their target.  Under the master protocol, there may be 4 or 6 or 10 different “sub-protocols” running simultaneously (typically randomization of patients to standard chemo with or without novel agent X) that will all share a basic process and be able to open and close as they become available or fill up.  An institution that is part of a large network, in this initial case the SouthWest Oncology Group (SWOG), can open this master protocol and then be able to offer their patients with squamous NSCLC any of a changing number of novel agents that are matched for the particular mutation found in that person’s tumor. And if they don’t have one of the specific targets, there will be a safety net protocol for all of the other people who are eligible for the master protocol but don’t fall into one of the narrow subgroup protocols.

The early iteration of the trials will be smaller “phase II” trials, but any that achieve a threshold level of activity will then transition readily into larger phase III testing that are designed to lead to fast approval and commercial availability of the agents being tested.

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Dr. Leighl’s Highlights in Lung Cancer 2012, Part 4: Squamous Cell NSCLC and Anti-PD1 Immunotherapy

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Anti-PD1 FigureDr. Leighl continued her presentation on “Highlights in Lung Cancer, 2012″ with a discussion of the challenges that many patients with squamous NSCLC face, typically not having a cancer with a “driver mutation” like an EGFR mutation or an ALK rearrangement.  However, she notes that several new targets that may be especially relevant for patients with squamous NSCLC are becoming the subject of growing clinical research. In addition, one exciting development from 2012 that appears perhaps particularly beneficial for patients with squamous NSCLC is anti-PD1 antibody immunotherapy, an agent now known as nivolumab.  

Here are the video and audio versions of the podcast for this portion of the webinar, along with the associated figures:

Leighl Highlights in LC 2012 Pt 4 Squam and Anti-PD1 Audio Podcast

Leighl Highlights in LC 2012 Pt 4 Squam and Anti-PD1 Figures

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Abraxane Approved for Advanced NSCLC: Now What Will That Mean?

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It’s been over two years since I reported the details from a positive trial for Abraxane (albumin-bound paclitaxel) as a weekly treatment combined with carboplatin and compared with standard “solvent-based” Taxol (paclitaxel) along with carboplatin.  While positive for showing a 8% difference in response rate, which was the primary endpoint, it didn’t show a significant difference in overall survival (OS), as revealed in the completed publication of the trial earlier this year.  Beyond these very basic results, there have been some notable positive features of Abraxane from the trial:

- Patients with squamous NSCLC appeared to benefit more significantly, with a response rate of 41% vs. 24% on the carbo/Abraxane vs. carbo/Taxol arms, respectively, there there was no difference in survival between the two arms

- Survival was significantly longer in the subset of patients age 70 or older (median OS 19.9 vs. 10.4 months, P = 0.009) and in patients enrolled from North America (12.7 vs. 9.8 months, P = 0.008).

- Abraxane doesn’t require steroid premedication that is required before Taxol and can be challenging for many patients 

While Abraxane was relatively rarely used in lung cancer before now, as a relatively expensive medication  without a striking benefit over other alternatives and that hasn’t been FDA approved, the situation changes today for US-based patients, since the FDA voted to approve it as a first line treatment along with carboplatin for patients with advanced NSCLC.

What does this mean? What should this mean?

People who have read my posts and comments in the discussion forums here at GRACE have seen that I have been less than wildly enthused about Abraxane.  It’s not that I haven’t felt it represents a modest improvement, but rather that the striking cost differential for Abraxane vs. standard “solvent-based” Taxol seemed to me to be disproportionate to the more modest incremental benefit in how it helps patients.  But I’d confess now that I have more mixed feelings now and would probably be inclined to favor Abraxane for a reasonable subset of my own patients.

First, I need to acknowledge the inconsistency in my being rather fond of Alimta (pemetrexed) for non-squamous NSCLC while being critical of Abraxane based on cost.  Abraxane is expensive but comparable to Alimta, and I and most other lung cancer specialists have readily used Alimta for appropriate patients, often for very long periods of time (and therefore at a considerable cost).  It’s not that far cheaper chemo agents — such as standard Taxol, Taxotere (docetaxel), Gemzar (gemcitabine), or (Navelbine (vinorelbine) — wouldn’t be an appropriate option. It’s just that the overall balance of efficacy and tolerability for Alimta has made it somewhat of a darling of myself and many other lung cancer specialists. But that has also required us to turn a blind eye to the cost of the regimen  — especially if we added Avastin (bevacizumab) to the regimen!

I’d personally be most inclined to use Abraxane in patients with squamous NSCLC, since that’s a group in whom the response rate appeared more provocatively superior.  In this group, I have historically favored a platinum/gemcitabine combination, since it’s also often very well tolerated and doesn’t require steroids , and doesn’t lead to much hair loss in most patients.  Typically, I’ve favored cisplatin/gemcitabine for many of my most fit patients with squamous NSCLC, since there’s some modest evidence that outcomes are marginally better with cisplatin than with carboplatin, but a large proportion of patients who start with cisplatin find it very difficult to tolerate.  And while the carbo/gemcitabine regimen is typically easier for patients to feel well on, it often causes very significant drops in blood counts that can make it difficult to continue on a regular schedule and without ongoing dose reductions.   These problems with low blood counts tend to be especially common in older patients.  So while Abraxane is associated with hair loss, it has the appeal of being a generally well tolerated agent to combine with carboplatin without severe drops in blood counts and that doesn’t require steroid premedication (a relatively minor factor in my experience, but a plus), that may enable my patients to receive treatment as planned, with fewer dose delays and reductions than what I’ve historically done.

I’m intrigued by the findings from the subgroup analysis that indicated more favorable results in patients in North America and also in patients 70 and older, but it’s important to highlight that each of these groups represented only about 15% of the entire trial population.  The finding specific to North America may be related to practice patterns of giving more post-trial therapy after progression, or some other unmeasured factor, but it may also be a random finding that doesn’t hold up to more careful testing.  As for the elderly, it may be that the weekly chemo regimen with Abraxane is a better choice than a bigger slug of Taxol once every three weeks.  There will be subsequent research on this question (including by GRACE faculty member Dr. Jared Weiss), but in the meantime I’d just consider Abraxane to be a very fine choice older patients, and arguably a preferred one for older patients with a squamous NSCLC, even in the absence of more definitive evidence.

One other major factor will be whether payers readily cover Abraxane or indicate a clear favoring of a less expensive alternative.  Historically, they haven’t tended to dissuade oncologists from an FDA approved regimen, but I’ll admit that I’ve had far more input about giving a more expensive agent like XGEVA (denosumab) vs. Zometa (zoledronate) in the last 6 months than ever before.  Sad to say, but we may well find that a physician’s preference becomes less relevant as we become subjected to pressure to follow payer-imposed limitations.

What do you think? Are you impressed that Abraxane adds true, meaningful benefit and a new treatment option, or is it a slightly improved version of Taxol with a very big markup in price?

 

 


My Top 5 Notable ASCO 2012 Abstracts in Metastatic NSCLC

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The annual conference of the American Society of Clinical Oncology in late spring is the biggest event in the cancer world, where more of the big trials are presented than at any other time all year.  In the lung cancer world, it’s looking like this one won’t be a blockbuster but will have some promising and interesting findings to discuss.  As a preview, I wanted to offer my top 5 for what I think will emerge as the most important results we’ll see, based on the recently released abstracts of the meeting.  Lung cancer is divided into two tracks: today, I’ll cover the metastatic lung cancer track, and then I’ll next offer a top 5 on the track covering stage I-III NSCLC, SCLC, and other less common thoracic cancers 

Without further adieu, here are my top 5 in metastatic NSCLC: Continue reading


Prevalence of EGFR Mutations in Patients with Adenocarcinoma: Moving Beyond Never-Smokers

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The question of “who should be tested?” for an epidermal growth factor receptor (EGFR) mutation and potentially other molecular markers is among the most timely questions in lung cancer management today. The field has changed dramatically since the initial description of the mutation, associated with a high probability of an impressive and often prolonged response to EGFR tyrosine kinase inhibitor (TKI) therapy, back in 2004. For several years after that, mutations had been known to be neither absolutely necessary (occasional patients would have phenomenal responses despite not having a mutation identified) nor sufficient (response rates to EGFR TKIs among patients with an EGFR mutation have been in the 65-75% range, not 100%) to see a gratifying response. Moreover, it was also known that certain clinical/demographic characteristics, such as being Asian, female, a never-smoker, and having an adenocarcinoma or bronchioloalveolar carcinoma (BAC) tumor histology was associated with a higher probability of a significant response to EGFR TKIs as well, and that these characteristics are associated with a higher probability of having a lung cancer with an activating EGFR mutation (it has been clarified in the last few years that particular mutations in exons 19 and 21 are far more common than others and are the ones most consistently associated with a dramatic response, as discussed in Dr. Pennell’s terrific review of the subject).

Though I had previously felt there to be a potential role to be played by “clinical selection” of patients who might be best served by starting with an EGFR TKI inhibitor, such as for a never-smoker presenting with a lung adenocarcinoma, or potentially anyone with a BAC, the IPASS trial clearly illustrated that EGFR mutation status was a reliable means of selecting which patients are better served by prioritizing an EGFR TKI over standard chemotherapy, while clinical selection failed: as I described in my post “Confessions of a Former Clinical Selector“, the trial highlighted that even Asian never-smokers with a lung adenocarcinoma did better with chemotherapy than an EGFR TKI if they didn’t have an EGFR mutation.

Since then, multiple trials have confirmed that while a difference in overall survival (OS) hasn’t been clearly demonstrated, patients with an EGFR mutation have a very significantly improved progression-free survival (PFS) after starting an EGFR TKI compared with standard chemotherapy. Accordingly, testing for EGFR mutations has become far more common, though not a uniform practice. The National Comprehensive Cancer Network (NCCN) guidelines for non-small cell lung cancer (NSCLC) now call for EGFR mutation testing in all patients who don’t have a squamous NSCLC tumor (since mutations are known to be unlikely — though are still seen rarely — in patients with a squamous tumor). Surveys of oncologist practices in the US over time have shown that more oncologists are testing than previously, but only perhaps a third to 40% of patients are being tested, and the probability of someone being tested having an EGFR mutation is about 40%, quite a bit higher than the 10-15% prevalence of the EGFR mutation among NSCLC patients in North America. This means that oncologists are being selective about who to test, and they’re focusing on patients who have a higher probability of testing positive.

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