GRACE :: Lung Cancer




Immunotherapy as First-Line Treatment




Dr. Jack West, Swedish Cancer Institute, raises the question of whether to use immune checkpoint inhibitors as first-line treatment of lung cancer, alone or in combination with chemotherapy.

Download Transcript

How Did You Like This Video?

Please feel free to offer comments and raise questions in our Discussion Forums.



A class of agents known as immune checkpoint inhibitors has really incredibly invigorated the field of lung cancer and many other cancers over the last year or two. These agents are given intravenously and essentially take off a braking mechanism for the immune system and by doing that, can stimulate it to recognize and attack your own cancer. These agents, at least a couple of them, have been approved by the FDA as of now, in late 2015, and the question is whether they should be used earlier than the second line setting where they’ve already been approved.

Two agents, one known as Opdivo or nivolumab, and another known as Keytruda or pembrolizumab, are approved in patients who have already demonstrated progression after receiving a first line chemotherapy. So the question is: should these treatments be given earlier in therapy? There are two leading considerations in how we might do this. One is that we might give an immunotherapy in combination with standard chemotherapy. There are other ways to do this that might give the immunotherapy instead of standard chemotherapy. There are studies looking at various combinations being done with any of the many immune checkpoint inhibitors that are in development right now.

An interesting trial that is being done now is with pembrolizumab, or Keytruda — this is the KEYNOTE-189 trial that is looking at whether the addition of Keytruda to standard chemotherapy improves outcomes for patients when they get it first line. Specifically this trial is for patients with a non-squamous cancer and these patients can have any level of PD-L1 expression, the protein that tends to be associated with better activity of the immune checkpoint inhibitors — there’s no restriction on PD-L1 expression and patients just have to have not received prior therapy for advanced lung cancer. These patients are then randomized to receive the two drug chemotherapy combination of cisplatin or carboplatin with Alimta, or that same chemotherapy combination with Keytruda (pembrolizumab). That study is being done now and we hope to learn more about it in the next year or two, to learn whether it is beneficial to give these immunotherapy agents in combination with chemotherapy, compared to giving them sequentially.

Another very similar study, though looking at squamous lung cancer, is called EMPOWER 131 — this is with an immune checkpoint inhibitor known as atezolizumab. This agent is being looked at in combination with either carboplatin and Taxol, or carboplatin and Abraxane, a very similar agent. There are two arms of this study where a patient gets a combination of chemotherapy and the immune therapy, and the third arm is just carboplatin and Abraxane alone. We should learn more about the potential benefits of combining immune checkpoint inhibitors with chemotherapy in the first line setting from this, looking at both patients with squamous and non-squamous histology in different trials.


Histology-Specific Regimens – Squamous

GRACE Cancer Video Library - Lung



Dr. Jack West, Swedish Cancer Institute, reviews the choices for a first-line chemotherapy regimen based on a squamous histology.

Download Transcript

How Did You Like This Video?

Please feel free to offer comments and raise questions in our Discussion Forums.



There are a few common subtypes of non-small cell lung cancer. These are broken down by histology — the appearance of it under the microscope. The most common is called adenocarcinoma; the second most common is known as squamous histology and this accounts for somewhere in the range of 20% to 25% of the non-small cell lung cancers out there.

There are many standard chemotherapy regimens that are commonly used for patients with advanced non-small cell lung cancer, and overall they tend to produce very comparable results, making it very reasonable to choose one or another without a lot of difference, but there are certain regimens that might be more or less favored. For instance, in the setting of squamous lung cancer, there are a couple that we really choose to avoid in these patients because they are either unsafe or less effective.

So in terms of safety, one of the agents that we really prefer to not give is called Avastin and it is not a standard chemotherapy, but sometimes added to chemotherapy as a third agent that blocks the tumor blood supply. This can be helpful in some patients with non-squamous histology, but it has led to an unacceptably high risk of bleeding complications in patients with squamous histology. Because of that we do not give it in that setting — it is not considered safe.

Another agent that is really not favored is known as Alimta or pemetrexed, and that is because it does not seem to have good efficacy — it doesn’t do better than giving a placebo drug in that setting.

There are certainly other good choices. A cisplatin or carboplatin drug combined with an agent like Taxol, also known as paclitaxel, is a fine choice. There is also a related drug called Abraxane, which is also known as albumin-bound paclitaxel or NAB paclitaxel. This agent was added to carboplatin and compared to carboplatin and Taxol in a large group of patients with advanced lung cancer of a few different types, and the patients with squamous histology had a higher rate of tumor shrinkage if they received the carboplatin and Abraxane combination, than carboplatin and Taxol. It’s not an overwhelming difference and there wasn’t a clear difference in survival, but because of this some people might favor carboplatin and Abraxane.

Another choice that might be considered and favored in patients with squamous lung cancer is a platinum with Gemzar, also known as gemcitabine, and that’s because there was a randomized trial that gave cisplatin and Gemzar, or cisplatin and Alimta to patients with different types of lung cancer, and that study showed that the patients who got cisplatin and Gemzar did better overall than the patients who got cisplatin and Alimta. That might have been in large part because Alimta is not very effective in squamous lung cancer, but in fact we do tend to favor giving Gemzar as a leading partner with a platinum drug, if not a taxane. The taxane drugs: Taxol, Abraxane, or Taxotere, all seem to have efficacy that is every bit as good in the patients who have a squamous or non-squamous lung cancer.

So there are certainly several options, but some may be particularly better for patients with squamous histology.


Elderly Patients: Selecting Appropriate Systemic Treatment Agents

GRACE Cancer Video Library - Lung



Dr. Jared Weiss, UNC Lineberger Comprehensive Cancer Center, evaluates a variety of particular systemic treatment agents for possible use in elderly patients.

Download Transcript

How Did You Like This Video?

Please feel free to offer comments and raise questions in our Discussion Forums.



It is my privilege to speak to you today about elderly patients; consideration of which chemotherapeutic agents might be best. So we’ve seen a lot on CancerGRACE about the advent of targeted therapy and this theme that when you combine a target with a targeted therapy, like a lock and key model, you as a theme get a treatment that has less side effects, is more convenient because they’re often oral, and tend to work better.


This of course has made lots of work for our medical students as we subdivide by histology, by driver mutations, and an even more complex systems view that probably starts to approach reality. But in the simplest way when thinking about targeted therapies such as erlotinib or gefitinib for EGFR mutants, or crizotinib for ALK or ROS1, and other emerging targeted therapies — as a theme these drugs are very effective and less toxic, and so to my mind, even though we don’t normally speak about them as geriatric drugs, to me they’re the epitome of geriatric drugs because of these themes.


In terms of traditional chemotherapy, there’s really only one agent that I would consider to have any data for superior efficacy in the elderly. You’re looking here at the design of a randomized phase III trial that randomized patients to carboplatin and regular cremophor solvent-dissolved paclitaxel, versus carboplatin and a newer nano albumin-bound formulation called Abraxane.


Patients were randomized one to one, you can see the basic results by age at the bottom of this slide. Why I’m showing this to you is that the only subgroup that had a major survival difference was the elderly. In patients of at least 70 years of age, there was a rather important improvement in survival, 19.9 versus 10.4 months — that is statistically significant. I would call that clinically meaningful but it is a retrospective subgroup analysis and so it requires confirmation in prospective studies. Two important studies are ongoing to look at this. One is looking at older patients with this regimen for their first treatment, and the other looking at such patients for their second treatment.


This was a randomized trial that compared for first treatment cisplatin and pemetrexed, versus cisplatin and gemcitabine. We’ve covered this trial a number of times on GRACE before in terms of looking at histology-specific differences in drugs and we’ve seen on GRACE before that pemetrexed is a particularly effective drug for patients with non-squamous histology, which mostly means adenocarcinoma, where it’s less effective in patients with squamous histology. We’ve also seen that it tends to be one of our better tolerated chemotherapy drugs, and these results held in this definitive trial both for younger patients and for older patients. While I don’t tend to use cisplatin in older patients (we’ll get to that) I do think that pemetrexed is a particularly geriatric-friendly drug for patients with non-squamous histology.


ECOG 4599, another trial we’ve covered multiple times over the years looked at the standard platinum doublet carboplatin and paclitaxel, with or without the addition of the VEGF inhibitor bevacizumab, otherwise known as Avastin.


We know that trial showed a small but real survival advantage in unselected patients, but why I show it to you today is that treatment advantage really seems to slim down when we look at older patients. So in my practice I don’t tend to use bevacizumab except for my really, really most fit older patients.

All the rage these days, of course, in thoracic oncology are the immunotherapeutic agents. These drugs as a theme are more effective in the second line than chemotherapy and less toxic — these make them good geriatric drugs so bear with me a moment.


Here’s the data on nivolumab in squamous cell carcinoma, second line of therapy, compared to my second least favorite geriatric drug docetaxel. We can see here a dramatic improvement in survival, and perhaps equally important, a better tail to the curve — more patients living a very long time on the nivolumab.


A similar effect shown here in non-squamous histology, and as far as to why this is making its way to a talk about geriatric oncology, here’s the toxicity.


It’s very rare in looking at thoracic oncology trials to ever have this favorable of a rate of grade 3-4 or high-grade toxicity, even for placebo. So these drugs are more effective and less toxic — these are very geriatric-friendly drugs.

Bringing it back to chemotherapy, which is what unfortunately still the majority of patients get — I think it’s worth taking a minute to talk about which of these drugs are particularly geriatric-friendly and which perhaps should be avoided for most older patients.


So cisplatin is my least favorite drug for older patients. Why? It’s our most nausea- and vomiting-inducing drug, perhaps of any we use in oncology. It has a high rate of harming hearing and there is already age-related hearing decline, it’s one of our worst drugs on the kidneys and kidney function does tend to naturally decline with age. There are plenty of other reasons to hate cisplatin as well, making it my least favorite geriatric drug.

In contrast, its little brother carboplatin I regard as a much more geriatric-friendly drug. It has much, much less for side effects, particularly on the kidneys and for patients who already have a little bit of age-related kidney decline, the dosing formula for carboplatin, it’s called the AUC formula, inherently accounts for this, so you just don’t have to worry about it — you get the right exposure to the drug sort of automatically even if there is some preexisting decline in kidney function.

Paclitaxel I would call a middle-of-the-road geriatric drug, particularly I would call it more favorable when used on a weekly schedule. Docetaxel, as I mentioned, is my second least favorite geriatric drug — there’s a lot of count suppression, a lot of fatigue. When I do use it for older patients, I tend to reduce the dose some from the standard dose. We’ve discussed nab-paclitaxel, otherwise known as Abraxane, because of the subgroup survival data suggesting it may be more effective in older patients. Pending the confirmatory ongoing studies, I think that this is a very geriatric-friendly drug. Gemcitabine I would call on the better side of geriatric drugs, it’s mostly excreted by the kidneys so you need to pay attention if there is kidney decline, but it’s a pretty geriatric-friendly drug — an effective drug with lower side effects. Pemetrexed or Alimta we’ve already talked about as a particularly geriatric-friendly drug, I would comment though that this drug is excreted mostly by the kidneys, and so if kidney function is not ideal, it’s a drug that needs to be used with extreme caution or perhaps not at all.

I thank you for your kind attention.


Will HER2 Inhibitor Drugs Help Lung Cancer Patients?


HER2 inhibitors have been successfully used to combat breast cancer, but research has shown that a small percentage of lung cancer patients have a HER2 mutation as well. Dr. Leena Gandhi talks about the role that HER2 drugs may play to fight lung cancer.

Dr West

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


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?



Ask Us, Q&A
Lung/Thoracic Cancer Expert Content



GRACE Cancer Video Library - Lung Cancer Videos




2015 Acquired Resistance in Lung Cancer Patient Forum Videos


Join the GRACE Faculty

Breast Cancer Blog
Pancreatic Cancer Blog
Kidney Cancer Blog
Bladder Cancer Blog
Head/Neck Cancer Blog

Subscribe to the GRACEcast Podcast on iTunes


Email Newsletter icon, E-mail Newsletter icon, Email List icon, E-mail List icon

Subscribe to
   (Free Newsletter)

Other Resources


Biomedical Learning Institute