GRACE :: Lung Cancer
Dr West

Should Alecensa (Alectinib) be the new first line ALK inhibitor for ALK-positive NSCLC?

Probably the most immediate potentially practice-changing presentation from ASCO was the Japanese J-ALEX study in the subset of about 4-5% of patients with non-small cell lung cancer (NSCLC) who have the molecular driver known as an anaplastic lymphoma kinase (ALK) rearrangement, which we now routinely test for from the tumor tissue of patients with a non-squamous metastatic NSCLC.   The current historical standard of care as first line treatment is Xalkori (crizotinib), which is an ALK inhibitor that happened to be readily available when the ALK rearrangement was first being studied in NSCLC about 5-7 years ago. Though it was granted an accelerated FDA approval back in 2011 based on early very promising activity and has since been confirmed to be superior to chemotherapy as first line treatment in ALK-positive patients, it is a less active ALK inhibitor than many other “second-generation” ALK inhibitors such as Zykadia (ceritinib) and Alecensa (alectinib), both now FDA-approved for patients who have developed progression after Xalkori or who are not able to tolerate it, as well as other agents still in development, including brigatinib (likely to become approved soon), and a few others further behind in development but also very active against ALK-positive NSCLC.

A question that logically follows is whether it is better to give one of these more active second generation ALK inhibitors as first line therapy, where they are likely to be more active for longer than if given for “acquired resistance” after Xalkori, or whether it’s better to start with Xalkori and have other powerful ALK inhibitors left for later.  Should we use our best drug up front or only the most effective drug required to do the job for now, saving something in the tank as we think more about advanced lung cancer as a distance race than a sprint? How much do we prioritize control now vs. options later?

There are several trials that have been initiated that all test a second generation ALK inhibitor vs. Xalkori.  Two of the first to be completed compare Alecensa to Xalkori, a large, global trial known as ALEX, and a smaller trial done in Japan only, known as J-ALEX, which reported early and remarkably interesting results at ASCO 2016.

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Dr West

Keytruda (Pembrolizumab) Beats Chemo as First Line Therapy for Patients with High Tumor Expression of PD-L1: Where are We Now?

It seemed inevitable, I think.  Several immuntherapy agents known as PD-1 or PD-L1 checkpoint inhibitors have been shown to lead to better survival, higher response rates, and a better side effect profile than second line chemotherapy with Taxotere (docetaxel) in broad populations or subsets with tumors positive for the marker PD-L1 that correlates with a higher probability of a good response. At this point, both Opdivo (nivolumab) and Keytruda (pembrolizumab) are FDA approved second line treatments that are widely favored over Taxotere, though the approval for Opdivo doesn’t require PD-L1 testing or a specific level, while Keytruda’s approval is for only patients with PD-L1 expression (technically >50% expression, the high level seen in about 25-30% of NSCLC patients, though it also has (somewhat less) activity in patients with ANY degree of PD-L1 expression, which gets up to 70-75% of NSCLC patients).   And patients who progressed could cross over to receive Keytruda, so the trial didn’t just compare patients who got Keytruda first line to patients who never got a chance to benefit from an immunotherapy.

Of course, as the song goes, “how ya gonna keep ‘em down on the farm, after they’ve seen Paree?”. Once these clearly active agents got an inroad, the gravitational pull into first line treatment has been tremendous.  There are literally dozens of trials that have been done comparing immunotherapy to standard first line treatments — single checkpoint inhibitor vs. chemo, single checkpoint inhibitor + chemo vs. chemo alone, single checkpoint inhibitor vs. chemo vs. combination, combinations of a PD-1 or PD-L1 checkpoint inhibitor with a different immuotherapy agent such as a “CTLA-4″ inhibitor, and on and on. Multiple checkpoint inhibitors that are remarkably similar are each the subject of a similar and largely redundant group of trials, and in patients with an EGFR mutation these trials are being done against and in combination with EGFR inhibitors, in patients with an ALK rearrangement these trials are being done comparing to and in combination with ALK inhibitors, etc.  In the coming years, there will be an avalanche of trial results on them.

But today, we got the first press release on results, here with Keytruda compared to first line chemotherapy alone in the subset of patients with high PD-L1 expression (>50%), which is the ~30% of patients most likely to do especially well with immunotherapy.  Though we don’t have any numbers yet, we learned that the trial was positive for the primary endpoint of progression-free survival (PFS) as well as for the secondary endpoint of overall survival (OS). It enrolled 305 patients, randomized to either Keytruda at a fixed dose of 200 mg (a relatively low dose, compared with prior tested doses of 2 mg/kg or 10 mg/kg in other studies) IV every 3 weeks, compared with any of a range of platinum-based doublet combinations. Of note, the far more specific side effect data presented in the press release applies not to this particular trial but other data with the agent, and not at the dose tested, so I don’t think we can say much about the efficacy or side effects of this regimen in this patient population until we see the actual trial data presented.

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Dr West

Can “Local” Therapy in Metastatic Lung Cancer Alter the Path for Systemic Disease?

After completing my unpacking from ASCO and beginning to see a path of light as I dig out from under the backup of work that accumulated, I wanted to begin covering a few of the most relevant content from ASCO. Though covering only preliminary work, an abstract presented by radiation oncologist Daniel Gomez from MD Anderson Cancer Center was among those that I think could have sweeping implications. But for now, I think it’s also important to provide some context so that the results are not misinterpreted as practice changing yet.

We know that patients with good initial disease control from metastatic lung cancer are most likely to demonstrate progression at sites where they already have residual disease. This led to the question of whether there is a value of “local therapy” (surgery or radiation to treat a specific area of disease) in patients with limited residual disease after at least 4 cycles of initial chemotherapy or, for patients with an EGFR mutation or ALK rearrangement, at least 3 months of targeted therapy. Patients could not have had a malignant pleural effusion (cancer in fluid outside of the lung, which is a common complication in lung cancer) and had to have no more than 3 sites of visible disease on scans. After first line therapy, patients with this definition of limited residual disease were eligible for randomization to one of two arms:

1)      standard systemic therapy maintenance or surveillance, at the discretion of the treating physician, or

2)      local consolidation therapy with any combination of radiation, surgery, or other ablative therapy followed by standard systemic therapy maintenance or surveillance, at the discretion of the treating physician.

For those patients assigned to the consolidation therapy arm, the trial allowed for any of a multitude of sites to be treated with any combination of local interventions, potentially radiation to some sites along with resection of others, or even chemo/radiation.

Importantly, patients assigned to the standard arm without local therapy were permitted to cross over to receive local therapy after progression. The “primary endpoint” being evaluated was progression-free survival (PFS), the time between randomization and imaging revealing significant progression.

The study was conducted at three large cancer centers, but all but six of the treated patients were enrolled from MD Anderson.  Notably, they enrolled just 74 patients from these three centers over three years for starting first line systemic therapy, with 49 of them eligible for subsequent randomization. The trial was reported at ASCO after it was stopped early by MD Anderson’s Data Safety Monitoring Committee, which did an early analysis that revealed a significant improvement in PFS.

The difference was certainly impressive, with the median PFS (the time when half of the patients have shown progression, and the other half have not) of 11.9 months for the local consolidation therapy arm, compared with just 3.9 months in the arm assigned to standard systemic therapy maintenance therapy or surveillance.  Subset analyses showed that patients with just one residual area of disease did significantly better than those with 2 or 3 areas of disease. In addition, the 8 patients with an EGFR mutation or ALK rearrangement had a longer PFS than the patients without a driver mutation.

While these are very intriguing results, we must be very cautious in interpreting them. As noted above, the final randomized trial population was fewer than 50 patients, which is only a tiny fraction of the patients with metastatic NSCLC who had been seen and treated at these three participating centers over a three year period. This suggests that the patients studied here are not broadly representative of most patients and are far more likely to represent a very unusual group that has an unusually small amount of disease. With all but six of the patients coming from MD Anderson, we must view these results as being close to a single center trial, which is always a red flag for “selection bias” (good results are likely to come from the enrolled patients not representing the broader patient population but a very cherry-picked population that isn’t like most others).   

But the more important issue is the very problem of using PFS when the treatment itself undermines the ability to assess that endpoint because you’re resecting or radiating the disease that is most prone to progress. Once half of the patients have had their visible cancer resected or ablated, only the standard treatment arm without local therapy is now at risk for local progression. We wouldn’t be surprised to learn that prophylactic appendectomy significantly reduces the risk of subsequent appendicitis; we need to show that the intervention does more than just making the scans look better, just as if we had used Adobe Photoshop to erase the remaining lesions and just pretended they weren’t there.

Of course, seeing a survival benefit would be very powerful, but the results are not mature, with too many patients on both arms still alive, and the survival analysis compromised by the cross-over of patients on the standard systemic therapy arm to local therapy at the time of progression. But short of that, it would be helpful to see that local therapy changed a measure of the disease process beyond the areas directed treated with surgery or radiation. Toward that end, the investigators did an exploratory analysis that assessed the “time to new site failure” (TNSF) and found that the patients on the consolidation arm also had a significantly longer TNSF, 11.9 vs. 5.7 months (P<0.0497).

Time to New Site Failure Gomez

Though the trial enrolls far too small a population to say anything definitive and the choice of PFS as the primary endpoint was a major shortcoming, the finding of a significantly longer TNSF with local therapy provides a very important proof of principle if it holds up. Beyond the unsurprising finding that surgery and radiation can make scans look nicer for a while and lead patients and physicians to congratulate ourselves about that, the exploratory analysis of TNSF, which is not a definitive answer to the question, indicates that treating areas of “oligo-residual disease” (areas of disease when there are just one or a very few sites of visible disease after first line systemic therapy) may kill enough cancer to significantly postpone development of diffuse disease, potentially even improving overall survival in the process.

For now, it is critical to remember that this was a very small population of patients winnowed from a much larger one, highlighting that this concept doesn’t apply to patients with disease progression, more than 3 areas of residual disease, or a pleural effusion. Even within the tested population, the results showed that survival was far better for the subset of enrolled patients with just one residual spot. In other words, patients with more than even just one area of remaining disease may not have “oligo-metastatic” or “oligo-residual” disease (“oligo” meaning few), but actually conventional “poly-metastatic” disease (“poly” meaning many), for which systemic therapy may well be the only modality that offers a benefit.

This work deserves to be followed up by a large trial across North America, as is currently being developed, so that we can clarify if it is truly the case that local treatment can alter the disease trajectory of systemic disease and change outcome beyond just the appearance of the scan.  Importantly, however, if it is too broadly inclusive and allows patients with more than 1-2 areas of residual disease, it will have a far greater chance of undermining its ability to demonstrate a benefit because the benefit is much less likely to be real for all but a highly selected subgroup of patients with advanced NSCLC.


Dr West

Divergent Paths for Tagrisso (Osimertinib) and Rociletinib for EGFR Mutation-Positive NSCLC and Acquired Resistance: What Happened, and Where Are We Now?

 

For patients with an activating EGFR mutation and who develop “acquired resistance”, the pattern of progression that occurs after a sometimes long period of good initial response to an oral EGFR tyrosine kinase inhibitor (TKI) like Tarceva (erlotinib), Iressa (gefitinib), or Gilotrif (afatanib), the evolving story of the treatment options has been a wild ride with several ups and a few downs. Over the last two years, several “third generation EGFR TKIs” with a strong affinity for EGFR activating mutations and, importantly, a different mutation called T790M, which is seen in 50-60% of patients with EGFR mutation-positive acquired resistance, but very low affinity for “wild type” (normal, non-mutated) EGFR molecules (which mediate the common, problematic side effects with EGFR TKIs, such as rash and diarrhea).  Given the very different paths that the two leading entrants – Astrazeneca’s Tagrisso (osimertinib, also previously known as AZD9291 and transiently as merelitinib) and Clovis’s rociletinib (also known as CO-1686) – it’s high time to review what has happened to get to where we are now.

The annual ASCO meeting in 2014 included very prominent presentations about these agents (Tagrisso and rociletinib, respectively), at that point still in early trials with several dozen patients each, that showed both agents had marked activity against the subset of patients with acquired resistance whose tumors test positive for T790M. At that time, AZD9291, which ultimately became osimertinib and then branded as Tagrisso, was a half-step ahead in terms of a slightly larger number of patients tested, but both agents were very promising for a population in which alternative treatment options other than standard chemotherapy. Though some concerns were raised about hyperglycemia (high blood sugar levels) in patients on CO-1686, my view at the time was that in people facing the threat of an advanced cancer, taking pills or even possibly insulin to manage blood sugar levels wasn’t likely to be a major issue if it worked effectively. Like many other lung cancer specialists and general oncologists alike, my perspective was that access to either agent would be a welcome opportunity for patients eligible for an accessible clinical trial. 

These two agents have been widely studied in a range of global trials as they continued their footrace over the next 12-18 months. In August, 2015, the remarkably early results with these two agents was featured in back to back articles (on Tagrisso and rociletinib, respectively in the prestigious New England Journal of Medicine.

But since that time, the paths of those two agents have diverged remarkably.  Tagrisso became FDA-approved in November, 2015 after continuing to demonstrate a response rate of significant tumor shrinkage in about 55-60% of T790M-positive recipients and up to 90% experiencing “disease control” that includes less significant shrinkage and stable disease. Importantly, these responses tend to last for many months to a year or longer, and this longitudinal treatment has been associated with a very low risk of significant side effects, with most patients experiencing either no issues or a rash and diarrhea that is so minimal that, in my experience, they haven’t felt warrants a hint of complaint.  The value of offering Tagrisso for T790M-positive acquired resistance has really changed the standard of care for EGFR mutation-positive patients with progression, making it instantly critical to seek and hope to find a T790M mutation, with a valuable subsequent treatment option to pursue before moving on to other options routinely offered for advanced NSCLC.

The path of rociletinib has been very dramatic over the past 6-7 months, but unfortunately it has been in a downward trajectory. Though provocative work over the past year has shown that this agent could work well in patients with T790M detected even in plasma, perhaps obviating the need for repeat tissue biopsies, the side effect profile with further use made it arguably a less attractive option than Tagrisso.  In my own experience, the constellation of nausea, diminished appetite, and diarrhea could create a cascade of weakness and misery that required aggressive dose reductions in a significant minority of patients and an occasional patient expressing dramatically “if this is what I need to do to have my cancer respond, I’d rather die” (though other patients certainly tolerate it better). But the biggest hit came in November, 2015, when the FDA reported that it was planning to delay a decision on potential approval of rociletinib after updated information revealed that the response rate reported to rociletinib of 59% was actually an “unconfirmed” response rate that dropped to about half that rate when looking only at confirmed responses (though the latest published update pegs response rate at 45%). The fortunes for rociletinib, along with Clovis’s stock price, dropped like a rock.

Tailspin

 Since then, clinical trials with rociletinib have continued on, and the FDA has continued its review process for the drug. The Oncology Drug Advisory Committee (ODAC) to the FDA, eviewing the evidence in April, came back with a 12-1 vote against approval until results from a randomized trial of rociletinib vs. chemotherapy be completed and demonstrate a clear benefit for rociletinib.  Then, in early May, Clovis announced very suddenly that the FDA, which almost always followed ODAC’s thoughtful recommendations, had notified the company that the FDA would not be offering an approval until further data supported its use. In that same press release, Clovis announced that it was terminating all trials with rociletinib (and was laying off 35% of its employees).

One important issue that the potential approval of rociletinib raised was the question of whether it should be compared to osimertinib or not. Technically, rociletinib didn’t need to be better than its predecessor to the market in the same space, but it is hard to determine what value there is in offering an agent with seemingly less activity and worse side effects than an agent we already have available. This issue of a strong incumbent will be a critical factor for other would-be challengers, further behind in development, which enter a world with Tagrisso as an entrenched, effective therapy in this setting, so how might other agents fit in?

A key relevant question here is how similar or dissimilar these agents truly are. One might well assume that there is a great deal of “cross-resistance” to drugs in the same family, as we see minimal activity of one first or second generation EGFR TKI after another (such as trying Tarceva after Iressa, or Gilotrif after Tarceva), just as you wouldn’t expect to have many people wildly excited about having a Pepsi after drinking a two liter bottle of Coke. But in fact, Dr. Lecia Sequist and colleagues from Massachusetts General Hospital recently reported that they have seen several cases of tumor shrinkage or prolonged stable disease on Tagrisso – including in the brain as well as other parts of the body — in patients who had demonstrated clear progression on rociletinib previously. As someone who had patients progressing on rociletinib in clinical trials, I followed this lead and have treated several of my patients with Tagrisso and also seen several very encouraging responses after progression on rociletinib. This is an important finding for patients in this setting who may benefit.

These advances are very significant, but we must still acknowledge the work that still needs to be done. Third generation EGFR TKIs may prove to offer meaningful benefits to the 40-50% of patients with T790M-negative acquired resistance, or we may need to search for better options elsewhere. It will also represent a great breakthrough if we can do repeat biopsies to check for T790M or other mutations in circulating plasma of patients rather than be required to pursue invasive biopsies at several time points over the course of treatment.  Though we probably can’t predict future developments much better than we might have predicted the drama in this space over the past two years, I can predict that it will be eventful and that we will only have a better understanding of and treatments for EGFR mutation-positive NSCLC in the future.

What do you think of these developments?


GRACE Video

Immunotherapy Combinations

GRACEcast-526_Lung_West_Immunotherapy_Combinations

 

Dr. Jack West, Swedish Cancer Institute, discusses current trials seeking to determine the efficacy of combining immunotherapy agents in lung cancer.

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The class of agents known as immune checkpoint inhibitors have really invigorated our study of lung cancer, and many other cancers over the last few years. Agents like Opdivo, also known as nivolumab, and Keytruda, known as pembrolizumab, are now commercially available, FDA approved as a second line therapy for patients who have progressed on first line standard chemotherapy. We are now actively asking the question of whether we might be able to move these immunotherapies into the first line setting and also asking whether we might do well by giving a combination of immune therapies, rather then just one treatment at a time.

So these agents, immune checkpoint inhibitors, are largely categorized into PD-1 or PD-L1 inhibitors, and those are just targeting two separate sides of an interaction between two receptors. The PD-L1 is on the tumor cells, PD-1 is on the immune T cells, and so blocking either side of this can lead to a beneficial effect because this effect leads to a braking mechanism on the immune system — you take away that braking system and you turn off the brakes and lead things to move forward, and that’s what we often see.

There are other agents that can also lead to braking mechanisms and that have been studied in other cancers. An agent such as Yervoy, which is known as ipilimumab is a CTLA-4 inhibitor and this is an agent that’s been approved in melanoma. In fact, the combination of Opdivo (nivolumab) and Yervoy (ipilimumab), as two different ways of blocking the immune system, have been shown to be beneficial as a combination in melanoma compared with either one on its own. Because of that, we’re looking at combinations of immunotherapies compared with single immunotherapy approaches, or standard chemotherapies.

One interesting study being done right now is called CheckMate 227 and it is looking at first line treatment of patients with advanced lung cancer that is either squamous or non-squamous histology. It does not require any level of PD-L1 expression on the tumors, the protein associated with tendency toward better efficacy of immunotherapies, partly with the thought that the combination of two immunotherapies may make even the cancers that don’t express PD-L1 respond well. This trial is looking at first line therapy with either standard chemotherapy of cisplatin or carboplatin with Alimta for non-squamous cancers, or Gemzar (gemcitabine) for squamous cancers, compared with either Opdivo alone or a combination of Opdivo and Yervoy — Opdivo being a PD-1 inhibitor, Yervoy being a CTLA-4 inhibitor — and asking the question of whether immunotherapy is as good, better, or worse than standard chemotherapy as a first line treatment, and whether the combination of two immunotherapies is better than first line therapy. 

I should mention that there are other trials looking at very similar versions of this question using different combinations of immunotherapies. There are many companies looking at several different immunotherapies in development and they are overall really very comparable and all quite exciting.

You can learn more about this specific trial from the link on the screen,

CheckMate 227 Clinical Trial

but I would encourage you, if you talk to your doctor and they recommend a trial with an immunotherapy in the first line setting, potentially comparing it to chemotherapy, to carefully consider it — it does not have to be this specific trial to be of interest.

We’re going to learn more about this in the coming years and we’re going to figure out the best way to integrate immunotherapies with our standard treatment approaches today.


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