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New Approval for Zykadia (LDK378/ceritinib) in ALK-Positive NSCLC: Why It Matters Even if You’re Not ALK-Positive

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Yesterday, the FDA approved the oral second generation ALK inhibitor LDK378, also known as ceritinib and newly christened Zykadia, for ALK-positive NSCLC who have progressed on or are intolerant of XALKORI (crizotinib). It is a treatment option that represents a major step for the 4-5% of NSCLC patients in the US who test positive for an ALK rearrangement, to be sure, but there are several implications for people outside of this narrow population as well.

The approval is based on the extremely favorable results with Zykadia in a phase I trial published in the New England Journal of Medicine earlier this year by Dr. Alice Shaw and colleagues, in which a total of 130 patients were treated with the agent, which is 20-fold more potent in inhibiting ALK than XALKORI. An initial 59 were part of the dose escalation phase, which ended when the dose of 750 mg was selected as the maximum tolerated dose. Beyond that point, an additional 71 patients were enrolled in an expansion phase and received the dose now approved as a starting dose.  The objective response rate was 58% for the 114 patients who received a dose of at least 400 mg daily: encouragingly, this was nearly identical in the 80 patients who had received and become refractory to XALKORI vs. the 34 patients among the 114 who were XALKORI-naïve (56% vs. 62%, respectively).  Below you can see a “waterfall plot” in which each patient’s response is represented by a downward line  on the right (for tumor shrinkage) or upward line (on the left), with the length of the lines proportional to the degree of change; the “waterfall” transition being so far toward the left illustrates that most patients are experiencing tumor shrinkage, and you can see from the long lines on the right that many are experiencing a lot of shrinkage.  The bottom portion of the figure shows a “before vs. after” PET scan, with most of the disease now no longer visible.

Slide1 

Notably, most of the patients who didn’t achieve a response that qualified as a significant one still had some tumor shrinkage or disease stability, so the “disease control rate” was approximately 80%.  The median duration of response was approximately 7 months, though there are several patients who remain without progression for a few years and ongoing.

An additional important benefit of this agent, as well as several other second generation ALK inhibitors such as alectinib and AP26113, is that patients with brain metastases demonstrated responses.  While XALKORI does not penetrate into the central nervous system (CNS), which is a “sanctuary site” in which we often see new disease appear in patients on XALKORI, Zykadia may be far better at preventing new disease from appearing in the CNS and can potentially treat pre-existing disease there. 

Toxicity is a potential challenge, more so than with XALKORI, especially gastrointestinal issues. Nausea was noted in 82%, diarrhea in 75%, vomiting in 65%, fatigue in 47%, and liver function tests were noted to be abnormally elevated in 35%.  These issues were dose-related, and many of the researchers with the greatest experience with this agent have conveyed that the dose of 750 mg daily may be too high for many people, but that they have often had a more successful balance of efficacy and tolerability after reducing the dose to 600 mg or sometimes 450 mg per day (4 or 3 tablets, respectively).

Obviously, this is a significant treatment opportunity for the 4-5% of patients with an ALK rearrangement, whether they have progressed on XALKORI or not. For those who have progressed and don’t have good access to a trial with Zykadia or another promising agent, this approval now enables them to avail themselves of a treatment with responses seen in nearly 2/3 of patients and disease control in about 4 out of 5, and with responses that typically last for many months or sometimes a year or years.  It can also be an attractive option for others, such as my patient with a brain metastasis in his midbrain, a location where there is greater risk in doing a stereotactic radiosurgery approach (Gamma Knife) — perhaps Zykadia will provide a response within the brain after he has demonstrated progression of the lesion on XALKORI.  

Though some will probably be inclined to use it as a first line treatment for ALK-positive NSCLC, I think there are several practical and theoretical reasons not to do so. Practically speaking, if it costs $10,000 per month (I don’t know the cost yet, but I’m going to just make the leap that it will be painfully expensive), use will almost always be limited by whether an insurer covers it, and the approval is specifically for post-XALKORI treatment. Beyond that, we know that many patients do very well on XALKORI for a very long time, and this still leaves Zykadia as a great backup plan.  In contrast, by starting with Zykadia, even if it’s somwhat more longitudinally effective as initial treatment than for ZALKORI-refractory disease, you wouldn’t expect that XALKORI, 20 times less potent as an ALK inhibitor, will provide any benefit, so you’ll have no great backup plan. There also isn’t any real evidence yet that other second generation ALK inhibitors work after Zykadia.

The approval is significant in other ways as well. It’s the first approval and proven effective therapy for “acquired resistance” to a targeted therapy in lung cancer, the progression we see after an initial great response to an ALK or EGFR inhibitor in patients with the right driver mutation.  While it’s wonderful for patients with one of these mutations to respond well, the question of what to do when progression sets in remains a vexing issue. For the first time, we have a way to get the genie back into the bottle.  As new agents are being tested in acquired resistance for EGFR and ALK, we’ve broken the impasse and have shown that it’s possible to do good trials on narrow populations with an uncommon target and who have developed acquired resistance.  Patients will find their way to these studies, in droves.

It’s also important that the drug was approved relatively quickly by the FDA, just a few years after the first patient received the drug. Given the high response rate, the FDA didn’t require a randomized trial with hundreds of patients — it is now getting the drug into the hands of oncologists and patients in a very timely way, pretty much as soon as the safety and efficacy could be clearly established.  This bodes well for future targets that may be found in only 1-5% of the broader lung cancer population.  I suspect that pharmaceutical companies are reassured that it is worth developing agents for these patients.

Finally, it’s encouraging for the 1% of NSCLC patients with a ROS1 rearrangement, who have a very high probability of responding well to XALKORI but who don’t have many other target-specific options available, including in clinical trials.  We will likely see ROS1-positive patients trying Zykadia soon, if they can get it.

More to come. These are exciting times.

 


7 Responses to New Approval for Zykadia (LDK378/ceritinib) in ALK-Positive NSCLC: Why It Matters Even if You’re Not ALK-Positive

  • njliu says:

    Impressive! 3 questions:
    1. What does 20-fold more potent than Xalkori in a layman’s term?
    2. What are the potential “zykadia” equivalents for EGFR that are in the trial pipeline and the respective current status?
    3. With such extreme potency, does it mean the threat of complications from drug side effects could be more than the disease?
    Regards, NJ

  • neilb says:

    Any trial results involving ceritinib and ROS-1? Or trials in progress?–Neil

  • ssflxl says:

    I am glad to hear another effective second generation ALK agent, but there isn’t really an effective second generation EGFR agent (not counting Afatanib) when one become resistant to Tarceva/Iressa. Some of us are still waiting.

    ssflxl

  • Dr West
    Dr West says:

    NJ,

    20-fold more potent means that it takes 20-fold lower concentration of the drug to bind the same number of receptors in in vitro models.

    Here is a post about some recent agents for acquired resistance in EGFR mutation-positive NSCLC:

    http://cancergrace.org/lung/2014/03/09/new-agents-for-acquired-resistance-in-egfr-mutation-positive-patients-c01686-and-azd9291/

    There isn’t a clear association of higher affinity to the target and greater toxicity. It’s often the “off-target” effects that cause adverse reactions. However, here the “maximum tolerated dose” of Zykadia is pretty challenging but also potentially a good bit more than necessary. Other second generation ALK inhibitors don’t have as significant side effect profiles.

    Neil,

    I believe that AP26113 is being tested in ROS1-positive NSCLC, and I would imagine that others are going to try to pursue this, even if it isn’t a top priority yet.

    -Dr. West

  • Alissa says:

    My husband had some success on Xalkori for 14 months. Upon progression, he entered a trial for an ALK+ drug, ASP3026. He has major improvement. 14 months later, he is presenting with brain metatases (doubled in size over the last 8 weeks- all around 1 cm), a large tumor in the spinal cord at C-2/3, and a new lesion on the liver. He is expected to start Zykadia in the next few weeks. Is there any evidence that this may work, as a 3rd line ALK inhibitor? Also, what kind of evidence, if any, that it penetrates the Blood/Brain barrier?

    If this doesn’t work, the oncologist says we may consider one of the PDL-1 immunotherapy trials. The docs consider my husband a walking miracle. He is a 8.5 year, Stage 4 survivor, still working and living life. This will be his 10th line of therapy.

    Your thoughts?

  • Dr West
    Dr West says:

    Please see where I responded to your question on the discussion forum.

    Good luck.

    -Dr. West

  • rohan says:

    Hi Doctor West. First time forum user. I’m primary carer for my wife Lee. Just wanted to share her journey so far with you and would appreciate your input as to likely hood of recurrence, long term outlook. I know everyone is different but have been bombarded over the past 33 months. Lee’s story: 58 years old.
    08/11 DX with nsclc 2.7cm tumour in right lower lobe. T1N2M0 from petscans, mediastynoscopy, xrays, broncoscopy, developed pneumonia. LN positive from mediastynoscopyfor nsclc.
    09/11 chemotherapy cisplatin/navelbine 4 x cycles. 2 plueral taps done, more pneumonia, Plueral effusion DX malignant.
    10/11 CT scans show initial tumour reduced to 1.7cm
    11/11 unable to cope with cisplatin/navelbine combo and did not complete 2 and part of 4th cycle
    12/11 placed on Alimta for maintenance chemo every 3 weeks.
    09/12 Pets revealed NED after 14 cycles of Alimta
    10/12 Lobectomy conducted.microscopic nsclc throughout right lung and 2 lymph nodes. Pnuemonectomy thorocotomy conducted 2 weeks later confirmed 3 more lymph nodes pos for microscopic nsclc. Restaged as PT4N2Mx
    11/12 Radiotherapy of chest 5 days/week for 5 weeks plus 1 cycle of carboplatin unable to fully complete due to unknown infection.
    12/12 TOE done and suspected tumour on tricuspid valve or blood clot. Placed on dexmethasone and Clexane
    01/13 Scans of heart and TOE done showed no tumour
    03/13 Full body scans done NED
    10/13 Full body scans done NED
    11/13 Racing heart beat tests done placed on beta blockers daily
    05/13 Ultrasound of liver and full body scans done NED

    Lee struggles daily and gets very short of breath with simplest of tasks. Now suffers with depression, anxiety which seeking help with. What is her outlook please. Rohan

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