At ASCO this year … “one that got away”

An abstract that we missed at the ASCO meeting this year came to our attention when we read this article by Dr. Jeffrey Kirshner: “Ten practice changes I will make after attending ASCO 2017“.

Dr. Kirshner’s article referred us to a late-breaking abstract (abstract no. LBA2501) presented at ASCO by Hyman et al. At first glance this paper appears to have little to do with prostate cancer. In fact, however, it may well do.

The paper addresses the effectiveness and safety of a new type of drug known as a selective small-molecule pan-tropomycin receptor kinase (TRK) inhibitor in the treatment of cancers expressing TRK gene fusions. And even though there were no prostate cancer patients in this 55-patient clinical trial, we know that there are three types of TRK gene fusion that can be identified in patients with prostate cancer (affecting 50 to 70 percent of all prostate cancer patients):

  • The commonest of these fusions joins the TMPRSS2 gene with genes encoding the three ETS transcription factors: the ERG, ETV1, and ETV4, genes; this can lead to the over-expression of these oncogenic transcription factors in an androgen-regulated manner.
  • Fusions containing another androgen-regulated promoter for the SLC45A3 gene have also been reported to be fused to the same three ETS family members and behave in a similar fashion to TMPRSS2, although this fusion occurs less commonly.
  • And a fusion of SLC45A3 to the fibroblast growth factor receptor 2 (FGFR2) gene, which encodes a receptor tyrosine kinase implicated in various cancers, prostate cancer included.

Data reported by Hyman et al. show that the new drug (called larotrectinib or LOXO-101) showed that:

  • An overall response rate (ORR) of 78 percent was observed among 46/55 patients evaluated to date.
  • Responses occurred in adult and pediatric patients with 12 unique tumor types.
  • Responses are ongoing in 29/33 patients (88 percent).
  • The average (median) duration of response (DOR) has not yet been reached.
  • The majority of responders remain on treatment without progression.
  • The longest responder remains on treatment at 23 months.
  • 8 patients remain in response at > 12 months.
  • 16 patients remain in response at >6 months.
  • The most common treatment-related adverse events reported are:
    • Fatigue (in 30 percent of patients)
    • Dizziness (in 28 percent of patients)
    • Nausea (in 28 percent of patients).

The authors conclude that:

Larotrectinib has demonstrated consistent and durable antitumor activity in TRK fusion cancers, across a wide range of ages and tumor types, and was well-tolerated. Larotrectinib could be the first targeted therapy developed in a tissue type-agnostic manner, and the first developed simultaneously in adults and pediatric [patients]

The “New” Prostate Cancer InfoLink suspects that this new drug may become the second new agent to be approved by the FDA based exclusively on its mechanism of action (with no reference to the organ in which the cancer initially developed). However, we would like to see some data showing effectiveness in at least a few prostate cancer patients before we get too excited. If this drug is not going to be effective in the treatment of prostate cancer because it doesn’t work on the prostate cancer TRK gene fusions, we’d like to know that too. [See additional comment below.]

The full set of slides used by Hyman et al. in their presentation at ASCO is available on line. A media release issued by the drug’s developer is also available on line.

We understand that the drug’s developer (Loxo Oncology) believes it may be able to submit a New Drug Application to the US Food & Drug Administration and other regulatory authorities before the end of 2017.

5 Responses

  1. According to some opinions I have seen, this drug will also likely spark some controversy around cost. Not the cost of the drug, but the cost of testing to find those who the drug is likely to help. Apparently, a relatively small percentage of people would be helped by the drug, so testing everyone to find, say 1 in 100, would be considered expensive. If you are excited about personalized medicine (as I am), this drug is a wonderful breakthrough. But it does bring up the question of how we do personalized medicine in a cost-effective manner. (There were a couple of good articles over on STATNews about this, but they have moved the articles to Stat+ which is behind a paywall.).

  2. Dear Doug:

    This is one of the inevitable problems that come with personalized medicine. The rich may be able to afford all the cool tools needed to implement it. Many of the rest of us may find it to be out of reach. I would also expect that the cost of the drug itself will be massively higher than the cost of the test.

    I have no more idea about how we deal with this as a society than (apparently) anyone else does. What I do know is that we can’t all afford to eat caviar whenever we feel like it either.

  3. I found an article not behind a paywall that discusses the issue a bit:

    This article includes an estimate of TRK involvement in a cancer to be about 0.5 to 1 percent, which would mean testing between 100 to 200 cancer patients to find one that the medicine could help. It also mentions that at the major cancer centers, a complete genetic workup is considered standard of care. (I was surprised by that.) Not sure if they mean genetic workup of both the patient (germline) and the tumor tissue.

    We are witnessing amazing advances in biological understanding!

  4. I’m afraid there’s no choice; society has to attach an economic value to a life and (ideally) pay no more than the economic return expected on treatment. There is no room for emotion because of course the value to many/most of us of continued life of ourselves or a loved one is infinite.

    I live in a country where, albeit very imperfectly, at least an attempt is made in that direction. Being “rich” in some ways makes matters worse; it can actually be useful to have someone say “enough” and I have many anecdotes to share of where that has not happened. Of course there are anecdotes of expensive or unorthodox miracle cures but there are more anecdotes of outrageous snake-oil frauds.

  5. I am pleased to be able to confirm that Loxo Oncology believes that LOXO-101 can reasonably be expected to be as effective in the treatment of NTRK fusion driven forms of prostate cancer as it appears to be in other cancer subsets.

    However, they have also confirmed for me that no prostate cancer patient with an NTRK fusion driven form of the disease has been treated with LOXO-101 to date, primarily because such a small percentage of prostate cancer patients have been subject to genomic profiling studies that would permit recognition of the relevant NTRK fusions.

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