Dr. Jack West

Reviewing the Personalized Therapies in Lung Cancer Conference: Part 1

March 20th, 2014 - by Dr. Jack West

Over the last couple of years, I’ve attended and spoken at a lung cancer conference that I find to be particularly gratifying. Each fall, the Annual Personalized Therapies in Lung Cancer conference is held at a location in southern California. I wanted to provide a summary of what was covered at the last one, back in November, since it covered a broad range of the topics I think are most interesting here, using an interactive, case-based format integrated into the presentations.

The first session focused on existing targets, specifically the HER/EGFR family and ALK, though the discussions were more forward-looking than reviews of information we already know. Dr. Paul Bunn, former ASCO President and President and then Executive Director of the International Association of the Study of Lung Cancer, started the day with a summary of “game changers” in lung cancer in 2013, a whirlwind tour of the emerging landscape of acquired resistance and discussion of rare variants of mutations. Dr. Phil Mack from the University of California at Davis then described the shifting world of lower costs and wider availability of whole genome sequencing for lung cancer, though he noted that this is still creating a haystack of data in which we’re still looking for needles. Of course, this field will be changing rapidly, and we should expect our practices to follow as the price and turnaround time decrease as the number of clinically useful targets increases.

Dr. Ron Natale from Cedars-Sinai in Los Angeles provided a great summary of the data comparing first and second generation oral EGFR inhibitors.  Specifically, he covered the very consistent evidence that Iressa (gefitinib), Tarceva (erlotinib) and Gilotrif (afatinib) all handily demonstrate overwhelmingly greater activity than standard chemo as first line therapy for patients with an activating EGFR mutation, but we don’t have any direct comparisons of these agents to say that one is clearly superior to another. With regard to less common mutations, those not on exons 19 or 21, work with Gilotrif demonstrated that it isn’t particularly effective outside of those classic, activating mutations.  And looking at the efficacy and side effect profiles of Gilotrif and Tarceva in different trials side by side, it appears that they are very similarly active, with greater diarrhea and probably rash and mouth sores with Gilotrif.

Dr. Fred Hirsch from the University of Colorado then looked at the potential role of IV antibodies to EGFR, such as Erbitux (cetuximab), in advanced NSCLC. He recapped the questions around the FLEX trial, marginally positive for a survival benefit, but with so little absolute difference between the arms that Erbitux hasn’t really entered into routine use. He noted that a related antibody, necitumumab, was actually positive for a survival benefit in the SQUIRE trial, as related in a press release, though we haven’t seen the actual results yet and don’t know if it will become a new, routinely used agent or another near miss like Erbitux.

Dr. Karen Kelly from the University of California at Davis then covered irreversible EGFR inhibitors like afatinib and highlighted the unknowns about whether it is an improvement beyond the reversible EGFR TKIs Iressa and Tarceva.  She reviewed the encouraging phase II research work with dacomitinib (which has just been reported to demonstrate no improvement in efficacy compared with Tarceva in EGFR TKI-naïve patients, and no improvement compared with placebo in EGFR TKI-treated patients with acquired resistance), as well as offering her commentary on Gilotrif – noting that we really won’t know whether it is superior to other options until the outcome of a couple of randomized phase III trials being conducted now are completed – one against Tarceva, and another against Iressa.

Turning to ALK, Dr. Alice Shaw from Massachusetts General Hospital then reviewed established data with XALKORI (crizotinib) and then cataloged exciting new work with second generation ALK inhibitors LDK-378 (now ceritinib, from Novartis), alectinib (from Chugai/Roche), and AP26113 (from Ariad) – all with significant activity in XALKORI-resistant patients, and all with activity against brain metastases, unlike XALKORI. She also noted that several heat shock protein inhibitors (HSP90) have also demonstrated activity in ALK-positive patients and are now beginning to be studied in this setting as well.

I closed the session with a discussion of approaches for acquired resistance for EGFR mutation-positive patients. Starting with the concept that limited progression is appropriate to consider for local treatment like surgery or radiation, and slow, multifocal progression may also not require any change in treatment, I then spoke about options in patients who have more significant progression that warrants a change in systemic therapy. I spoke about the potential value of continuing the same targeted therapy with concurrent chemotherapy, vs. discontinuing it when switching to chemotherapy. I also touched on the early work with CO-1646 from Clovis, AZ9791 from Astrazeneca, the combination of Gilotrif and Erbitux, and the HSP90 inhibitor AUY922.

The next session covered more general topics, personalizing therapy outside of molecularly targeted therapies.  GRACE’s own Dr. Jared Weiss from the University of North Carolina, Chapel Hill discussed the growing collection of data supporting use of doublet chemotherapy for elderly patients and those with a marginal performance status.  He also summarized the work with Abraxane (nab-paclitaxel) that revealed a very promising efficacy in patients over 70, and which is leading to a subsequent study specifically in the elderly.

The morning ended with a presentation by Dr. Daniel Morgensztern, from Yale, who reviewed the full range of evidence and options in maintenance therapy.  This summary highlighted that there is no single approach of choice, but a choice of approaches.

All of that was just what we did before lunch! I’ll summarize the afternoon’s presentations in part II.

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Dr. Jack West

New Agents for Acquired Resistance in EGFR Mutation-Positive Patients: C01686 and AZD9291

March 10th, 2014 - by Dr. Jack West

Since the introduction of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for patients with lung cancer, we have seen a subset of patients do remarkably well, with dramatic and long lasting responses. Unfortunately, within a few months of those impressive responses, we learned that people invariably develop acquired resistance to these agents.  Over the past period of more than a decade, lab-based scientists, oncologists, and of course patients have been eagerly seeking treatments that can lead to promising responses again in patients who have developed acquired resistance.  A couple of new agents show promise that we haven’t seen before in this setting, and they are now the subject of emerging clinical trials that show the promise of breaking an impasse that has existed for more than a decade.

The first of the two I’d like to highlight is CO1686, from Clovis. This “third generation” oral irreversible EGFR inhibitor effectively blocks not only activating mutations but the most common mechanism of resistance, the T790M mutation that is detected in about 60% of tumors that demonstrate acquired resistance after a response. It also has the potential advantage of not inhibiting “wild-type” (non-mutated) EGFR at the typical doses used, which means that it doesn’t cause the same severity of rash and diarrhea that the EGFR inhibitors we’ve had available thus far produce.

Though CO1686 is still early in testing, Dr. Jean-Charles Soria recently said that 6 of 9 patients with a  T790M mutation-positive cancer demonstrated a significant response at the newly established phase II dose of 900 mg by mouth twice daily, and with no rash.  Though still obviously still in early stages of development, the early promise of two-thirds of the patients in the target group responding is leading to multiple new trials, including

  • A phase II/III study comparing CO1686 head to head against Tarceva (erlotinib) in newly diagnosed patients with advanced non-small cell lung cancer (NSCLC) that is EGFR mutation-positive
  • A phase II trial of Co-1686 in T790M-positive patients after progression on one prior EGFR TKI
  • Another phase II trial of T790M-positive patients after progression on >1 EGFR TKI or chemotherapy
  • A phase II trial of 2nd line or later CO1686 for patients who have a T790M mutation detected by a serum assay; and
  • A phase III randomized trial vs. chemotherapy in second line or later.

Clearly, this reflects a major investment and a lot of optimism in this agent.

A second agent that has shown similar promise is AZD9291, another third generation EGFR inhibitor with essentially the same mechanism of action.  Dr. Malcolm Ranson and colleagues reported on results from an 89 patient trial of patients with an activating EGFR mutation and acquired resistance, though this study allowed patients with either a T790M mutation or not.   The study included testing of the drug at a wide range of doses, from 20-240 mg/day, with no dose reductions required, and almost exclusively mild (grade 1 of 4) rash and diarrhea seen.  What was especially encouraging was that 15 of 35 evaluable patients had a response, including 9 of 18 with a T790M mutation. The follow-up plans for this agent are still being defined, but there is a lot of excitement about this agent as well.

Though we’re talking only about a few dozen patients and still learning about these agents, I’ve never been as optimistic about breaking through the impasse of acquired resistance in EGFR mutation-positive patients.  I hope to share more information about these agents and perhaps others very soon.

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Dr. Jack West

What about treating patients who have medical problems? Treating lung cancer in patients with kidney issues or neuropathy

March 4th, 2014 - by Dr. Jack West

One of the challenges of cancer care is that we guide our treatments by what clinical trial evidence tells us is best for particular patient populations. However, trials exclude patients who have significant medical issues other than cancer. So what do you do for patients who have lung cancer but also have common medical problems like compromised kidney function or pre-existing numbness and tingling (neuropathy) from diabetes or vascular disease?  A purist in evidence-based medicine would say that patients who don’t have good kidney function or who have other medical problems that would exclude them from the trials of our standard treatments can’t get treated, but fortunately most oncologists are more flexible than that. What’s the right way to proceed? The answer is that it falls to best medical judgment. But can we be more specific than that?

In the setting of renal insufficiency, which is common as patients get older, as well as being a result of years of high blood pressure or diabetes, we need to substitute out the treatments that are most threatening to kidney function worsening. Specifically, this means avoiding the particularly kidney-threatening cisplatin, considering avoiding carboplatin (or perhaps giving it and carefully monitoring kidney function and dropping if it kidney function worsens, and then substituting non-kidney damaging agents instead). If kidney function is only minimally impaired, it may be very acceptable to give carboplatin plus a taxane: Taxol (paclitaxel), Abraxane (nab-paclitaxel), or Taxotere (docetaxel)), Gemzar (gemcitabine), Navelbine (vinorelbine), or Alimta (pemetrexed). An alternative, and the leading one if kidney function is quite compromised or gets worse on carboplatin-based chemo, is to give a nonplatinum doublet, which basically means pairing two drugs for lung cancer that are more commonly partners for cisplatin or carboplatin. Common nonplatinum doublets include Gemzar/Navelbine or Gemzar with one of the taxanes.  About 15 years ago, there was a significant hope that these agents might turn out to be an improvement from platinum-based doublets, with comparable or slightly superior efficacy and improved tolerability. That didn’t turn out to be the case: the nonplatinum doublets were typically of the same or very slightly lower efficacy, and the same or slightly better tolerability. Overall, they were a lateral move and never took hold as a leading choice, but they are certainly a fine choice and arguably the ideal one for people with limited kidney function.

Then there’s the case of patients with peripheral neuropathy. The taxanes and especially Taxol are the worst offenders here, as is cisplatin, and Navelbine can also worsen neuropathy. Here, we commonly favor carboplatin with a less neuropathy-inducing partner drug, so Gemzar is often a leading choice, or Alimta for a non-squamous lung cancer.

It’s also reasonable to consider single agent chemotherapy, though several recent trials have shown that carboplatin doublet chemotherapy is associated with better outcomes as first line treatment than single agent chemo, even in patients with a marginal performance status.  But it’s certainly reasonable to consider single agent chemo in individual patients with significant organ compromise, or simply in patients who are particularly wary about significant side effects.

Though there are certainly other problems that merit individual treatment recommendations, these are among the most common ones. In the end, it still comes down to individualized judgments and considerations of the circumstances of the particular patient.

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Dr. Jack West

The Importance of the OLIGO in Oligometastatic or Oligoprogression

February 24th, 2014 - by Dr. Jack West

There is a principle in management of lung cancer that some patients who have a very limited degree of metastatic disease or progression after a good response may do unusually well with local treatment, such as radiation or surgery, for the isolated area(s) of disease that are metastatic or growing. The idea for this stems from the concept of the “precocious metastasis”, which is essentially the idea of “the one that got away” — perhaps if there is just a very limited metastatic deposit of cancer or one area progressing and everything else is well contained, that area of escape can be obliterated without other areas of escape popping up elsewhere.

In the last few years, approaches like video assisted surgeries with wedge resections and focal radiation (stereotactic body radiation therapy, or SBRT) are now also making it more feasible to do additional local treatments with fewer side effects than in the past. This has led to a huge trend toward more and more surgeries or radiation treatments to areas of metastatic disease.  The question is whether this is really beneficial or whether it’s done largely because it’s easy to mislead patients and even ourselves as doctors that more is better, especially when it’s a profitable thing to do and someone else is paying for it. But I fear that these principles are being applied far beyond where they make good sense.

The term “oligometastatic” comes from the Greek root “oligo”, meaning few, along with metastases, and that fits when there is just one area of metastatic spread, or perhaps two. The problem is when local treatments are applied for 3 or 4 or more areas of disease. An isolated area of metastatic spread or progression may well represent a rogue area with its own biology, and there is an arguable reason to hope that we can resect or ablate that area and not have other areas of disease crop up. On the other hand, 5 areas of metastatic disease isn’t oligometastatic disease — it’s frankly metastatic disease, and it is unfathomably unlikely that the underlying cancer process can be controlled by just treating the areas you can see today. It would be like picking off a bunch of dandelions from the stems in your lawn and presuming your job is done. If you see 5 dandelions, you can be sure that eradicating those 5 won’t end the problem, and that plenty more will follow. Unfortunately, whether it’s a poor understanding of biology or an economic motivation to treat people in situations where it’s not oligometastatic at all, far too many practitioners of local therapies are all too eager to encourage patients to pursue treatments that cannot be reasonably expected to be helpful.

Another principle is that it makes more sense to pursue a local therapy if you’ve had a long period of follow-up to be sure that your isolated area of disease isn’t just isolated for a brief moment in time. Following a single lesion growing or remaining isolated for many months is far more convincing for it being truly “oligo” than having a single lesion on the first scan done after a new treatment was initiated, which may well be just a snapshot of a moment in time before more areas of disease emerge.

To reiterate, I do believe that local therapy for an area of isolated metastatic spread or progression in the face of otherwise very good control makes sense, even though there isn’t a clearly proven value to treating metastatic disease with local therapy. But that approach is predicated on the word “isolated” and the concept of oligometastatic disease.  There’s a real problem in following a slippery slope of treating multiple areas of metastatic disease with local therapy just because we can and it’s profitable.  Even a small risk of complications is unacceptable when there is no foreseeable benefit to treating multiple areas of truly metastatic disease.  In the coming years, we will need to come to terms with the fact that this approach isn’t actually helping patients, and we’ll need to apply the term oligometastatic more appropriately if we have any hope of showing that this approach of local therapy actually helps selected patients. We’ll have to actually apply this approach selectively.

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Dr. Jack West

Preview of IASLC Targeted Therapies in Lung Cancer Conference

February 17th, 2014 - by Dr. Jack West

In a few days I’ll be heading back to Santa Monica, CA for the now 14th Annual Target Therapies of Lung Cancer Meeting, sponsored by the International Association for the Study of Lung Cancer (IASLC). This meeting is always an exciting one that introduces early work with an incredible array of new treatments while, on top of that, providing status updates for a few dozen agents and combinations. How much do we cover? There are nearly 200 short presentations packed into 2.5 days, along with a few keynote lectures as well.

Obviously, that’s too much information for me to provide a synopsis of every brief talk (most are 5 minutes, a minority 10-15 minutes), but it gives you a sense of the magnitude of research being conducted on targeted therapies. What I wanted to do now was tell you about the main topics of what we’ll be discussing. I’ll plan to cover many of these categories with a post summarizing some of the concepts, agents, and combinations in the weeks after the conference.

The meeting kicks off on Wednesday night with a keynote presentation by Dr. Pasi Janne from Dana Farber Cancer Institute, with whom I did my residency in Boston before I moved to Seattle. He went on to do much of the pioneering work on discovery of the activating EGFR mutations, and he’ll turn to discussion of the field in 2014, including “current opportunities and challenges.” I’d bet that his talk will merit a post in its own right.

The main program begins Thursday, focusing on EGFR mutation-positive NSCLC. We’ll be covering ideas for acquired resistance, such as whether to treat with the same targeted therapy beyond progression, radiation for focal progression (a talkl being delivered by our own Dr. Weiss), and even the potential role of Iressa (gefitinib) if it might return to the US. Of course, current questions also include second generation, irreversible EGFR inhibitors such as dacomitinib and Gilotrif (afatinib), the latter being studied with and without Erbitux (cetuximab). And then there are even third generation EGFR inhibitors such as CO1686, AZD9291, EGFR816, and HM61713 that may prove to be effect options for patients with acquired resistance to a first generation EGFR tyrosine kinase inhibitor (TKI).

Beyond single agents, another question for managing EGFR mutation-positive NSCLC is whether combinations are more effective than single agent therapy. Combinations of various EGFR TKIS with the Met inhibitor onartuzumab (MetMAb) or crizotinib, the heat shock protein inhibitor AUY 922, the ALK and Met inhibitor crizotinib, and several others are all being explored.

Of course, most people with lung cancer don’t have an EGFR mutation, so the conference will then turn to treatment options for patients with EGFR wild type (no mutation). We’ll discuss Erbitux with and without radiation, the monoclonal antibody necitumumab that was recently announced as improving survival combined with chemotherapy in the “SQUIRE” trial.Sym 004 is alsoa combination of EGFR-directed antibodies that is being looked at in this setting. We’ll also discuss the evidence supporting approaches like the serum-based VeriStrat test, arguably useful for predicting utility of Tarceva (erlotinib) compared with chemotherapy in the EGFR wild type population.

The meeting will then shift gears to cover therapies for ALK-positive patients, including a variety of new ALK inhibitors and also heat shock protein inhibitors that areincreasingly being recognized as a potentially effectively treatment for patients with an ALK rearrangement. There are so many of these agents being tested and presented that I’ll need to cover this topic in a dedicated post after the meeting.

With several new treatments with high response rates and prolonged duration of response in the metastatic disease setting, it’s appropriate to ask about the pros and cons of importing targeted therapies into earlier stage disease. We’ll discuss some previously conducted and also some current trials looking at adjuvant (post-operative) EGFR or ALK inhibitors for the patients with their respective driver mutations.

With so many potentially important targets, every year we need to ask what the best way to test should be, ranging from genomic sequencing to a test generally done in local hospitals called immunohistochemistry, to a more specialized test called fluorescence in situ hybridization (or FISH) done at regional labs, to a gene or protein signature that looks for patterns in the tumor to predict clinical behavior and/or responsiveness to treatments.

The meeting continues with an entire afternoon of discussion about a wide range of novel targets, including RET, ROS, BRAF, HER2, Met, FGFR, DDR2, IGF-1, and even more. Each of these has several drugs targeting them that is being developed for potential utility for lung cancer. With about 50 short presentations covering just this collection of novel targets, I hope you can get a sense of how much research is being done.

Amazingly, this only covers the first half of the meeting. I’ll provide a preview of the second half in an upcoming part II.

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