Quick ASCO Summary: Potential New Options for Lung Cancer

[NikoleV]

Quick ASCO Summary: Potential New Options for Lung Cancer

June 15th, 2013 - by Dr. Jack West

http://expertblog.lungevity.org/2013/06 ... ng-cancer/

Continuing with a second part after my summary of new presentations on management options for some of our current tools against lung cancer, today I wanted to briefly cover some of the more promising new agents and approaches emerging in lung cancer at ASCO 2013.

Probably the biggest story in lung cancer from last year was the anti-PD1 immunotherapy now called nivolumab, an “immune checkpoint inhibitor” that essentially turns off the brakes of the body’s self-regulation that can keep our immune system from recognizing and fighting cancer cells. PD1, or “programmed death-1″ is a target protein on the T-cells of our own immune system, and PDL1 is the ligand (binding partner) for it, a protein on the tumor cell side. This year, we got an update of nivolumab that essentially corroborated that the preliminary results from last year in some heavily pre-treated patients are still holding up, are durable (1 year or longer) in many of them, and seem to now be about as common in those with an adenocarcinoma or non-squamous NSCLC as in squamous, where it appeared that there may be particular activity. This year, there was also some very early work combining this immunotherapy with nivolumab along with first line doublet chemo, and this work showed that the combination was feasible and had activity that looked like it may exceed what we expect to see from standard chemo alone. More to come on that, but the general momentum is such that the results with these immune-based treatments are promising enough that we should expect to see them not only left as second, third, or fourth line treatments but will soon see them tested more as first line for metastatic NSCLC and potentially soon in earlier stage patients who we’re treating for cures.

Another early trial was with an anti-PDL1 agent called MPDL-3280A, which was also just tested in the first few dozen patients with lung cancer and found to have an objective tumor shrinkage rate (objective response) rate of 20-25%, with some of these being quite dramatic and potentially long-lasting — though this work is still too early to say much. However, it’s also important to note that the response rate of 20-25% almost certainly underestimates the benefit of this drug and other immunotherapies because it doesn’t include patients with “pseudo-progression“, a very important phenomenon with some immune-based treatments in which existing lesions may appear to grow and/or new lesions appear, then actually shrink dramatically after a subsequent scan is done if patients continue on this treatment. If biopsied, these lesions may actually show lots of T cells, the immune reaction fighting cells attacking the cancer, which may infiltrate a tumor or even make a tiny one appear as a new lesion (presumed to be the reason why a “new” nodule may appear and then melt away). This is critical to recognize, because oncologists aren’t used to seeing pseudo-progression, but the point is that if patients appear to be doing well clinically, it may be premature to discontinue an immunotherapy just because a new lesion happens to appear or existing lesions may grow — this may just precede a subsequent dramatic response.

A couple of trials highlighted some potential new advances in second line treatment for metastatic NSCLC. The first is nindetanib, or BIBF-1120, an oral anti-angiogenic drug that actually inhibits several potentially relevant targets in cancer cells. A global phase III trial (the kind that can lead to a new treatment being approved for commercial use if found to be favorable) randomized about 1300 patients to second line Taxotere (docetaxel) chemotherapy alone to the same chemo with nindetanib and demonstrated a marginally significant improvement in progression-free survival (PFS) overall, but in patients with an adenocarcinoma, there was a much more striking improvement in PFS and overall survival (OS) (more than a 2 month improvement in median OS). The combination in second line was actually especially favorable in the patients with a metastatic lung adenocarcinoma that progressed early on first line doublet chemotherapy. This trial may be sufficient to lead to nindetanib becoming approved by the FDA and commercially available in the next 12 months, at least for patients with a lung adenocarcinoma (less likely to be approved for all metastatic NSCLC).

Another second line trial was with the “heat shock protein inhibitor” (or HSP-90) inhibitor ganetestespib, also tested in combination with Taxotere and compared with Taxotere alone, in a randomized phase II trial (which can give a signal of value of the drug but isn’t big enough to confirm it should be approved for commercial use). This trial, called GALAXY-1, initially included patients with squamous as well as non-squamous NSCLC, but there were some safety concerns with the squamous cell NSCLC patients in the early part of the trial, so it continued to enroll only non-squamous patients. It showed an impressive superiority in PFS and OS for the combination in adenocarcinoma patients, and this was particularly true in the subset of patients who were enrolled on the second line trial more than 6 months after their initial diagnosis. This factor likely represents something about a more favorable biology of these cancers. In any event, there is a new, phase III trial moving forward (GALAXY-2) that will do the same randomization of Taxotere with or without ganetespib, only enrolling patients with metastatic non-squamous NSCLC (it may be only lung adenocarcinoma — not sure) who were diagnosed at least 6 months prior to the time of initiating second line treatment.

Interestingly, it seems that the nindetanib may be a particularly appealing choice for patients with patients who progress early on first line chemo, while ganetespib may be particularly appealing for those patients who do much better with first line chemo +/- maintenance therapy.

The final group of new agents I wanted to touch on is a series of second generation ALK inhibitors that are being tested in the approximately 4% of patients with an ALK rearrangement. While XALKORI (crizotinib) was a major contribution in lung cancer, albeit for a small subgroup, it was only “accidentally” discovered to be effective as an ALK inhibitor while being developed as a MET inhibitor. In contrast, the second generation ALK inhbitors, including one from Novartis called LDK-378, one from Ariad called AP-26113 (which also inhibits EGFR, but not nearly as well as it inhibits ALK), and one from the Japanese company Chugai called CH5424802, all have very impressive activity in ALK-positive patients, with response rates ranging from about 60-94%, seemingly as good in patients who have progressed on XALKORI as in those who are XALKORI-naive, leading to some very long-lasting responses (most still ongoing), and some responses of brain metastases, where XALKORI isn’t effective. These drugs are all in rapidly enrolling clinical trials and hold a great hope as an appealing option for patients who have already received and progressed on XALKORI, or perhaps as a first line treatment alternative to XALKORI.

That’s enough for now. I think there’s reason to be hopeful about many of these strategies.