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Immune-based approaches in lung cancer tend to generate significant buzz among patients and the general public, as well as in the media, but not as much optimism within the oncology world. Much of that is for good reason: while the concept of a minimally toxic, long-lasting anti-cancer approach like a vaccine is very appealing to all of us, oncologists have seen many hyped immune-based therapies deliver far less than their promise. This is for several reasons. One is that cancer cells derive from normal host cells, so it can be hard to find targets on a cancer cell that aren't also seen on normal cells. If the immunologic treatment fights normal tissues as well, it can lead to autoimmune complications. Also, many of the early studies measure success as an immune response measured on skin or in a test tube, not the more meaningful endpoints that we really care about, like tumors shrinking or people living longer. Who cares if your blood cells seem to recognize the target in a lab test, if it doesn't translate to a patient actually doing better because of that? Also, the idea of a vaccine is generally employed before someone has the disease: you get vaccinated not when you have measles, but before you get it, so your immune system can mount a response at the first minimal threat of it. We think of immune-based therapies being most effective against a minimal tumor burden, which is not something we see enough in lung cancer, especially advanced disease. Finally, chemotherapy as well as progressing cancer can leave the body relatively immunosuppressed, so that the immune system may not have the ability to mount a strong enough response to combat a cancer meaningfully. At the end of the day, we don't have vaccine therapies for active cancers yet. But as I write this, I wonder when I'll need to go back to revise that statement. The FDA is considering a vaccine for advanced prostate cancer, and there are a few good leads in lung cancer as well. Today I'll focus on L-BLP 25, now also known as Stimuvax®
Stimuvax is a synthetic human protein called MUC1 that is comprosed of a 20-amino acid peptide that is capable of producing a robust immune response. Although the protein MUC1 is present on both normal epithelial tissues of the body and cancer, the pattern of sugars that are put on the MUC1 protein of cancer cells is different from the pattern on normal cells:
The vaccine consists of the immune-reponse inducing peptide (specific for the kind appearing on cancer cells), along with an immune system stimular called an immunoadjuvant or just adjuvant (same word as the one we use for post-operative treatment, but different meaning here). These are enclosed in what is called a liposomal vehicle that enhances recognition of the cancer antigen (target piece of protein) by the immune system and facilitates better delivery. The vaccine approach involves injecting it under the skin (subcutaneously) to be taken up by the patient's immune cells so they can be trained to detect and combat the cancer cells that have this particular protein on them.
There was a key clinical trial of this vaccine (abstract here) in NSCLC that has generated significant interest, based on the improved results in at least some of the patients who participated. Completed in Canada and the UK, it randomized 171 patients with stage IIIB (not just with a malignant pleural effusion, but also many with unresectable but what would generally be considered curable stage IIIB disease without an effusion) or stage IV NSCLC to the vaccine with supportive care or supportive care alone after first-line treatment with chemo, and sometimes radiation as well (a standard component for locoregional stage IIIB NSCLC, although not always given, for unclear reasons), but only for patients who had a response or at least stable disease after initial treatment. It was therefore a maintenance approach administered at a time when the tumor burden would potentially be reduced, if not exactly minimal. The schema is as shown:
The trial evaluated survival and safety of treatment, as well as quality of life. The treatment involved a single low dose of a chemo (cyclophosphamide) to stimulate the immune system, followed by eight weekly injections of the vaccine under the skin. After that, patients on the vaccine arm could also receive a maintenance vaccine injection once every six weeks. Quality of life was not very different between the two groups and was modestly better in vaccine recipients (which could possibly be because they were happier to be receiving the vaccine), certainly no evidence that the vaccine bothered people much. The formal toxicity evaluation showed that treatment was well tolerated, primarily with local skin reactions like redness and slight swelling at the injection site:
The median survival for everyone was 4.4 months better in the group that received vaccination (17.4 vs. 13 months). This included about 60-65% of patients with advanced disease and 35-40% with earlier stage, locoregional disease that can be treated curatively and have a very different, better survival. When they broke down the groups by stage, there was really no difference in outcome among the patients with advanced NSCLC ("wet" IIIB or stage IV):
In contrast, the differences were striking for the minority of patients with stage IIIB NSCLC without a pleural effusion, also referred to as locoregional stage IIIB, with median survival in the final paper 30.6 vs. 13.3 months, highly favoring the vaccine recipients. Here is the survival curve from an earlier presentation for patients with stage IIIB locoregional NSCLC, starting after the end of chemo or chemoradiation:
That's pretty impressive, but with the caveat that these results are based on only 65 patients, and overall they were treated pretty unconventionally, not just because of the vaccine. In contrast with the ideal standards of care for locoregional stage IIIB NSCLC, only 23 patients received chemo and radiation concurrently, and only 19 received a dose of 50 Gray or more. It's a bit squirrelly (not a technical term), enough that we would all prefer to see these results reproduced in a larger setting.
Fortunately, that's what the world will now get. Building on the momentum from the smaller phase II trial, the manufacturer just opened the START trial (Stimulating Targeted Antigenic Response to NSCLC Trial). This study is a randomized (2 getting vaccine for every 1 getting placebo), double-blind (both sides will get injections on the same schedule, so it won't be clear who's receiving active treatment), placebo-controlled trial of 1300 patients with stage IIIB unresectable locoregional ("dry", without a malignant pleural effusion) who have demonstrated a response or stable disease after at least two cycles of platinum-based chemo with radiation. Patients will be enrolled from about 140 centers in North America and Europe. Information on the trial can be found here or here.
I and many others in oncology remain somewhat skeptical about vaccine-based therapies for lung cancer, but the results from the phase II trial are intriguing and leave me more hopeful about such an approach than I have ever been before. It would be fabulous to have a maintenance/consolidation therapy for unresectable NSCLC that was minimally or non-toxic, that could work for a prolonged period of time, and that improves survival meaningfully. And this kind of approach could easily translate into post-operative management for earlier stage patients as well, where we are really dealing with a very minimal residual tumor burden, if there is any at all. Time will tell.
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Hi elysianfields and welcome to Grace. I'm sorry to hear about your father's progression.
Unfortunately, lepto remains a difficult area to treat. Recently FDA approved the combo Lazertinib and Amivantamab...
Hello Janine, thank you for your reply.
Do you happen to know whether it's common practice or if it's worth taking lazertinib without amivantamab? From all the articles I've come across...
Hi elysianfields,
That's not a question we can answer. It depends on the individual's health. I've linked the study comparing intravenous vs. IV infusions of the doublet lazertinib and amivantamab...
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That's beautiful Linda. Thank you,