This year's American Society of Clinical Oncology (ASCO) conference in Chicago was chock full of the latest in cancer research and advances, but one retrospective study in particular could help radically change the way cancer immunotherapy trials are conducted going forward. The change could end up significantly improving clinical outcomes without actually changing the nature of immunotherapy itself, only how and when it is administered.
The study I am referring to was conducted in the United Kingdom, and it found through retrospective analysis that cancer patients who took antibiotics during immunotherapy lived about half as long as those who avoided antibiotics. The study was conducted by aggregating data from 303 patients using data from January 2015 to March 2017.
At first glance the data might not sound so useful because cancer patients who are on antibiotics are generally sicker than patients who are not, so patients taking antibiotics are less likely to survive for as long a time anyway. In other words, the study may not seem to be saying anything about a link between antibiotics and the effectiveness of any given immunotherapy, but only on overall health and cancer survival rates, which is not very informative. However, this particular study was able to work around this shortcoming because researchers were able to determine overall sickness by factoring in prior treatment and the extent of a patient's particular disease. Effectively, researchers were able to determine whether patients on antibiotics were actually sicker overall, or whether they were similarly healthy to patients not on antibiotics, but just happened to be taking antibiotics as a precautionary measure. Antibiotics as a precaution is common for cancer patients who often are on antibiotics in order to prevent infections after having their immune systems compromised due to various cancer treatments.
Specifically, the study found that patients who took antibiotics during immunotherapy lived about half as long as those who didn't. Patients not on any antibiotics survived 178 days on average without cancer progression versus 97 for those on antibiotics. Overall survival was half as long at 317 days for antibiotics versus 651 without. The researchers aren't sure exactly why, but speculate that bacteria in the gut may help recruit immune cells to keep these bacteria under control. Since antibiotics clear the gut of much of these bacteria, there is no need for the body to keep these immune cells active in the background while antibiotics are being administered. The effect is speculated to be less immune cells available for activation and recruitment via immunotherapy. The immunotherapy then becomes less effective overall, so the theory goes.
If the theory is correct, these results could have a significant impact on immune checkpoint inhibitors like Merck's (MRK) Keytruda and Bristol Myers Squibb's (BMY) Opdivo, which rely on a concentration of immune cells to jumpstart therapeutic effects. Below a certain immune cell threshold and Keytruda and Opdivo become ineffective.
I conducted a manual search on Clinicaltrials.gov for phase III trials containing the words pembrolizumab, the generic name of Keytruda, and nivolumab for Opdivo, and "antibiotics", trying to see if antibiotics were ever considered an exclusionary criterion for patients in these trials. The only thing I found that even comes close to separating patients on antibiotics out into a separate trial arm was this trial testing Opdivo on non-small cell lung cancer patients. This trial separated two patient arms into early switch treatment with nivolumab after 4-6 weeks of chemotherapy, versus a second arm that first treated patients with best supportive care before resorting to Opdivo. Best supportive care often includes antibiotics. The point was to see if earlier treatment with Opdivo as opposed to first resorting to best supportive care until disease progression can improve overall survival. However, antibiotics were not even excluded from the first arm anyway. Effectively then, not a single phase III trial for either Opdivo or Keytruda filtered out antibiotic use in any useful sense.
Keytruda and Opdivo are already very successful blockbuster drugs for Merck and Bristol Myers Squibb, and could be even more successful now that doctors are aware of a possible link between antibiotics and lowered effectiveness for these treatments. Antibiotics will still be necessary for patients with active infections, but prescribing them as a precautionary measure for cancer patients who might contract an infection could start become less commonplace for patients about to undergo immunotherapy, giving a better chance for these immunotherapies to kick in.
Further, these findings could spread down the line for other immunotherapy companies in the CAR-T space, like Gilead (GILD), Celgene (CELG), and Bluebird Bio (BLUE). There is no data yet suggesting a link between antibiotics and CAR-T therapy specifically, but given the results on immune checkpoint therapy, retrospective studies will probably be done on the CAR-T groups as well.
Another group of companies that could be affected positively by this research are those that are trialing immune checkpoint inhibitors in combination with their own drugs to try to amplify response rates. Now that there is some evidence that antibiotics can lower response rates, we could soon start seeing immune checkpoint inhibitor combination trials that separate patients on antibiotics into different arms, or perhaps even add antibiotic treatment as an exclusionary criteria. As I mentioned in my previous article on this topic, Amgen (AMGN), Seattle Genetics (SGEN), Tesaro (TSRO), Eisai (OTCPK:ESALY), Advaxis (ADXS), and Syndax Pharmaceuticals (SNDX) are all pursuing combination treatments with either Keytruda or Opdivo, and none of the trials address antibiotic usage by patients. This could soon start to change, increasing the chances of effectiveness for these combinations.
It's not something that will immediately affect sales for these drugs, but it is something to watch for in terms of a shift in strategy in late stage clinical trials for cutting edge therapies. It seems that the more these companies separate patients on antibiotics into different arms, the better chances they will have to prove that their therapies actually work.
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