Breakthrough Rectal Cancer Drug Trial: What It Means For You

Dr. Diane Reidy-Lagunes:

The recent headlines take your breath away: “Groundbreaking Cancer Treatment Produces Remission in Every Patient on Trial,” “Cancer Drug Makes History as Rectal Tumors Vanish in All Trial Participants.” But what does it really mean for you as a patient and science as a whole? How do you make sense of a medical study? We're going to talk about it right now.

Hello, I'm Dr. Diane Reidy-Lagunes from Memorial Sloan Kettering Cancer Center and welcome to Cancer Straight Talk. We're bringing together national experts and patients fighting these diseases to have straightforward evidence-based conversations. Our mission is to educate and empower you and your family members to make the right decisions and live happier, healthier lives. For more information on the topics discussed here, or to send us your questions, please visit us at mskcc.org/podcast.

Locally advanced rectal cancer is curative, but the curative treatment can be brutal. Radiation can lead to infertility, early menopause and sexual dysfunction, while surgery can lead to long-term bowel and bladder problems, and 15% of the time, a permanent colostomy bag. That's why a recent clinical trial headed up by my colleagues at Memorial Sloan Kettering has grabbed the attention of medical oncologists and cancer scientists around the world. Like a miracle, in a subset of patients with the right genetic makeup, an IV infusion of an immunotherapy caused a complete remission. The doctors were shocked. The cancer disappeared in every single patient enrolled on trial. What does that mean for our patients? First, let's take a quick listen to our clinical trial participants – Sascha, Nisha, Avery and Imtiaz – and what it was like to hear the words, "Your tumor is gone."

That day, I didn't see the tumor, so I was thinking, “Where is a tumor?” Then maybe I thought it's hiding somewhere inside. The doctor told me, “There is no more tumor.” It's a miracle.

The world just stopped for a second and I couldn't believe it. You could ask her, like I barely reacted because it was just like, I was not expecting to hear that news.

The first thing I did, called my mom. Yeah, we both cried. It was life changing.

I'm not religious at all, but my friends had taken me to a healing mass prior and then I got the news from Dr. Cercek. They called to say that it was working. So it was a combination of everybody saying it is miraculous and then also combined with it actually being miraculous.

You go from feeling, “Oh, am I going to die? Am I going to lose my colon?” And then to find that, “Oh, you're going to be fine.” It's just like, wow. It was an amazing feeling.

I'm a miracle right here standing without any surgery and don't have cancer.

Dr. Diane Reidy-Lagunes:

Today, I am honored to have Dr. Andrea Cercek and Dr. Luis Diaz as my guests. They are both my dear colleagues and friends at MSK. They are the principal investigators of this study and they made this happen. Andrea and Luis, welcome to the show.

Dr. Luis Diaz:

Thanks Diane.

Dr. Andrea Cercek:

Thanks so much for having us.

Dr. Diane Reidy-Lagunes:

Andrea, this is nothing short of miraculous. What was this like when you gave the news to your patients?

Dr. Andrea Cercek:

It was incredible. It's our dream to be able to tell every single person that their tumor's gone, that they don't need radiation, especially obviously in the beginning where we didn't know what to expect. You know, as Sasha mentioned, she was geared up. She was ready to go for radiation. She was coming to New York, and I got to call her and tell her, “Actually, we met at the Tumor Board and we don't see any signs of a tumor and everyone agreed we can just observe you.” So it was absolutely incredible.

Dr. Diane Reidy-Lagunes:

Absolutely incredible. Luis, can you distill down this magic, like what this drug is and how we actually got here in terms of how the story originally started?

Dr. Luis Diaz:

About 40 years ago, there was something called mismatch repair deficiency that was first discovered. Mismatch repair deficiency is when there is a tumor cell that can't repair its DNA, so that every time it divides, it accumulates more and more mutations.

Dr. Diane Reidy-Lagunes:

So the machinery that they needed to repair itself is actually the damage, and so they just get more and more damage and more and more mutations.

Dr. Luis Diaz:

That's right. And these mutations do all kinds of strange things, but one of them is it makes tumors grow very effectively. And the other thing is sometimes the immune system can see them as foreign. But tumors are really tricky, and these types of tumors figured out ways to become invisible to the immune system with something called PD1. And in about 2010, 2011, there was something called a PD1 inhibitor, a checkpoint inhibitor, that was discovered, and it was working really well in melanoma, and it was working really well in lung cancers. And we tried it in these mismatched repair deficient tumors, and it worked remarkably well. So when I arrived here at Memorial Sloan Kettering, one of the first conversations Andrea and I had was we should try this together in rectal cancer because it was such a difficult disease for our patients. The surgery's brutal, the side effects are lifelong, and even if you're cured, oftentimes you have side effects that are quite severe. And sometimes you're not cured. So Andrea came to me with this idea and a plan to how to do it, and we agreed to take this on together. And the rest is history, as they say.

Dr. Diane Reidy-Lagunes:

Amen. And Andrea, like Luis said, this is a type of immunotherapy. People have seen it on commercials – Keytruda, Opdivo – but what was so important about this study? Why did it make such a dramatic moment?

Dr. Andrea Cercek:

I think that the incredibly exciting thing is that every single patient that completed treatment, that had all six months of treatment, had a complete response, so there was no visible tumor. And we just don't see that. None of them needed radiation, none of them needed surgery, many of them were really young. I think that was the most moving thing, that we were able to achieve better efficacy with less toxicity, which doesn't happen. As Luis said, we see that they're living with it forever, they're living with the toxicities forever. And here, they're kind of finished their six months and felt absolutely nothing. In fact, felt as good as they did maybe two years ago before this cancer started growing. So I think that was absolutely remarkable and what people reacted to.

Dr. Diane Reidy-Lagunes:

Absolutely. And I think, again, as Luis described, you all knew that it was the right patient population to try this in. And I would imagine now next steps in other tumors we can try it, like bladder cancer for example, where that's also with tremendous quality of life issues to remove your bladder. But if you have this particular genetic subtype, then perhaps that trial may be done. So I think you've started a paradigm, both of you, to potentially explore in this subsegment to use this type of immunotherapy. So it's not necessarily the drug itself that's so miraculous, because I think we've all had a lot of patients say, “I want that drug,” but rather the patient population that you've selected and the stage for which you did it that was so unique, in terms of this early stage.

Dr. Andrea Cercek:

Absolutely. We didn't seek out this drug in particular. We wanted a single checkpoint inhibitor. We wanted a PD1 inhibitor, and any one of them would've sufficed. This is just the company at that time – it was a small company that said, “Okay, we'll take a chance with you. We'll do this study.” – that's how we arrived with Dostarlimab. But we don't believe it's the drug. It's the fact that we are giving it to this subpopulation that are mismatched repair deficient or MSI high, and early-stage tumors. We think really that's the key. And to your point, we have a second cohort open for all mismatch repair deficient solid tumors, including as you mentioned, bladder cancer where this could be very impactful, gastric cancer, where they would need to have their stomach removed and maybe if we can replicate this response, they won't need to.

Dr. Diane Reidy-Lagunes:

Amazing.

Dr. Luis Diaz:

And in terms of the design, we said, “Okay, now we're going to see if they have a complete clinical response. We're going to take the chance and not do chemo, not do radiation, and not do surgery.” And that's not a simple decision.

Dr. Diane Reidy-Lagunes:

Yeah, I think you nailed it. It took a tremendous amount of courage on the patient's part to potentially enroll in a study where you're saying, "We have a curative therapy. It may impair your quality of life long-term, but we have this other potential idea." So, either one of you, how do you have that conversation with a patient?

Dr. Andrea Cercek:

It was not easy. Certainly now, it's gotten much easier of course, but in the beginning, they were involved long conversations and many people went back and forth even after we had already seen the first few patients have complete responses. Not everyone was comfortable with it, so I think they were just long involved conversations and sort of us reiterating that if we are keeping a close eye on them, if it's not working, we can always go to standard of care. And then they trusted us and you're absolutely right, it was very brave and really incredible that they signed up for this early on.

Dr. Luis Diaz:

It wasn't just us talking to the patient, but the surgeons, the radiation oncologists. Remember they're all used to doing surgery on these patients to try to cure them. Convincing the medical community in changing the standard of care is a heavy lift. I think that with this study, like you said, we've turned the corner a bit and I think we're going to be seeing a lot more studies that take this approach.

Dr. Andrea Cercek:

I think to Luis's point, we do need to give credit to our colorectal group for their pioneering efforts in non-operative management, in emission of radiation, really their expertise in individualizing patient care in locally advanced rectal cancer. I think without the group, without these conversations and their support, this wouldn't have been feasible.

Dr. Diane Reidy-Lagunes:

And in fact, this didn't come from nowhere, right? You've dedicated your career, as have other members of our colorectal team here at MSK, to try to minimize the toxicities associated with rectal cancer treatment. Could you talk to us a little bit about what that means – non-operative management – trying to treat rectal cancer without the radiation, and the work that you and others have done before this?

Dr. Andrea Cercek:

Absolutely. In the field of locally advanced rectal cancer, because we use a combination of chemotherapy, radiation and surgery, one of the earlier things that we did here was to move chemotherapy from the postoperative adjuvant setting into the neoadjuvant preoperative setting, with the idea that we could really improve responses, theoretically not do surgery if the tumor’s completely gone, and also treat microscopic disease early on with chemotherapy. So that was one of the first changes that we made here that's now really been accepted worldwide in terms of giving chemotherapy upfront.

Dr. Diane Reidy-Lagunes:

Andrea, another area of yours is the fact that we know that colorectal cancer is starting at a younger age, and so you've developed our AYA or adolescent young adult colorectal cohort to really understand both research and clinically why this patient population may be a little bit different. Can you talk to us a little bit about that?

Dr. Andrea Cercek:

Sure. We've actually seen that colorectal cancer in people under the age of 50 is rising worldwide. And so back in 2018, we actually opened the first center worldwide focused on patients under the age of 50 with colorectal cancer. And the idea of the center was twofold: One was to support patients from diagnosis through treatment and into survivorship with all of our ancillary services including social work, support, psychiatric support, as well as early referrals to sexual health, fertility, integrative medicine, all the kind of support services that really individuals and their families need to get through this treatment. And then the second and equally important question was a research question to try to figure out why this is happening. And so that's been a very active area of research and actually what we've noticed is young onset cancer is rising actually throughout the GI tract – so it's affecting now the stomach, appendix, neuroendocrine – and so we've now expanded the center to all comers with GI cancers, gastrointestinal cancers, under the age of 50, both for the support services as well as for the research.

Dr. Diane Reidy-Lagunes:

Great. So Luis, getting back to the explosion of media from this trial that you created with Andrea, this hope is so critically important and as Andrea said, this is what we as oncologists dream about. But there has been an aftermath of hundreds, if not thousands, of oncologists around the world getting calls about this therapy. So have patients touched by cancer reached out to you? And how do you deal with that part, knowing that this particular type of regimen was uniquely for a certain patient with a certain genetic subtype?

Dr. Luis Diaz:

Both Andrea and I have gotten hundreds of emails and scores of phone calls and Memorial Sloan Kettering itself has gotten hundreds of phone calls, and not just for colorectal cancer but for every cancer. And the good news is that it was a piece of very inspirational news in a news cycle that has been very negative, and I think that's why it caught fire. I think in the backdrop of everything else that's going on the world, this is pretty special. But you're exactly right. Probably every medical center in the world is getting phone calls regarding, “How am I qualified for this therapy? How do I get this therapy?” And I'd say the good news is that we do have a relatively easy way to test for it. So what we've been instructing patients and their doctors to do is test your tumor for this marker. And because this checkpoint inhibitor is available worldwide, oftentimes that will be an option for these patients. But I think the important thing is that this is probably a marker that's only present in one of ten rectal cancer patients, and probably fewer pancreatic cancer or prostate cancers, maybe a little bit more endometrial cancers or gastro cancers. What I'd like to come of this is just an awareness of cancer and that we're making progress and that there is potential for very good outcomes, especially if we continue to push the science.

Dr. Diane Reidy-Lagunes:

I don't know if I know more of an optimist than you, Dr. Diaz. What do we tell the other patients that don't have this genetic makeup in their tumors?

Dr. Luis Diaz:

When we're talking about the rectal cancer patients, there's still a potentially curative option. It's not as attractive as avoiding radiation and surgery and chemotherapy, but it is still an option that we can pursue. And from work that Andrea and you and others have done here at Memorial Sloan Kettering, a good fraction of those – 20 to 30% – may actually be able to avoid surgery, which is a tremendous discovery that was really pioneered here at Memorial Sloan Kettering, and in Brazil by investigators there. And we're starting to see that in other disease types. But you're absolutely right. What I've been telling people is, continue to talk to your doctor. That's what we do, right? We take care of patients who have challenges, diseases, or sometimes we don't have the right answer. And we either have to continue working to find the right answer or give them the best thing that we have to help them. And so that's all we can do. We’ll all continue to do that.

Dr. Diane Reidy-Lagunes?

Where do we go from here, either one of you?

Dr. Andrea Cercek:

I think we obviously continue the work – we're expanding this approach – and I think importantly, we need to learn from it. We need to figure out why there is such an incredible response, such a robust response, in these tumors. Is it because they're early stage? Look at it even in the other remaining 95% of colorectal cancers that are not mismatch repair deficient and see if we could potentially take advantage of whatever we learned to engage the immune system.

Dr. Luis Diaz:

And if I could make a prediction, I think we will see responses like this in other tumor types. There are other markers that are not as common that will be just as effective, that will layer on top of this, and little by little will whittle away from that pie of patients who don't respond and turn them into patients that respond. I think, and Andrea shares this vision, that in the next three to five years, we'd like to make rectal cancer and the surgery and radiation associated with it completely a different disease.

Dr. Diane Reidy-Lagunes:

So again, in summary, certainly any patient with colorectal cancer should make sure that their doctors are doing the right genetic testing to see if they have this subtype, so that they could potentially be at least enrolled on studies like this. I think we do want to emphasize the point that these were still small numbers in a small trial for which we're building on, but incredibly exciting that you moved the needle.

Dr. Luis Diaz:

It’s been super exciting. And obviously, all of our colleagues here at Memorial Sloan Kettering make this type of thing easier. I think that's why this is such a special place, that we're able to take basic science discoveries and really apply them in a way to create something that's magical. One of the things that was most impressive was, Andrea and I were sitting in a lab meeting and we were talking to our statistician, “How likely was it to have 14 consecutive complete responses?” To have 14 consecutive complete responses, do you know what the chances were? You're more likely to win the lottery.

Dr. Andrea Cercek:

Twice! Twice, I think. One in trillion.

Dr. Luis Diaz:

One in a trillion. This is a one a trillion-type discovery.

Dr. Diane Reidy-Lagunes:

And we're going to grab it. Well, thank you both for being on the show and for all you do for our patients of today and tomorrow. And I do want to have a special thanks, as we said, to all the very courageous patients who agreed to participate in this trial and in all clinical trials. It's really only through patient participation that we can use this science to ensure our patients live happier and healthier lives. Thank you both for being here.

Dr. Andrea Cercek:

Thank you.

Dr. Diane Reidy-Lagunes:

Thank you for listening to Cancer Straight Talk from Memorial Sloan Kettering Cancer Center. For more information, or to send us any questions you may have, please visit us at mskcc.org/podcast. Help others find this helpful resource by rating and reviewing this podcast at Apple Podcasts or wherever you listen to your podcasts. Any products mentioned on this podcast are not official endorsements by Memorial Sloan Kettering. These episodes are for you but are not intended to be a medical substitute. Please remember to consult your doctor with any questions you have regarding medical conditions. I'm Diane Reidy-Lagunes. Onward and upward.