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The Cancer Letter – Roy Herbst: I hope Pragmatica-Lung will become the norm

The Cancer Letter – Roy Herbst: I hope Pragmatica-Lung will become the norm

Pragmatica-Lung is the first of what is likely to be a series of simpler trials with relaxed enrollment criteria and streamlined data collection requirements.

The results of such trial would be more generalizable to real-world patient populations.

“How do we make these trials simpler? We don’t need a 50-100-page document. We want to try to get a 12-page document. We don’t need a 40-page consent form. We want a couple-of-page consent form that patients can easily read and understand,” Roy S. Herbst, Ensign Professor of Medicine, professor of pharmacology, and chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital, said to The Cancer Letter.

Pragmatica-Lung is a phase III trial designed to assess overall survival for ramucirumab plus pembrolizumab in patients with non-small cell lung cancer who were previously treated with immune checkpoint inhibitors and chemotherapy and had progressive disease at least 12 weeks after initiation of checkpoint inhibitor therapy.

Pragmatica-Lung, therefore, will be geared toward evaluating only one endpoint—overall survival. A story about Pragmatica-Lung appears here on page <?>.

Herbst, vice chair for developmental therapeutics at SWOG Cancer Research Network, co-led S1800A and was the original steering committee chair of Lung-MAP. He is chair emeritus and senior advisor for the trial of the phase II Lung-MAP study.

“If this trial hits its survival endpoint, this becomes a standard of care. If it doesn’t, it’s a model for future trials,” Herbst said. “I think people will be watching our trial. We will need to get it open quickly. We need to run it effectively and efficiently. And we’ll see how it goes. But I hope this will become the norm: simpler trials, quicker to open, open in more diverse populations, with access around the country.”

Herbst spoke with Paul Goldberg, editor and publisher of The Cancer Letter, and Jacquelyn Cobb, reporter with The Cancer Letter.

A video recording of the conversation is available here.

Paul Goldberg: Well, thank you, Dr. Herbst, for finding the time to talk with us.

Roy Herbst: It’s my pleasure.

Jacquelyn Cobb: We were hoping that you could walk us through the Pragmatica story. It’s clearly very complicated, with a lot of moving parts, and your insider perspective would be really helpful.

RH: My pleasure. I’m so excited about this, especially the benefit it will have to patients.

So, we’ve been running a large public-private partnership for years, called the Lung-MAP, the Lung Master Protocol, where we’ve had very close involvement with the NCI, FDA, the Foundation for the NIH—which has acted as our common broker—all the NCI cooperative groups, community oncologists, and patients.

Through that we’ve run over 25 clinical trials. These trials have gotten to all parts of the country because we’ve had over 700 sites open. We’ve run these trials with biomarker-driven components in the immunotherapy resistance space. We’ve enrolled 4,000 patients and treated well over a thousand.

So, then the question came, more recently, when one of our trials, S1800, was quite positive. This was a randomized phase II trial, that in the refractory space, patients with lung cancer, the most common cause of cancer death, who had already failed immunotherapy that they had been on for at least 12 weeks—so, not the primary refractory patients, but those who had some resistance or a significant resistance to immunotherapy—were on this substudy of the Lung-MAP. We treated over 160 patients nationwide.

We had two drugs that we used in that refractory population that had come through some phase I studies.

One was pembrolizumab, of course, a PD-1 inhibitor, and the other was ramucirumab, a VEGFR-2 antibody inhibitor; both antibodies. And because of our Lung-MAP public-private partnership, we were able to get the two pharmaceutical companies, Merck and Eli Lilly, to work together.

We delivered the treatments through the entire National Clinical Trials Network. A true example of intergroup collaboration. And the trial showed with a hazard ratio 0.69 that there was an improvement in the patients who got pembrolizumab/ramucirumab versus standard of care chemotherapy, which remains docetaxel or docetaxel/ramucirumab, gemcitabine.

So, we were very excited about this. Karen Reckamp, the lead author, presented this at ASCO as an oral presentation and our paper came out in JCO at the same time. So, we left ASCO really excited to get this to patients as quickly as possible.

This is a positive phase II trial and it came out of the Lung-MAP—and of course, the whole concept of Lung-MAP is to identify the right patients and test new drugs and combinations in scientifically guided clinical studies.

We got the team together on one of our regular calls… we have so many as part of our governance and said, what are we going to do next? We all want to see this combination in practice. So that’s how we left ASCO.

PG: So, with S1800, we’re not talking about a registration trial at all. We’re talking about time to progression.

RH: Right, it was a phase II trial, but importantly the primary endpoint was overall survival!

Progression-free survival and response were secondary endpoints only.

Interestingly, Paul—we didn’t see any difference in progression-free survival or even response rate, but we did see a significant difference in overall survival.

So, that sort of begs the question as we do the follow up trial: Do we even need to look for progression-free survival, because we didn’t see it in the phase II trial?

Do we even need to look at response rate?

Sometimes we have a better response rate with chemotherapy than immunotherapy.

Really, what we need to do now is confirm the survival result.

A key part of this trial is that the toxicity was reasonable, meaning the grade three toxicities were present but only in the 30-40% range, much less than the chemotherapy control.

This is a regimen that we have treated many patients with, both in this trial and in other phase I and II trials, that were company-led.

So, going forward, there really wasn’t any need to worry about additional toxicity assessment. Of course, we want to keep an eye out for toxicity, but really all we need now, to move forward, is to see that this trial, in a larger setting can confirm the survival result—because 150-160 patients really isn’t enough for an approval yet—we need to go to a bigger study.

So, that’s where we left ASCO.

Then, we’re very fortunate because we’re working so closely with Dr. Ellen Sigal and Friends of Cancer Research—such an innovative individual and group.

Ellen called me up—and we’ve been working closely together for years—and said, we have to look at innovative ways to work with regulatory authorities, work with the NCI, with the FNIH, with the FDA: How can we bring this forward?

So, this has been a large collaboration among the team. Until just a few weeks ago, I was the overall principal investigator of the Lung-MAP.

I have been the steering committee chair for the last decade. I am now chair emeritus and senior advisor as we have passed the new leadership roles to Dr. Hossein Borgai (ECOG-ACRIN) as chair and Dr. Karen Reckamp (SWOG) as vice chair. I plan to stay very involved and am very excited to focus more on translational studies using the biospecimens collected from the study.

This has been a labor of love.

We have all these patients; we have all these team players working together. We have Jhanelle Gray, she’s the lung committee leader in SWOG, Karen Reckamp, Konstantin Dragnev and Mary Redman our lead statistician.

We had our FDA collaborators, our NCI collaborators and representatives from all the adult collaborative groups.

We asked, what can we do now to get this to patients even more quickly? So, there were a couple of things. One, working closely with our industry partners, Merck and Lilly, we filed for Breakthrough designation. And we have now formally obtained that!

This is extraordinary for a trial that came out of the cooperative groups, I can tell you Chuck Blanke, our SWOG group chair, was thrilled, as was I, that we took this all the way to Breakthrough designation.

But all that really means is now you have to do another trial to get the drug approved.

So, then the thought was, as we do this trial, do we want to do an expensive and lengthy, 1500-patient trial, where we take these two drugs that are already approved, for which we have so much data, with so many data collections—PFS, response rate, overall survival, toxicity assessments?

Or do we want to do something more simple or pragmatic? So, in consultation with a very forward-thinking FDA oncology center led by Rick Pazdur and with full support of the NCI, we moved forward with this novel more pragmatic design.

PG: Wasn’t this Pazdur’s idea, this whole thing? He said that, I believe, at the Friends of Cancer Research meeting.

RH: Yes. This came first from Rick Pazdur and his team, including Harpreet Singh [director of FDA’s Division of Oncology 2 in the Office of Oncologic Diseases], working with Ellen Sigal and the Friends, and then of course very immediate support when we mentioned the idea to the NCI.

Myself, Dr. Reckamp, and Dr. Jhanelle Gray were all then involved. When we heard this, we all immediately said, “Wow, isn’t this the way to go?”

So, I had to look up “pragmatic,” what it meant in the dictionary.

What it really means and implies is to be more patient-friendly, to be more simple.

You do trials—I have led trials in lung cancer for over 25 years and led the Clinical Trials Office here at Yale for over a year during an interim period—there’s so much data to collect and so much regulatory work that’s involved in a trial.

Additionally, we want these trials to be delivered at the point of care.

One of the amazing things about Lung-MAP is that these trials got out into diverse populations.

We’re still not nearly where we need to be, but we had more under-represented patients—African American patients, patients lacking insurance, patients who live in rural areas—on the Lung-MAP trial than we did on other NCTN and standard lung trials.

Patient access to trials is critical.

How do we make these trials simpler? We don’t need a 50-100-page document. We want to try to get a 12-page document. We don’t need a 40-page consent form. We want a couple-of-page consent form that patients can easily read and understand.

And the biggest thing was, and Rick Pazdur kept saying this to us, “All you need is survival, guys. You don’t need to worry about PFS. You didn’t even see it in the phase II trial. You don’t have to grab all these concomitant meds, you don’t have to worry about every little adverse event, just the significant ones.”

And I’ll tell you, Paul, Jacquelyn, when we did this, none of us believed him. We were like, ‘We can’t do this.’

Everyone got very nervous. And then the people that got the most nervous, of course, were the pharma companies, as they should, because they’re used to a very standard way of doing this.

It took a while—it took a number of calls, and I was very fortunate to have been a part of all that. I still remember as we brought more and more people into the loop.

The NCI, by the way, was immediately supportive. Meg MooneyJim DoroshowShakun Malik immediately wanted to do it.

We had the FDA’s support, but we had to get everyone comfortable with this idea. So, we had a series of meetings, and I know now hear pragmatic trials are going to be proposed across all disease types.

We just happen to have the lung cancer trial, which is one of the first. But then the idea was how do we actually do this?

And that’s where, again, with Ellen Sigal and the Friends sort of acting as our broker with the leadership of SWOG and the help of FNIH, we pulled this together.

So, we have a trial now, we call it S2302, and I believe we’re going to call it the Pragmatica-Lung trial.

It’s going to be a one-touch trial- for survival. We care exclusively about survival, and that allows us to make the hazard ratio a little bit higher.

We figured that the randomization will take care of all problems. Rick Pazdur, maybe he even told you this as he keeps saying this to me, this is a prospective, randomized real world study.

But we’re not going to be as specific in the eligibility criteria. Of course, we need the criteria that got us here, meaning patients with lung cancer who are refractory to immunotherapy, who have been on immunotherapy for at least 12 weeks (84 days).

But after that, it’s all a much simpler trial design, easier to identify patients, collecting many fewer data points. That’s going to require much less infrastructure.

We want this trial to be done where people are, in the community practices, through the NCORPS, and other clinical trial organizations.

And the amazing thing is that it has really taken off. I was at the CTSA meeting just a few weeks ago and I heard FDA commissioner Robert Califf mention the pragmatic trial. Of course Ellen, Rick and Monica mentioned it at the Friends meeting.

We just had our AACR Diversity and Clinical Trials course as part of the BMS Foundation Clinical Trials Diversity Program. And Harpreet Singh spoke about this in her talk. And now we’re discussing it here in The Cancer Letter.

This idea of more directed trials, one touch trials focused on the most important endpoint is innovative. In this case, survival is the endpoint. I would say that in some cases, it might not have to be survival, but in this case, since there was no PFS positivity in the phase II trial, survival is the end point.

PG: It’s sort of fascinating that PFS is not just a lousy surrogate, but just not a surrogate.

RH: Well, we’ve seen that more and more, especially with immunotherapy, the benefits of immunotherapy are often at the tail of the curve.

If you think of the survival curve with immunotherapy, it often looks like a hockey stick. My statistician friends would term it non-proportional hazards.

Many patients don’t benefit early on, but it’s that tail of the curve, the long-term benefit. Now, someday, I hope we’ll be talking, and I will be able to tell you who benefits early and how to better choose or combine drugs to help others—that’s something we’re doing here as part of our Yale SPORE in Lung Cancer (YSILC)—research focused on biomarkers and personalized immunotherapy.

But right now, it is clearly possible that even without an effect on response or PFS, you can still have an overall survival benefit.

And, remember ,some of these chemotherapies—docetaxel, which we’ve been using since I was a fellow—I don’t want to tell you how long ago that was, does produce some response, but a great deal of toxicity as well, and it’s not a lasting response.

Immunotherapy tends to have a more durable benefit.

And it makes sense, by the way, the whole idea that if you use a vascular growth factor inhibitor, you’re having an effect on vascular flow and other aspects of dendritic cell function that will promote T-cell infiltration to tumors.

For years, people have shown that those agents increased chemotherapy and oxygen delivery to tumors. I did some of this work myself in Beverly Teicher’s lab with Tom Frei, when I was an instructor at Dana Farber.

It’s very possible we’re warming up the immune environment and allowing more T cells to get to the tumor.

So, I’m absolutely thrilled that we had a positive trial and then everyone sort of jumped on this. In fact, the speed of design and overall collaborations exceeded my wildest expectations.

We had amazing support and innovative guidance from the FDA. We are all working hard together as a team to make this happen. All the regulatory groups, the NCI, the companies all aligned—think about the companies, this is a very new thing for them, and we are so grateful.

But I’ve got to tell you, Merck and Lilly have been so willing to be innovative and to take the chance on this new trial design. We have Breakthrough designation. We can still do a big trial the old way.

But I’m very hopeful that this trial will help more patients sooner. We’ll get this therapeutic combo to patients and answer the question one way or another.

It is randomized, so some patients will get a control, but we’ll get this done quickly and with well less than a thousand (hopefully closer to 700) patients.

What good are these drugs if we don’t get them to the right patients, we don’t get it to them quickly and safely? Safety, of course, is a major issue.

I’m very excited to be part of the lung pragmatic trial team with some of the people I mentioned to you earlier.

JC: Absolutely. With such a big team and so many partners, who actually holds the IND?

RH: Well the IND for this will be held by SWOG. It’s the same way the Lung-MAP works now—and I’m very proud of that.

When we started the Lung-MAP, it was a SWOG trial. And then we moved it into all the cooperative groups. And now, as I’ve left the PI role, I feel more than ever Lung-MAP is truly a partnership with a strong and sustainable governance.

When you have a partnership like this, you need governance involving each of the groups, whether it be the ECOG-ACRIN, the Alliance, the NRG, SWOG—they all hold leadership positions on the different committees.

The FNIH has been a tremendous ally to keep our trial on track.

Now, we are conducting the lung pragmatic trial outside of the Lung-MAP.

So, for this first one, SWOG is taking the lead on it, just because it came out of a trial that was SWOG-led, myself and Karen Reckamp and actually I want to give a large call out to my good friend and colleague Dr. Vali Papadimitrakopoulou, now at Pfizer, who worked so closely on this before she left academia for industry.

So, this trial is moving, and SWOG is going to hold the IND, and run the study with very close cooperation among all the other parties.

We have assurances for this lesser data collection with the approval of the FDA. And the FDA has been very supportive.

The other thing to keep in mind is there’s no other approved therapy in this space for this group of patients. If there had been something here, it might have had an effect on the bar.

But right now, the bar is not very high. Hence, the need for a rapid, prospective, pragmatic study.

And that’s what made it possible to do this as one of the first demonstrations of a pragmatic trial. And so we call it the Pragmatica-Lung trial.

And SWOG and the NCI steering committee and the other groups are moving it right along.

Chuck Blanke with SWOG has been so supportive, and the team there, Mary Redman, our lead statistician—have all just done an excellent job with this, and will really help us to make this happen.

PG: Can we talk about randomization for a moment? Because recently, ODAC voted down a trial that had a synthetic control arm. And in this case, this is actually randomized. 

This is not a standard approach to real-world evidence. This is, actually, these two drugs versus chef’s choice. So, what does it say to you as a clinical trialist?

RH: Well, I love the idea of real-world data, but as opposed to retrospective, this is prospective—you’re right—it’s a randomized trial.

So, it’s a true application of doing a real-world trial in a prospective randomized way.

I think what you’re alluding to is when the control arm is dealer’s choice. But we actually have some data from our 1800 trial that about 75% of patient people will use docetaxel/ramucirumab, but they don’t have to. Some will use docetaxel, some will use gemcitabine.

Now, we debated on this, and the feeling is: It will all equal out in the randomization.

The trial is still going to be close to 700-800 patients, and the randomization will take care of it.

And if there isn’t a significant benefit—how worthwhile is this anyhow? This is going to have to beat chemotherapy from 20-30 years ago.

The somewhat less formal design is the thing that’s different, which does make some people have palpitations, but I think that it will all come out in the randomizations.

Now, will the difference that we see here be as big, in terms of hazard ratio, as we saw in the phase II trial? It might not be, but the FDA has told us that they’d be willing to consider anything in the 0.7-0.8 range, maybe in the middle, which is what came out of ASCO’s guidelines years ago.

So, you don’t have to, with each trial in immunotherapy, see a hazard ratio of .5-.6, in my opinion. This is now in refractory immunotherapy. So, even if we were close to 0.8, but if we had significance, based on the statistical design, I think we’ll be okay.

It’s an experiment, but it’s a good one, because, as Ellen Sigal constantly tells me, and she’s been my mentor for years, we’re helping patients.

We’re getting drugs to patients faster. That’s the goal. And we’re asking questions at the same time. I can’t tell you how amazing it is.

The FDA is our regulator here, so they have to keep a bit of a distance. But they’ve given us tremendous advice and inspiration. It’s a SWOG IND trial, but the entire collaboration has come together.

The other thing I want to point out is we have the buy-in of all the other cooperative groups. It’s a competitive space out there, there are many trials. We’re hoping that because we’re using the NCTN network, they’ll be quick to open the trial at cancer centers right now.

Our cancer center here at Yale, as are others, all are looking to get drugs to patients in the networks, and this is a perfect opportunity/mechanism.

We want to have clinical trial accruals. We want to have pragmatic trials that we can get to the community. But thinking about our cancer centers focus on community outreach and engagement and other things, all these are going to be very critical to make sure that we get accrual.

And that’s going to be on us. We talk about that each week on our pragmatic call, we have to make sure that this trial accrues. And that’s why I’m so glad that even before it’s fully open, you’re talking to me about it.

As it moves forward, we’re going to need social media, we’re going to need to run seminars, or go out to the point of care to raise awareness.

I’ve run so many trials over the years and sometimes you have to set up regional meetings involving caregivers, patients, or sometimes both.

Now, we can do them somewhat by Zoom, but we’re going to have to make sure coordinators and others are aware of the trial. The PIs, and the team of PIs, have to be available to help patients and caregivers when they have questions about the trial.

But, hopefully, there’ll be fewer questions, because of the more limited eligibility criteria.

There’s more limited data collection. It’s pragmatic.

PG: We’re not going away on this story. We will keep on it for as long as it takes. It’s probably one of the most important stories we’ve done in years and it’s huge. So, one question is the power calculation, you went for a very high-power calculation.

RH: Well, I don’t want to say the exact numbers, because it’s still not fully approved or out there, but we did go a little bit higher than we normally would.

However, it became an issue of sample size versus working with what would be acceptable to the companies providing the drugs.

Let’s not forget, we have two companies providing additional support including both drugs and financial support for this trial in addition to the already existing NCI funding.

We didn’t want to go too high. We also want to have a sample size that allows us to do the trial in a reasonable way. We’re not going too high, this will have to come in 0.8 or less to be significant and we’ve powered it so that would be the case.

PG: I guess I was asking, Why do you need it? I’m not, certainly, I don’t have an opinion, I don’t feel entitled to it. But why did you think you needed more power?

RH: Well, you want to have—again, I’d rather not discuss details until the trial has the stamp of approval—but you know, want to have a look at your alpha and beta, and you want to make sure you want to do a trial with 85% or more power.

So, we’re meeting all the standards that have currently been applied to intergroup studies. The trial, again, where we’ve targeted a hazard ratio that’s reasonable to be clinically significant in this setting, but where we’re not going for as low as we might in another study with a larger sample size, because we wanted to make a moderate sample size that would allow for it to accrue in a reasonable period of time.

When the trial officially opens, we’ll put that information out there. But until the trial’s publicly available, I’d rather not comment on the exact statistical design. I can assure you that it’s been reviewed with intergroup, with CIRB, it’s gone through CTEP, the NCI lung steering committee, and it’s been reviewed by the industry and the FDA.

PG: I guess what is interesting here is that you do want to look at the subsets, you are looking for more clinical significance here, too.

RH: Right. But we have limited subset analyses, and remember the one thing you’re looking for in this trial: survival.

It’s funny, I don’t know if Rick told you this, but every time we, as a group, would talk to Rick—and you know how we are as investigators, “Oh let’s add a squamous subset”—he was just ready to pull his hair out.

He said, stop it! He would tell us, just keep it simple. It’s like the old adage.

But again, once the trial’s done, we’ll have the data and we can analyze it. We’re in an era where I’m hoping that someday there’ll be more molecular markers we can use either in the blood or the tissue.

We will get tissue, the initial biopsy that was done on each patient, but we’re not going to be getting any new biopsies. If you require a new biopsy in a trial, you’ve immediately cut away 30-40% of the people who would otherwise enroll in the study.

Patients will have refractory lung cancer. So, we’re not requiring new biopsies, but we will have the old biopsies we can go back to and we can always look at subsets, but we’re not powering for different subsets, we’re powering it for survival, and then everything else will be an additional analysis later on.

But really, if this trial hits its survival endpoint, this becomes a standard of care. If it doesn’t, it’s a model for future trials. And it might not. I’m hopeful it will. But then, we’ve got other things coming up the pipeline.

The amazing thing now is we’ve never had more companies and groups come to us at Lung-MAP with new drugs and studies. I think coming out of the pandemic, there are so many drugs being developed in the lab, and I’ve never seen more new drugs or combinations or mechanisms.

I’m hoping the Lung-MAP will help, both with trials like this in the immuno-refractory population, but also targeted therapies—looking at new biomarkers and new mutations.

Then, ultimately, Paul, Jacquelyn, we’re going to personalize immunotherapy. So, at some point we’ll do even better than this trial.

We’ll know who will benefit most from pembrolizumab/ramucirumab because we’ll have a marker that can predict it. Right now, we’re going to have to learn retrospectively from this dataset, from the Lung-MAP trial, from the pragmatic trial and look backwards.

PG: It’s fascinating to see where we are in terms of the political structures in oncology now, because there’s Monica in charge of NCI, who really gets it. There’s Rick, whose idea this is. SWOG jumped in, you jumped in. Ellen Sigal totally understood it immediately, and was brokering it. So, it’s kind of an interesting time to try something completely different, which this is.

RH: Right. Well, the NCI, even before Monica got there, was behind it.

But, gosh, Monica couldn’t be more excited about it. I have known Monica since I was an intern at Brigham and Women’s, and she was a senior resident, and I’ve spoken to her about this, and she’s been nothing but supportive.

By the way, as the Alliance chair, she actually helped keep Lung-MAP going all these years. So, I think she probably will see this as something that she helped grow and now you can take it to the next level.

And we have to do something different. Because immunotherapy, as one example, has changed the world in lung cancer, but we still have so many people who are succumbing to the disease.

The next step is not going to be easy. It’s going to require some science, it’s going to require scientifically guided trials and then validation.

And we can’t validate everything with a big phase III trial. We don’t have enough patients, as far as waiting for those results. And we don’t have enough money, and we don’t have enough resources. And also, it’s the diversity issue. And this is something I’ve been very passionate about.

PG: Let’s talk about that.

RH: It’s very fresh in my mind. I’ve been working with Robert Winn, and as part of the BMS Foundation, we just welcomed our next group of about 60 scholars into a two-year cohort, where they start with an American Associated for Cancer research (AACR) led course on clinical trial design with a focus on diverse populations chaired by Robert, Yu Shyr, and myself working with the AACR, and then they’re funded over the course of two years through the BMS Foundation, and Gilead has gotten involved now, to help them bring trials into diverse populations.

And I spoke about the Lung-MAP trial there, and about this trial as an example of how we can be more diverse. Why? Because trials like this being less complicated, less expensive, it can be run at the point of care.

Bottom line there is more access.

And I’m sitting here now at Yale University, I’ve been at MD Anderson, I’ve been at DFCI, I’ve been at Sloan Kettering in my career. Not everyone can get to those places. It’s a very different population you see when you go to community practices where more than 80% of patients are treated.

So, by having trials where the coordinator doesn’t have to read 50 pages, he or she gets 10, 12 pages and sees the trial is using two drugs that they already know how to use. We don’t have to put 10 pages, Paul, of how to use pembrolizumab. They just go to the package insert, they go on the computer.

These are the types of trials that can be run at the point of care, where people don’t have the desire or resources to travel far distances. They can be treated by their local doctors, whom they trust, and they can get into these trials.

This won’t be the whole answer, but I think it will help. And we’ve already seen on the Lung-MAP trial increased diversity, we’ve seen an increased number of rural patients enrolled as well.

So, if you look at the map of people who have gone on the Lung-MAP trials versus the map of all trials for lung cancer in the U.S., you can see the middle of the country gets filled up, because people that live far from major centers can get on these studies.

So, this pragmatic trial is Pragmatica Lung—Trial One. But I hope that when we next talk, there’ll be two or three of these.

And then, I also know there’s talk of one in melanoma right now, and I know the GI group is talking about it.

This is going to be the way to do it. Simpler trials, real-world, randomized, but getting it out to the entire nation because that’s how you will get more diverse patients enrolled.

What good are these drugs if we don’t get them to the patients who need them?

PG: Monica was very clear on this at the Friends meeting. She basically said, “This is it. This is an example of how we’re going to do this, or how we’re going to reorganize.”

RH: It’s amazing. I was watching her online when I was in Santa Monica chairing the diversity in clinical trials course, so I wasn’t able to be there.

But it was great to see Monica, and Rick, and Ellen all discuss this in such a positive way.

And clearly, having everyone focused together, whether the trial’s positive or not, it’s a step in the right direction. Because it’s the way we need to do these studies and help patients with all cancers, lung cancer being just the first one.

But we’re very happy this came out of Lung-MAP.

We have several other what we call sub-studies moving forward. Perhaps we can do the same thing with them once we get the results, if possible.

PG: What about just this idea that people on clinical trials generally do better on either group, because they’re in clinical trials. There’s some selection that goes on, self-selection as well. 

In this case, you’re really getting people who are sicker, people who are less wealthy, people who are in worse shape.

RH: I think that’s a reason why that hazard ratio target has to be a little bit higher.

But you’re absolutely right. This is going to be much more real-world, and we have to account for that. But I think that’s the whole reason to do this—that we can get more people on trial with real-world issues and comorbidities.

We’ve discussed that with Rick and Harpreet and others, and the feeling is that randomization should take care of many of these issues.

Also, remember, oncologists tend to be, I want to be careful here, but I think oncologists—just because of the level of training and because of how many drugs have been approved in the last year in oncology, or in the last five years—they have to stay up on the data, and have to continuously be aware of the updates regarding efficacy and toxicity.

So, we’re hoping that for the post part the oncologists who administer these trials will have enough wherewithal, to make a choice of who to enroll—there are people who shouldn’t go on studies, or who shouldn’t get more therapy.

I actually just had lunch with Vince DeVita today, and we were discussing this very issue . That some patients should go on clinical studies, but some people may not be appropriate for a certain treatment and should get the best standard of care.

Again, patient safety comes first, but helping patients with these new drugs is the reason we’re doing these studies.

PG: What about other indications that you can see right away where you can do this? You mentioned two possible—colorectal and melanoma. Are there other indications to try it? This approach, pragmatically?

RH: I think it would all depend on where there’s results like this—where there’s a need for some validation of an important question where a phase II randomized study, or maybe it could even be a very good phase II single-arm study, shows some promise.

I think this could be open for any tumor type. I just mentioned the other two, because I know people have asked me about it, and that there’s preliminary discussions.

But, certainly, in areas where immunotherapy works, but there’s refractory disease. Melanoma is one, renal will be another. Colorectal is a disease where immunotherapy works, but not that well.

I think any area is really open for this type of design.

I think people will be watching our trial. We will need to get it open quickly. We need to run it effectively and efficiently. And we’ll see how it goes.

But I hope this will become the norm: simpler trials, quicker to open, open in more diverse populations, with access around the country.

And we have the support of the NCI, the FDA. We are lucky to have the input and support of Ellen Sigal and the Friends of Cancer Research. That’s important as Friends have just been so innovative. I got involved about 10-11 years ago.

Ellen Sigal called me up. I had never met her and said, “Do you want to come and lead one of our workshops on large protocols? Master protocols?”

And I spoke to her for about two hours, and that was the end of my free time. I haven’t had much free time in 10 years. But we’ve been working hard on this and it’s been really great. We are close colleagues and even better friends.

I think we need more innovation, caring about patients, how they feel, getting them the new drugs, and then results, and rigorous data collection. But now, we’re doing it in a way that is simplified so that it doesn’t become so burdensome, and many more facilities can run the trial.

PG: Is there anything we forgot? Anything we didn’t cover?

RH: I just want to say that I’m here speaking on behalf of, it must be, over a hundred people.

I just gave a plenary talk on this at the last SWOG meeting in October, and it’s just been such a village of people working to conduct this public-private partnerships and working with NCI and FDA and the Foundation for the NIH (FNIH), Stacey Adam and the entire group there have been incredible helping to bring this team of investigators together.

I want to end by saying that of primary importance it is all about caring for the patient. So, we need to collaborate. We need to bring the best science to clinical studies and answer these questions in a timely way. And this is one example of how we’re trying to do it in a more rapid and pragmatic way.

I use the word “pragmatic” all the time now. I was just visiting family at Thanksgiving, I was talking about, “Oh, we had a pragmatic Thanksgiving, we had it more quickly.”

We have to do this now. It’s a good approach. Be pragmatic, but careful, and help patients. I’m happy to be a part of this with the entire team.

PG: Well, it’s always better to have a pragmatic Thanksgiving than a Thanksgiving with excess data collection.

RH: Right? Too much stuffing, or something like that.

PG: Too much stuffing. Thank you so much.

RH: That’s what we’re trying to do. We want less stuffing, more meat!