Targeted Therapies in Oncology Staff

A Targeted Oncology Case-Based Roundtable event was co moderator by 

, hematologist/oncologist, Florida Cancer Specialists and Research Institute and pssistant Professor, Internal Medicine, University of Central Florida and 

, founding partner, Florida Precision Oncology R&C, FPO, a Division of 21st Century Oncology Thoracic Oncology, clinical affiliate associate professor, Charles E. Schmidt College of Medicine, Florida Atlantic University secretary, FLASCO. 

The 2 physicians dusccused the case of 71-year-old patients with non–small cell lung cancer.

At our cancer center, because we do a lot of liquid biopsy research, we do concomitant liquid and tissue biopsy at the same time. The benefit there is that you get the liquid result in 8 or 9 days, and you get the tissue result in 3 weeks. In more than 200 patients, we make the decision based on the liquid biopsy [70% of the time].

Have you used the reflex option from Guardant Health, where you do the liquid biopsy first, then they run the tissue reflexively in-house?

I usually try to use liquid biopsy as much as I can. In the type of practice that we have, sometimes they get a small sample [of the tissue]. They get a needle biopsy, and depending on what labs you use, they might not have a panel. They might do whatever marker is easier for them and exhaust the tissue. I find myself using liquid biopsy often, sometimes twice 8 weeks apart, to see what I catch.

When the patient comes in, I usually send for Guardant or Foundation at the same time. If for some reason the tissue is inadequate, I wait until I get the liquid biopsy. If there is a driver mutation already there, I stop. If there is not or you need more tissue, then go ahead and get more tissue. That way, liquid biopsy has made life a little easier to find driver mutations. But we do both, and that’s of a standard practice with all my colleagues.

Is there any particular molecular test you prefer on tissue?

for the past couple years. I prefer RNA-based tissue, and Caris is running an RNA-based platform so we can catch these fusions more accurately. We also had protocols for 

before, so that’s why my concern was to catch fusions. That’s why I preferred a platform that runs DNA and RNA.

That’s a very common pattern to integrate liquid biopsy up front. It’s reliable, fast, and obviously in accordance here with guidelines to check for all these molecular markers. They would probably favor a different sequence of liquid vs tissue, but liquid biopsy is so much more accessible than tissue biopsy that I think the reality overtook the guidelines. Everybody [is] testing 

with these broad panels, then the PD-L1 testing in a second step, and everybody is using next-generation sequencing [NGS] already.

When you have plasma testing up front, you probably would already have information to the full extent. [Is] anybody rebiopsying for tissue biopsy if there’s an insufficient quantity?

Yes, if the liquid biopsy results are not convincing, [if] there is anything that’s not detectable, and if the patient is a nonsmoker, I would go for a rebiopsy. [If] they’re very symptomatic, then I do chemotherapy alone without immunotherapy, then do the rebiopsy.

That’s a very reasonable path. It just takes so much time to repeat it and get the tissues resent. Do you still run into the 14-day rule, [where] hospitals don’t want to send out these tissues for analysis?

Yes, of course. For Medicare patients who are diagnosed as inpatient, then yes. It might be more time efficient if they’re willing to rebiopsy them, especially if they were in another institution that’s not going to release the tissue until 14 days. [In that case], it will be faster to rebiopsy, then send from your own institution.

Yes, I have a lot of them, but nobody has progressed so far from my cohort, so that’s good.

I think all of us are chemotherapy-friendly by training, so we like a strong overall response rate [ORR], and the combo gives a higher ORR. All the combos are 60% to 70%, whereas the single-agent immunotherapy is usually only a response rate of 40%.

That doesn’t mean the combos have a better survival, but most of us prefer first to secure a good response if the patient tolerates [the treatment] because the combo is more toxic than single agent.

I also chose the combination of chemo and immunotherapy for those reasons. You mentioned the patient was symptomatic, so we want to use immunotherapy, but we also want to get a quicker and higher chance of responding. That’s why I chose [No. 1].

Is the person who voted for the combination immunotherapy willing to comment on their choice of medication?

I was tempted because there is a 2-cm single solitary brain mass, so this would be 1 patient I would at least consider ipilimumab [Yervoy] plus nivolumab [Opdivo] plus maybe 4 cycles of chemotherapy there, or just give ipilimumab plus nivolumab. I know there’s a lot of tumor burden there, too, [so I would also try not] to give radiation up front.

If I look at the American Society of Clinical Oncology data from this year, for single-agent ICIs, it’s

clear that the closer you get to 100%, you have an incremental benefit with each 10% that you’re increasing.1 I voted for the addition of chemotherapy up front as well, because I think the patient was symptomatic enough and had large enough tumor burden that I’d be concerned about it.

For these isolated brain metastases, we use radiation therapy more and more generously, but that’s more like a practice pattern rather than an evidence-based approach. They’re all valid here, but I think this would be a symptomatic patient case.

Basically, I would do that same thing. If the patient is symptomatic, I would look for a response quickly. In that case, regardless of the PD-L1 [status or whether he’s] a high expressor, I will work with the chemoimmunotherapy. [In a different scenario, if the patient is asymptomatic] or has stage IV disease, then I will go with the single agent.

Looking at the first-line therapy, the single-agent pembrolizumab [Keytruda], carboplatin and pembrolizumab, atezolizumab [Tecentriq], or cemiplimab [Libtayo] here in the first-line setting as preferred regimens.

Then, with similar level of evidence but emphasized by the NCCN panel here, is ipilimumab plus nivolumab plus chemotherapy, then carboplatin, paclitaxel plus bevacizumab [Avastin] plus atezolizumab. Is anybody using the quadruplet in any setting?2

I don’t know. Maybe if you give a cisplatin plus pemetrexed [Alimta] adjuvant, then the patient fails 6 months later—I don’t think we should repeat the pemetrexed then.

That was my standard of care before, but I changed my approach to those patients when [the patient progresses] on 

mutation, especially if the truncal mutation is still present.

Do you continue the osimertinib [Tagrisso] when you start the quadruplet?

I will not use the quadruplet, but I will keep the osimertinib.

When the patient progresses on an EGFR inhibitor you don’t do the quadruplet anymore? What do you do?

After reviewing everything and looking [at] all the data developing on antiangiogenetic plus 

mutation, the IMpower150 [NCT02366143] is driven by the addition of bevacizumab more than any other thing.3

With osimertinib, one of the beautiful things of that drug is protecting the patient [from] brain metastases or getting a great response in the brain. If the progression is below that and the brain is fine, I would not remove the osimertinib in my patients, especially if the truncal mutation remains. So I will add chemotherapy, but I will keep osimertinib on board.

This is getting challenging to pick, and we’ve heard a lot of good arguments for each of these approaches. The brain metastases, the molecular selection, the clinical features—this is not going to be as straightforward as carboplatin/paclitaxel used to be for us, and [it’s] never going to be straightforward again. In the nondriver mutations, we still have a lot of prioritizing to do.

You can use any of the 3. We start with pembrolizumab, and probably the market share is pembrolizumab, followed by atezolizumab, and now cemiplimab.

All of them are important. With efficacy, we’re seeing similar effects, but are there any differentiating factors in the trial design or in the data, the way that you would be including in the decision-making which one to choose? Do you have any formulary preferences? Is there anything that’s institutionally mandated in your case?

I basically take everything into consideration. I try to look at the patient, the goal of care, and then I select [treatment]. I’m more biased toward pembrolizumab, because I think there is a lot of data with it. Before we had nivolumab and other PD-L1 inhibitors that have a longer treatment interval at 4 weeks or 6 weeks, pembrolizumab was 3 weeks vs nivolumab, which was 2 weeks, for example.

I don’t think it makes much sense to switch from [one] checkpoint to another. I just use pembrolizumab in everybody. There [are] no head-to-head data, and it’s just confusing to the staff and everybody else to switch every time a patient walks in. Without head-to-head data, as you said before, it’s practically impossible to do cross-trial comparisons in these patients, so I just pick 1 and use it for most everybody.

I don’t know [whether] you all noticed recently that NeoGenomics wants to switch away from using the 22C3 [test] to their own in-house assay. They were not going to stop running 22C3, and a lot of hospitals use that. So I thought, “How are they going to do that without any validation?”

The 22C3 assay is kind of the standard. It would be hard for me to see why NeoGenomics—I’m not sure [whether] this is a technical issue or [whether] they’re using a different platform, but aside from the SP142 assay, they have a pretty good congruency. What do you use in your practice?

[I use the 22C3 assay], but when we have a long consultation, I send this to Caris or Tempus, someone that [has] DNA and RNA NGS. I don’t recall on Tempus, but on Caris, if it’s lung cancer, they will report [the 3 of them] to you.

They will report [to] you [the] 22C3, SP263, and SP142 assays. In that case…if I want to use pembrolizumab, my 22C3 assay is there. That’s why at least Caris does that. I don’t know about other vendors. I don’t remember correctly [whether] Tempus does that too.

The problem is the technology. Dako and Ventana run different machines, so it’s not easy for each hospital in [the US] to buy both technologies. For us, [this is just for lung cancer]. We only care about these 4 or 3 markers. But remember, there are indications for other cancers, then they do the immunohistochemistry for other things, even for TTF1.

That’s why it was a pain in the neck [before], because if you have the Dako machine, you can only run the Dako. [If] you have the Ventana, you can only run SP142. But now that we have validated, SP263 doesn’t matter. If you only have the Ventana machines, you can do SP263. If you have the Dako machines, you do the CD28. Now I think we’re fine. If you run SP263 instead of SP142, I think they are equivalent now, according to what we have done. So your hospital needs to buy only 1.

The frontline indications here were all greater than 50% except for pembrolizumab.³ The 1 [to] 49 approval [is] controversial, and [it] probably shouldn’t be used alone. There were some differences with dosing: twice weekly over 3 and 4 weeks with atezolizumab, or 3 times weekly for cemiplimab, then 3 or 6 times weekly for pembrolizumab. I don’t want to open the box of when to stop. I’m not sure we have a safe end point here, and the warnings and precautions here [are] relatively similar.

So how long do you continue the single agent? It sometimes gets dictated by the circumstances. Two years in most trials, so that’s kind of a benchmark for most targets, below which we typically don’t stop. It’s sometimes also patient preference.

Usually 2 years, but recently I’ve been using circulating tumor DNA to see [whether] they’re really negative at that time point before discontinuation. Because some of these patients are not, and they might be deriving that benefit. And if you stop them, they might progress, and you don’t know [whether] they really progressed on PD-L1, [whether they are] resistant, or [whether they are] progressing because you took them off. It’s hard to answer that question in a timely manner, but if you know what their circulating tumor DNA status is, that helps you monitor them longitudinally after discontinuation.

1. Stenger M. Outcomes and toxicity with single-agent immune checkpoint inhibitor treatment in patients with cancer aged ≥ 80 years. The ASCO Post. November 11, 2021. Accessed November 24, 2021. https://bit.ly/3nPH897

2. NCCN. Clinical Practice Guidelines in oncology. Non-small cell lung cancer, version 7.2021. Accessed November 24, 2021. https://bit.ly/3HQ6bAW

3. Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. 

. 2016;387(10027):1540-1550. doi:10.1016/S0140-6736(15)01281-7

Articles

A 72-year-old White man presented with chest pain, cough, and dyspnea. He had a medical history of type 1 diabetes that was adequately controlled, and was a former smoker.

Roundtable Discussion: Dietrich and Santos Look at Targeted Treatments for Patients With NSCLC

: Please provide an overview of graft-vs-host disease (GVHD) after allogeneic transplant and the challenges it presents for patients.

Allogeneic transplantation is a potential curative modality for many high-risk hematological malignancies and some nonmalignant conditions as well. We believe the therapeutic mechanism of action [MOA] of allogeneic transplant is 2-fold. One, there’s enhanced cytotoxicity from the conditioning regimen that we give before every transplant, but once we ingraft donor hematopoiesis in the recipient, we hope those donor white blood cells can reconstitute, ultimately providing the recipient with an intact immune system. And 2, we hope to cultivate a therapeutic immunological graft vs malignancy effect. This immunological therapeutic mechanism is what we believe to be the dominant MOA in allogeneic transplantation. The issue with this is that transplants are not done from identical twins, so the donor and host are inherently unique allogenic individuals. When the donor immune system grows up in that recipient, there can be an attack on the recipient’s healthy tissues, and this is what GVHD is.

What are the differences between acute and chronic GVHD?

There are generally 2 types of GVHD: acute and chronic. They’re named that way partly because of the timelines when they commonly occur, but also because of their clinical aggressiveness and how long symptoms will remain and how long patients will remain on therapy.

Acute GVHD probably occurs in about 30% to 40% of individuals if we look at transplant patients as a whole—[that’s] the number of patients that we have to act upon or deliver some sort of systemic therapy for. Acute GVHD commonly involves the skin, the GI [gastrointestinal] tract, and the liver, and usually occurs in the first several months after transplantation. It’s important to note that these days, with all kinds of different conditioning regimens and RAF sources and transplant platforms, which have different kinetics of immunoconstitution, GVHD is no longer defined by the first 100 days for acute and afterward for chronic. It’s only defined by clinical manifestations of acute vs chronic.

Chronic GVHD tends to occur in the first few months after transplantation, rarely occurring before the first 3 months. It is less traumatic than acute [GVHD and] its rash is a bit different, not as angry and erythematous but looking more like psoriasis or eczema. It commonly involves the skin as well as the eyes and the mouth, which are more dry eyes−dry mouth syndrome, but chronic GVHD can involve almost any organ in one’s body. The joints can hurt, the muscles can become inflamed, and chronic GVHD also is a state of significant immune dysregulation. Not only do you have the direct attack on the organs that give you the classic clinical manifestations of chronic GVHD, but certain auto-immune phenomena can arise, such as nephrotic syndrome or polymyositis. These are commonly seen autoimmune manifestations in the context of GVHD.

What are the risk factors for acute and chronic GVHD?

The risk factors for GVHD are pretty much the same for both acute and chronic. We’ve classically defined clinical risk factors even before transplant and they start with histocompatibility or HLA [human leukocyte antigen] matching between the donor and the recipient. Other risk factors include an increased intensity of the conditioning regimen, specifically the use of total body radiation, [and] donor sources, in the sense that peripheral blood stem cells will give more GVHD, specifically chronic, when compared to bone marrow. Age of both donor and recipient [is another risk factor], as the older age of either will lead to a higher incidence of GVHD. There is also evidence that a female donor compared with a male donor will lead to an increased incidence of GVHD.
Interestingly, a recent risk factor identified has been the microbiome. This is the diversity of bacteria in one’s GI system or colon and there’s clear evidence, at least from an associative standpoint, that when the microbiome diversity is restricted, that often leads to a higher incidence of complications after transplant, such as GVHD. We haven’t proved a cause and effect, and it may just be a marker of illness, but much research is going on in that regard.

Chronic GVHD seems to follow acute GVHD, meaning that the sequence of events is set very early on. The biggest risk factor for chronic GVHD is prior acute GVHD, and that has been proved in many series throughout the years.

We generally regard acute and chronic GVHD these days as separate diseases. They have distinct clinical manifestations. Acute has the angry erythematous skin, maculopapular skin rash, as well as diarrhea when the lower GI tract is involved. And chronic GVHD looks more like classic autoimmune phenomena, like SjÖgren syndrome, eczema, and psoriasis. That’s because physiologically, we think they morph differently in the immune system. Acute GVHD is far more what we believe to be a direct T-cell engaged activity or a Th1 [T helper type 1]–driven immune response, whereas chronic GVHD is much more Th2 involved. There is involvement in B cells, the humoral immune system, and it’s not uncommon to see a peripheral eosinophilia in these patients as well. Most patients, when we talk about GVHD, usually fall into one box or the other.

What are current best practices for the prevention of GVHD?

Prevention for GVHD is given after any allogeneic transplantation. There are 2 big categories of GVHD prevention. One is graft manipulation, and this is much less common because it involves laboratory expertise and resources but involves taking the donor graft and manipulating it in certain ways. This is commonly referred to as T-cell depletion and can be done in positive selection and selecting for the hematopoietic progenitor cells or [through] negative selection in eliminating a certain subset of cells that may cause GVHD.

The [other,] more common GVHD prevention is with drugs or pharmacological agents. The international framework over the last several decades has been the backbone of calcineurin inhibitors paired with methotrexate or mycophenolate. More recent years have seen the addition of sirolimus [Rapamune] either with or instead of methotrexate, and many centers across the United States and certainly across Europe will add a polyclonal anti–T-cell globulin, often referred to as ATG [antithymocyte globulin], to help in GVHD prevention. There are other agents being studied and being added onto these backbones and those trials are ongoing.

The newer regimen in terms of pharmacological prophylaxis of GVHD that has emerged over the last decade is based around the administration of high doses of posttransplant cyclophosphamide, often given on day 3 and 4 after transplantation. The mechanism here is thought to be elimination of alloreactive cells in that first week as well as preservation of regulatory T cells, and this is generally paired with tacrolimus or sirolimus with mycophenolate. The post-transplant cyclophosphamide regimens were first shown to be very efficacious in haploidentical, or mismatched, transplantation.

 Now they are being tested in conventionally matched transplantation prospective trials to see if they can replace the standard of care that we commonly use. We anticipate these results over the next few years, and it’s a very exciting time as we continue to make progress.

How is GVHD managed in the frontline setting?

Initial treatment for GVHD, unfortunately, remains high-dose systemic steroids. In general, if we have to treat acute GVHD, we give 1 to 2 mg/kg/day of prednisone or its intravenous [IV] equivalent, depending on the patient’s clinical manifestations. Traditionally, if it’s skin only, we’ve leaned toward 1 mg/kg, and if it involves a lower GI tract or, more rarely, the liver, we generally increase to 2 mg/kg/day, often giving IV because of how sick the patient is. We have tried to improve upon this but have yet to do so. Unfortunately, about 50% of patients will become steroid refractory or need a second-line agent.

What is the definition of refractory in the setting of acute and chronic GVHD?

The definitions of “steroid refractory” have traditionally been the following: either patients get worse in the first 3 days of starting steroids, they don’t get better after at least 1 week, or they do respond [but] another organ develops manifestations; or they do respond, and then upon tapering of steroids their symptoms come back and they flare.

Chronic GVHD also uses systemic steroids. That’s more difficult as well because patients, months after transplant, have usually experienced some sort of comorbidity and tolerate steroids less well at that point. And for chronic GVHD, steroids are [used] for a much longer period of time. The dose is lower. We generally start at maybe 0.5 to 1 mg/kg depending on how aggressive we perceive the disease to be. But once chronic GVHD sets in, there is some that is likely causing irreversible organ damage and patients stay on steroids for a very long time.

A recent abstract from the Chronic Graft Versus Host Disease Consortium would suggest that only a third of patients ever get off steroids for at least a year after starting treatment for chronic GVHD, making it essential that once we start treating patients, we set expectations and understand what we’re treating. Research has also [been devoted to] trying to improve upon therapy for chronic GVHD as well, but initial treatment does remain high-dose steroids. Long-term follow-up shows that about 60% of patients that we start on steroids for chronic GVHD require a second agent. The definitions of steroid refractory for chronic GVHD are not as clear cut given the kinetics of the disease and response. In general, for practical purposes, we wait at least 1 to 2 months when starting an agent to determine if patients are refractory to such treatment to add further treatment.

What available treatments or strategies can be used in patients with steroid-refractory acute GVHD?

For acute GVHD, those who are refractory to first-line steroids, we did not have a standard of care until recently for steroid-refractory disease. Historical therapies often focused on what we believe to be the path of physiology, which was T-cell attack of the host tissues by the donor. The traditional therapies were anti–T-cell therapies that, unfortunately, gave more cumulative immunosuppression. Oftentimes what we dealt with was a lot of opportunistic infection and toxicity with very few patients surviving in the long run.

Modern therapies have focused more on specific pathways of inflammation that we believe are active in GVHD. Some trials are focused on organ resiliency, preservation of organ-specific stem cells, as well as looking at the vascular endothelium and trying to prevent thrombotic microangiopathy [TMA] to improve response rates. But these days, the options we have for patients with steroid-refractory acute GVHD [include] ruxolitinib [Jakafi], which was approved in 2019, the first agent to ever be approved in this space.

 Some centers still do use ATG products in low doses. There is some literature [about using] TNF [tumor necrosis factor] antagonists.

We ourselves have used a lot of vedolizumab [Entyvio], which is a monoclonal antibody against α4β7 integrin to modulate lymphocyte trafficking away from the intestinal tract. And there’s been some recent research on microbiome-directed interventions, such as third-party fecal microbiota transplantation, with multiple anecdotes showing success in steroid-refractory acute GVHD.

The MOAs here are all quite varied. Ruxolitinib targets JAK1 and JAK2, which are active in many signaling cascades. They are active in the IO1 and IO6 signaling cascade and they appear to also influence lymphocyte trafficking as well as preservation of regulatory T-cells. I mentioned the MOA of vedolizumab for microbiota transplantation; that all gets back to increasing the diversity of the microbiome and the interactions between the microbiome and your mucosal immune system that shape the immune system at large. With ATG you bluntly remove donor T cells in hopes that that can bring about the right action.

What about treatments for steroid-refractory chronic GVHD?

In chronic GVHD, historically, the treatment options were quite similar. We felt that we just had to suppress the donor immune system, and a lot of patients, again, suffered from opportunistic infection. We need to realize for chronic GVHD that by the time we treat it, there is some irreversible damage, and we should try to only reverse what we can reverse and shape our expectations for ourselves and our patients that way.

But after steroids, we do have an approved agent, ibrutinib [Imbruvica]. That’s a Bruton tyrosine kinase [BTK] inhibitor, which targets the B-cell arm in the immune system. There is evidence that the B-cell arm is active in many patients with chronic GVHD. A lot of exciting laboratory work had shown in male recipients with female donors the formation of these anti H-Y antibodies directed against the Y chromosome, showing there was some B-cell or plasma cell activity. Ruxolitinib has been shown to be quite active in chronic GVHD as well, and we use it very routinely for that indication. There is an agent called belumosudil [Rezurock], made by Kadmon Pharmaceuticals, that recently had exciting results in the ROCKstar clinical trials [(KD025-213; NCT03640481) and was approved] this year.

 And that targets ROCK [Rho-associated coiled-coil kinase], an arm thought to be active in fibrosis.

Please review the patient populations, design, and key safety and efficacy results from the REACH-1 and REACH2 trials.

A lot of the progress over the last few years in GVHD is due to the results we’ve seen from clinical trials involving ruxolitinib and the major REACH-1, REACH2, and REACH3 trials. The company and the investigators really should be applauded for carrying these out. Trials in GVHD are difficult to do. Patients are sick and they’re heterogeneous, but these trials have pushed us a step forward and we hope more progress is on the way.

REACH-1 [NCT02953678] was a phase 2 single-arm trial carried out at several centers across the United States that involved 71 patients with steroid-refractory acute GVHD and treated [them] with ruxolitinib. Patients were given a dose of ruxolitinib of 5 mg twice a day to start, and if after 3 days they tolerated it, the dose was increased to 10 mg twice a day. The primary end point in this trial was 28-day overall response rate [ORR]. That’s the consensually agreed-upon primary end point, as it has been shown that that generally correlates with long-term outcomes of 6-months overall survival [OS] and non-relapse mortality.

The ORR in REACH-1 was 55%, with 27% of patients achieving a complete remission. The best ORR at any time in these patients who received any doses of ruxolitinib was over 73%, and at 6 months the OS rate was about 50% of patients. In this high-risk population, responses were seen across all organ manifestations in general—the skin, GI tract, and the liver.4 All of us who collaborated on this trial or saw the results were impressed with what we had seen. It was on the strength of this study that ruxolitinib was FDA approved for steroid-refractory acute GVHD in patients 12 [years] and older.

REACH2 [NCT02913261] was a great validation of the REACH-1 results. REACH2 was a phase 3 international trial and it involved 309 patients with steroid-refractory acute GVHD. Patients were randomized to either ruxolitinib at 10 mg twice a day vs a control arm that was summarized as BAT [best available therapy]. The study couldn’t pick 1 control because there is no 1 international standard for treating steroid-refractory acute GVHD. Centers were allowed to choose among 9 commonly used options, and they were combined together to form the BAT control group.

Again, the primary end point was day 28 ORR and this favored ruxolitinib at 62% vs 39%.5 When looking at the secondary end points of durable response rate at day 56, after 8 weeks on the trial, median OS showed a benefit as to what had been seen in REACH- 1, and REACH2 showed that the main adverse events were cytopenias and thrombocytopenia and possibly an increase in the reactivation of cytomegalovirus. These results are impressive.

How has the approval of ruxolitinib for this indication changed treatment sequencing and outcomes for patients with steroid-refractory acute GVHD?

It should be emphasized that the durable response rate at 8 weeks, while it was 40%—about twice as much as the control— still leaves much room for improvement. Much more research has to be done to help these patients optimally. That’s where we stand for steroid-refractory acute GVHD.

More agents are on the way as we do more trials, but the REACH-1 and REACH2 trials have given us a standard. It has led to thinking, as more agents are studied, that we now have a control—that is ruxolitinib—and a benchmark to better design future randomized trials. The approval has given patients more access to an efficacious agent.

Please review the patient population, design, and preliminary safety and efficacy results of the REACH3 trial.

The main study [in chronic GVHD] was REACH3 [NCT03112603], a phase 3 international study involving about 329 patients. The eligible patients were adults with steroid-refractory chronic GVHD, and patients were randomized to ruxolitinib again vs a BAT arm. Investigators were able to choose from a variety of options that they commonly used to treat steroid-refractory chronic GVHD. The primary end point here was a 6-month ORR, as you have to give more time to observe a response and give more time for your agents to work [with chronic GVHD].

Again, the analysis favored patients who received ruxolitinib who had a 50% ORR at 6 months vs 26% in the control arm of BAT.

 It’s worth pointing out that a minority of these responses, under 7%, were complete remissions, which is not surprising for chronic GVHD. The secondary end points were failure-free survival, which also favored the ruxolitinib arm significantly, as well as a reduction in symptoms. With chronic GVHD we have to include patient-reported outcomes because that’s hugely important for these patients who will deal with this disease chronically in the long run. On the strength of this study, we [saw] that ruxolitinib [gained] approval from regulatory agencies this year (see pages 20-21).

It has brought about responses in many patients that we treat these days [for whom] we’re able to use the drug. And we believe it has a place in the treatment for chronic GVHD.

What are some remaining unmet needs and what does the future hold for patients with steroid-refractory GVHD?

Looking forward, we need to think about better ways to design studies for acute GVHD. It is clear that not all patients are biologically alike and there are some patients who are going to do well and others who are not. The ability to design trials using these methods of risk stratification will ultimately help improve the field. These biomarkers can, perhaps, help to steer patients toward 1 therapy or another if they can also be predictive of response. That’s the future. It’s taking a population that’s very heterogeneous, like [those who have] acute GVHD, [and] being able to risk stratify them based on some system and conduct such trials.

In the discussions that we have had nationally, what we’re looking at is that patients who are low risk and who are going to do well can get away without steroids and we can use other agents. A cooperative group trial already used sirolimus in this regard, and recently a completed trial also used itacitinib, a JAK1 inhibitor. We’ll see if we can replace steroids for a subset of the population or, perhaps, taper steroids even faster in such patients. For the high-risk patients, I’m not sure any of us think we can get away without steroids at the moment, and perhaps adding a drug to steroids. Maybe [when] trying something like ruxolitinib, which is approved, or any of the other agents being studied, the question is: how do we advance in chronic GVHD.

There are some issues that are similar to acute in the sense that chronic GVHD is a heterogeneous disease, both clinically and biologically. The world of biomarkers for chronic GVHD is a bit behind that for acute. If we’re able to develop some biomarkers that can help restratify those high-risk vs low-risk patients or ultimately can predict which patient will respond to which therapy, those will be huge advances in the field.

A lot of us who look at chronic GVHD need to think about what we tell our patients, not only before transplant but also once we start treatment. We need to frame the expectations of how long symptoms will [last] and what our expectations are, which inherently are to stop the progression first and then to improve. We need to accept that once chronic GVHD has set in, there is some element of organ irreversibility, and we need to acknowledge that with our patients.

Looking at all the clinical trials in chronic GVHD, complete responses are oftentimes in the single digits. That cannot be a realistic end point for this population, at least with the agents we have now. But looking forward, there’s a lot of research going on in all phases of therapy—frontline, refractory, and prevention—and I’m just grateful to be a part of this. It’s an exciting time for GVHD.

1. Chiusolo P, Bug G, Olivieri A, et al. A modified post-transplant cyclophosphamide regimen, for unmanipulated haploidentical marrow transplantation, in acute myeloid leukemia: a multicenter study. 

. 2018;24(6):1243-1249. doi:10.1016/j. bbmt.2018.01.031

2. FDA approves ruxolitinib for acute graft-versus-host disease. FDA. May 24, 2019. Accessed October 4, 2021. https://bit.ly/3uCSAGS

3. FDA approves belumosudil for chronic graft-versus-host disease. FDA. July 16, 2021. Accessed October 4, 2021. https://bit.ly/3A9d8rQ

4. Jagasia M, Perales MA, Schroeder MA, et al. Ruxolitinib for the treatment of steroid-refractory acute GVHD (REACH1): a multicenter, open-label phase 2 trial. 

2020;135(20):1739-1749. doi:10.1182/blood.2020004823

5. Zeiser R, von Bubnoff N, Butler J, et al; REACH2 Trial Group. Ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease. 

. 2020;382(19):1800-1810. doi:10.1056/NEJMoa1917635

6. Zeiser R, Polverelli N, Ram R, et al; REACH3 Investigators. Ruxolitinib for glucocorticoid-refractory chronic graft-versus-host disease. 

. 2021;385(3):228-238. doi:10.1056/NEJMoa2033122

7. FDA approves ruxolitinib for chronic graft-versus-host disease. FDA. September 22, 2021. Accessed October 4, 2021. https://bit.ly/3BfXCvu

During an interview, Yi-Bin Chen, MD, an investigator of the REACH trials, discussed acute and chronic graft-versus-host disease and treatment options. 

Investigator’s Perspectives on GVHD: The REACH Trials

RET inhibitors pralsetinib Gavreto) and selpercatinib (Retevmo) have already demonstrated significant efficacy in treating a broad patient population with tumors harboring 

fusions and mutations. Indeed, both RET inhibitors are approved for use in the United States for the treatment of patients with metastatic 

fusion–positive non–small cell lung cancer (NSCLC).

However, only pralsetinib has been approved by the National Medical Products Administration of China as a treatment for patients with locally advanced or metastatic 

fusion–positive NSCLC following platinum-based chemotherapy.

In findings presented during the International Association for the Study of Lung Cancer 2021 World Conference on Lung Cancer from 2 separate trials, pralsetinib and selpercatinib both showed significant efficacy in the treatment of Chinese patents with advanced 

In data from the Chinese cohort of the global phase 1/2 ARROW study (NCT03037385), pralsetinib demonstrated promising results in patients with advanced 

fusion–positive NSCLC regardless of previous therapies.

“Pralsetinib is a promising type of treatment with rapid and durable clinical activity in Chinese patients with 

fusion–positive non–small cell lung cancer regardless of the previous treatment. And the safety profile is manageable and the tolerable,” said lead study author Qing Zhou, MD, of the Guangdong Lung Cancer Institute in China.

There were 63 patients enrolled in the Chinese cohort of the study; 33 had prior platinum-based chemotherapy treatment, and 30 had no prior systemic treatment.

Those who had prior chemotherapy achieved an overall response rate (ORR) of 66.7% (n = 22; 95% Cl, 48.2%-82.0%) at a median follow-up of 17.0 months (range, 16.3-18.1); 3% (n = 1) had a complete response (CR), and 63.6% (n = 21) had a partial response (PR) (

Researchers reported that the median time to first response among this pretreated patient cohort was 1.87 months (range, 1.7-3.8). Six-month and 9-month duration of response (DOR) rates were 77.3% (95% Cl, 59.8%-94.8%) and 50.0% (95% Cl, 29.1%- 70.9%), respectively. Treatment duration was a median of 14.65 months (range, 0.9-20.0).

In the group of patients who had not received prior therapy, the ORR was 80% (n = 4; 95% Cl, 61.4%-92.3%), of which 6.7% (n = 2) experienced a CR and 73.3% (n = 22) experienced a PR. Median follow-up for these patients was 8.2 months (range, 7.1-8.6), and the median treatment duration was 7.13 months (range, 0.5-14.0). Median time to first response among the group was 1.87 months (range, 1.7-3.8). DOR rates were 76.7% (95% Cl, 55.6%-97.8%) and 38.3% (95% Cl, 0.0%-92.5%) at the 6- and 9-month marks, respectively.

Of note, 68.18% (n = 15) of responders who were on platinum-based chemotherapy previously and 79.17% (n = 19) of those without prior treatment remain on the treatment.

“I think pralsetinib should be a new standard of care for both Chinese patients and other global patients with 

 fusion–positive advanced non–small cell lung cancers,” Zhou said.

Data from the study reported that pralsetinib was well tolerated in the Chinese patient cohort with a manageable safety profile. Treatment-emergent adverse events (TRAEs) were experienced in all 68 patients, 7 of which discontinued treatment due to a TRAE.

“I think compared to other targeted treatment, we should pay more attention to the hematological toxicities,” Zhou noted, highlighting neutropenia, anemia, and decreased platelet count as some of the hematological AEs to look out for.

Common any-grade TRAEs included increased aspartate aminotransferase (AST) levels (80.9%), decreased white blood cell count (60.3%), increased alanine aminotransferase (ALT) levels (57.4%), increased blood creatine phosphokinase levels (45.6%), hypertension (35.3%), increased blood creatine levels (29.4%), increased conjugated bilirubin levels (27.9%), constipation (27.9%), increased γ-glutamyltransferase levels (27.9%), increased blood alkaline phosphatase levels (26.5%), malaise (25.0%), increased blood bilirubin levels (23.5%), and hypocalcemia (20.6%).

Grade 3 or 4 TRAEs that occurred in 5% or more were decreased lymphocyte counts (5.9%), leukopenia (5.9%), and hypophosphatemia (11.8%).

Selpercatinib demonstrated robust and durable efficacy with a favorable safety profile in Chinese patients with advanced, 

fusion– positive NSCLC in the phase 2 LIBRETTO-321 trial (NCT04280081).

Among a subset of patients with central lab–confirmed 

-fusion status, considered the primary efficacy analysis set (PAS; n = 26), the Independent Review Committee (IRC)–assessed ORR observed with selpercatinib was 69.2% (95% CI, 48.2%-85.7%), with 94.4% of responses ongoing at a median follow-up of 9.7 months. In all patients with NSCLC (n = 47), the IRC-assessed ORR achieved with the agent was 66.0% (95% CI, 50.7%-79.1%), with 96.8% of responses ongoing at a median follow-up of 10.3 months.

“These findings were consistent with previous data in global and East Asian populations from [the phase 1/2] LIBRETTO-001 trial [NCT03157128], suggesting that selpercatinib is a promising treatment option for Chinese patients with 

fusion–positive NSCLC,” lead study author Shun Lu, MD, PhD, said. Lu is a professor at Shanghai Chest Hospital at Jiao Tong University and chief of the Shanghai Lung Cancer Center in China.

The ongoing, open-label, multicenter, phase 2 LIBRETTO-321 trial being conducted in China is examining the safety and efficacy of selpercatinib in patients 18 years or older with treatment-naïve or pretreated locally advanced or metastatic tumors.

A total of 77 patients were enrolled in the study and divided into 3 cohorts. Cohort 1 (n = 30) was comprised of patients with advanced 

fusion–positive solid tumors who had progressed on or were intolerant to 1 or more prior standard first-line therapies or those who had declined or were not suitable to receive standard frontline therapy. Cohort 2 (n = 26) enrolled patients with advanced 

-mutant medullary thyroid cancer who had or had not received previous systemic therapy.

Lastly, patients enrolled to cohort 3 (n = 21) included those with advanced 

-altered solid tumors that met the requirements for cohorts 1 or 2 but did not have measurable disease, those with a 

alteration/activation that did not meet the criteria for cohorts 1 or 2, and those who were circulating tumor DNA positive for a 

alteration that was not known to be present in their tumor.

The analysis included 47 patients with NSCLC and a subset of 26 patients who had NSCLC confirmed via a central laboratory to have 

Study participants received oral selpercatinib at a twice-daily dose of 160 mg, administered in 28-day cycles. Treatment was administered until either disease progression, intolerable toxicity, withdrawn consent, or death. Notably, patients could continue the study regimen beyond progression if continued benefit was observed.

The primary end point of the study was ORR per RECIST v1.1 criteria and IRC assessment. Secondary end points comprised ORR per RECIST v1.1 criteria and investigator assessment, DOR, central nervous system (CNS) ORR, CNS DOR, clinical benefit rate, time to relapse (TTR), time to best response, progression-free survival, overall survival, pharmacokinetics, and safety.

Across the 2 groups, patients had a median age of 53 years (range, 26-72), and the majority were female (55.9%) and had an ECOG performance status of 1 (86.8%). The median number of prior treatments received was 2 (range, 0-9), and most patients had previously undergone treatment with platinum-based chemotherapy (68.9%). Additionally, 33.5% of patients were treatment naïve, 33.5% had CNS metastases, and 91.5% had measurable disease.

Additional data showed that in the PAS subset, selpercatinib elicited an ORR of 61.1% (95% CI, 35.7%-82.7%) in those who were pretreated (n = 18) vs 87.5% (95% CI, 47.3%-99.7%) in those who were treatment naive (n = 8) (

). In the all-NSCLC group, the ORRs experienced with the agent in those who were pretreated (n = 36) and treatment naive (n = 11) were 58.3% (95% CI, 40.8%-74.5%) and 90.9% (95% CI, 58.7%- 99.8%), respectively.

In the PAS subset, 1 patient achieved a CR to treatment (3.8%), and 17 achieved a PR (65.4%); the stable disease rate was 26.9% (n = 7). In the all-NSCLC population, 3 patients achieved a CR (6.4%), 28 achieved a PR (59.6%), and the stable disease rate was 29.8% (n = 14).

Additionally, 80% of patients with measurable CNS lesions at the time of enrollment achieved an IRC-assessed confirmed intracranial response at a median follow-up of 9.3 months.

The median TTR for both groups was 1.8 months, and the median DOR had not yet been reached in either group. At data cutoff, 94.4% of responding patients in the PAS subgroup continued to respond to treatment vs 96.8% in the all-NSCLC population.

In a safety population comprised of 77 patients, 97.4% experienced at least 1 treatment-emergent AE (TEAE) of any grade, and 97.4% reported a TRAE of any grade. The most common grade 3 or higher TEAEs experienced with selpercatinib included hypertension (19.5%), increased ALT levels (15.6%), and increased AST levels (15.6%). Frequently reported grade 3 or higher TRAEs included hypertension and increased ALT and AST levels (15.6% each).

TEAEs resulted in treatment discontinuation in 5.2% of patients (n = 4), with 3.9% (n = 3) considered related to selpercatinib. Moreover, 32.5% (n = 25) of patients required dose reductions. Additionally, 1 patient died because of grade 5 acute pancreatitis, although this effect was not considered related to treatment with selpercatinib.

Selpercatinib is currently being examined as initial treatment in patients with advanced or metastatic 

 fusion–positive NSCLC as part of the phase 3 LIBRETTO-431 trial (NCT04194944).

1. CStone announces new drug approval of Gavreto (pralsetinib) as first selective RET inhibitor in China, providing a new therapy for a subset of non-small cell lung cancer patients. News release. CStone Pharmaceuticals. March 24, 2021. Accessed October 1, 2021. https:// bit.ly/39W4P88

2. Zhou Q, Wu Y-L, et al. Efficacy and safety of pralsetinib in Chinese patients with advanced RET fusion+ non-small cell lung cancer. Presented at: 2021 World Conference on Lung Cancer; September 8-14, 2021; virtual. Abstract M02.02.

3. Lu S, Cheng Y, Huang D, et al. Efficacy and safety of selpercatinib in Chinese patients with RET fusion-positive non-small cell lung cancer: a phase 2 trial. Presented at: International Association for the Study of Lung 2021 World Conference on Lung Cancer; September 8-14, 2021; virtual. Abstract MA02.01.

Data continue to support the use of RET inhibitors is patients with RET fusion-positive non–small cell lung cancer.

RET Inhibitors Show Promise for Chinese Patients With RET Fusion–Positive NSCLC

As sotorasib (Lumakras) is the first agent to be FDA approved for the treatment of patients with 

G12C–mutant non–small cell lung cancer (NSCLC), there is a great deal of interest in the KRAS inhibitor and its potential benefit.

The FDA approved sotorasib for patients with locally advanced or metastatic NSCLC harboring a 

G12C mutation who have previously received at least 1 systemic therapy. The agency’s decision was based upon results from the phase 1/2 CodeBreaK 100 trial (NCT03600883).

 The study showed an objective response rate (ORR) of 37.1% (95% CI, 28.6%-46.2%), a median progression-free survival (PFS) of 6.8 months (95% CI, 5.1-8.2), and a median overall survival (OS) of 12.5 months (95% CI, 10.0-not estimable) among participants.

Following the regulatory decision, analyses of CodeBreaK 100 continue to further investigate patient and disease characteristics for factors that could affect potential benefit from this first-in-class KRAS inhibitor.

Two analyses presented during the International Association for the Study of Lung Cancer 2021 World Conference on Lung Cancer offered some characteristics that could lead to hypothesis-generating variations in clinical response patterns and duration of benefit from treatment with sotorasib in patients with 

Sotorasib elicited intracranial complete responses (CRs) and continued intracranial stabilization in patients with 

G12C–mutated NSCLC and stable brain metastases who had previously been treated with radiation or had undergone surgery, according to a posthoc analysis of the CodeBreaK 100 trial.

At a median follow-up of 12 months, sotorasib led to a confirmed ORR per RECIST 1.1 criteria of 25% in patients with NSCLC and baseline brain metastases (n = 40) compared with 42% in patients without baseline brain metastases (n = 132). The disease control rates (DCRs) were 77.5% vs 84.1%, respectively (

Additionally, the median PFS was 5.3 months (95% CI, 2.7-9.3) in patients with brain metastases compared with 6.7 months (95% CI, 5.3-8.2) in those without brain metastases. The median OS was 8.3 months (95% CI, 7.3-12.5) vs 13.6 months (95% CI, 10.0-not estimable), respectively.

Notably, the intracranial DCR was 88% among 16 patients with evaluable brain metastases.

“Brain metastases are common in patients with NSCLC, [occurring in 30% to 50% of patients], and are associated with poor outcomes,” wrote Suresh S. Ramalingam, MD, and colleagues in a presentation of the data.

 The standard of care for patients with NSCLC and brain metastases is docetaxel plus ramucirumab (Cyramza), which is associated with median PFS estimates of 3 to 5 months.

“[These data] provide the first evaluation of sotorasib in patients with NSCLC and stable brain metastases,” added Ramalingam, a professor of hematology and medical oncology and Roberto C. Goizueta Chair for Cancer Research at Emory University School of Medicine, and executive director of Winship Cancer Institute of Emory University in Atlanta, Georgia.

Patients with active brain metastases were excluded from the CodeBreaK 100 trial; however, patients with stable, asymptomatic brain metastases were eligible for inclusion.

In the posthoc analysis, the investigators retrospectively evaluated responses to sotorasib in target and nontarget stable brain metastases. They defined target lesions as measurable lesions suitable for accurate repeated measurements, and nontarget lesions as lesions too small for accurate repeated measurements.

In patients with baseline brain metastases (n = 40), the median age was 67 years (range, 46-83), and 98% of patients were current or former smokers. Most patients had an ECOG performance status of 1 (75%), and nearly a quarter had 3 metastatic sites (27%). Sixteen patients (40%) had received 1 prior line of systemic anticancer therapy. Regarding local therapies for the brain, 65% of patients had received prior radiotherapy, 20% had undergone surgery, and 12% had received radiotherapy and surgery.

In patients without baseline brain metastases (n = 134), the median age was 65 years (range, 37-86), and 90% of patients were current or former smokers. Most patients had an ECOG performance status of 1 (71%) and 1 metastatic site (45%) and had received 1 prior line of systemic anticancer therapy (41%). Regarding local therapies for the brain, 2 patients had received prior radiotherapy and 1 had undergone surgery. Of note, these local therapies may have been historic and have led to sufficient removal of the brain metastasis so that the patient did not have a confirmed brain metastasis at baseline during the time of enrollment.

Additional findings from the study demonstrated that the median tumor reduction rate was 27% in patients with brain metastases compared with 40% in patients without brain metastases.

Central Response Assessment in Neuro-Oncology (RANO) analysis demonstrated that 9.2% (n = 16/174) of patients had baseline scans, as well as at least 1 on-treatment evaluable scan; this confirmed that 9 patients had 1 lesion, 2 had 4 lesions, and 5 had 5 or more lesions.

In patients with target and nontarget central nervous system (CNS) lesions (n = 3), none achieved a CR, 33% (n = 1) achieved stable disease (SD), and 67% (n = 2) had progressive disease (PD). In patients with nontarget CNS lesions (n = 13), 15% (n = 2) achieved a CR, 85% (n = 11) achieved SD, and none had PD. In all evaluable patients with brain metastases per RANO analysis (n = 16), 13% (n = 2) achieved a CR, 75% (n = 12) achieved SD, and 13% (n = 2) had PD.

Regarding safety, 20% (n = 8) of patients with baseline brain metastases reported grade 3 treatment-related adverse effects (TRAEs) with sotorasib compared with 19% (n = 26) of patients without baseline brain metastases. Grade 4 TRAEs were reported in 0 patients vs 2 patients (1.5%), respectively. No grade 5 TRAEs occurred in either arm.

The ongoing phase 1/2 CodeBreaK 101 trial (NCT04185883) is evaluating sotorasib in combination with other anticancer therapies including pembrolizumab (Keytruda), trametinib, and more, in patients with 

Following the FDA approval of sotorasib for the treatment of KRAS G12C-positive non–small cell lung cancer, there is a great deal of interest in the KRAS inhibitor and its potential benefit.

Targeted Therapies in Oncology Staff | Authors

Articles

Roundtable Discussion: Dietrich and Santos Look at Targeted Treatments for Patients With NSCLC

Investigator’s Perspectives on GVHD: The REACH Trials

RET Inhibitors Show Promise for Chinese Patients With RET Fusion–Positive NSCLC

Further Analyses Expand Upon Duration of Benefit With Sotorasib in KRAS G12C+ NSCLC

Larotrectinib Excites in TRK Fusion Cancers for Both Adult and Pediatric Patients