Jared Kaltwasser

It’s been 5 years since the FDA approved the first chimeric antigen receptor (CAR) T-cell therapy to treat patients with previously treated lymphoma; yet, in many ways, the therapy is still in its early stages.

 “It’s far better than autologous stem cell transplantation,” said Sattva S. Neelapu, MD, professor and deputy department chair, Department of Lymphoma/Myeloma, of The University of Texas MD Anderson Cancer Center in Houston. “It’s offering hope for patients who previously did not have any other options and had a median survival of [approximately] 6 months.”

However, Neelapu said the therapy has not reached its full potential, neither in terms of the underlying technology nor its uptake among eligible patients. “There’s still a lot of room for improvement,” he said.

Neelapu will discuss the use of CAR T-cell therapies in lymphoma during a presentation on September 30, 2022, at 1:02 pm during the 10th Annual Meeting of the Society of Hematologic Oncology (SOHO 2022) in Houston, Texas. His talk, “CAR-T in Lymphoma Future Directions: Targets, Resistance, and Persistence,” will include some of the latest CAR T–related trial results, as well as a discussion of how best to optimize cell therapy.

Growing Armamentarium of CD19-Targeted Therapies

Axicabtagene ciloleucel (Yescarta) was the first CAR T-cell therapy approved for lymphoma but was quickly followed by similar therapies.

 “Currently, there are 4 different CAR products that have been FDA approved for lymphoma,” Neelapu said. “All of them target CD19.”

Three of those products are approved to treat large B-cell lymphoma. In addition to axicabtagene ciloleucel (axi-cel), the FDA also approved lisocabtagene maraleucel (Breyanzi) and tisagenlecleucel (Kymriah) for certain patients with B-cell lymphoma,

 as well as brexucabtagene autoleucel (Tecartus) for relapsed or refractory mantle cell lymphoma.

 In addition, axi-cel and tisagenlecleucel are also approved for follicular lymphoma. Neelapu said those approvals mean that a large number of patients are eligible for CAR T-cell therapy, but the existing data suggest the therapy will often be ineffective over the long term in the majority of patients. Only approximately 4 in 10 patients achieve long-term remission with CAR T therapies, Neelapu said.

What makes matters even more perplexing, he said, is that the treatment’s long-term remission rate remains at approximately 40%, even when it is moved up into the second line of therapy rather than the third.

“We generally expect that when we move to earlier lines, we see a better outcome,” Neelapu said. “But that was not the case.”

Although the results still outperformed the standard-of-care treatment with salvage chemotherapy followed by autologous stem cell transplantation, Neelapu said there is scope for further enhancement. Moreover, despite the fact that CAR T-cell therapies have been available for 5 years, their uptake in the commercial setting has remained relatively low.

Neelapu estimates there are perhaps 10,000 individuals with B-cell lymphoma in the United States who would qualify for CAR T-cell therapy each year. However, he estimates that only approximately 20% to 25% of those who are eligible are getting the treatment. There are multiple possible reasons for the relatively low eligibility-to-uptake ratio—one being access. Neelapu said there are approximately 120 centers in the US that can provide the therapy, which averages to just 2 or 3 centers per state.

“It’s not nearly enough,” he said. “It requires patients to travel to another center and stay locally for a period of at least 5 to 6 weeks—along with the caregivers—to be able to get the treatment, so it is not practical for everyone.”

In addition, the fact that the current CAR T-cell products are autologous means each product has to be custom made for a specific patient from the patient’s own T cells, which increases both the cost of the therapy and the wait time. In a best case scenario, Neelapu said it can take 5 weeks for a patient to receive the product from the time a need has been identified.

“So [although] the existing products appear to be probably the most effective [therapies] available for large B-cell lymphoma, there are limitations and various things can be done to overcome those limitations,” he said. “That’s where I think the future is.”

In his SOHO 2022 presentation, Neelapu will delve into those efforts. One focus, he said, is overcoming mechanisms of resistance among the roughly 60% of patients who relapse after CAR T-cell therapy. Investigators are working on ways to design new CAR T-cell products that will be more effective in patients, with resistance to CD19-targeting products. Those strategies include targeting different antigens or changing the way the product is designed and manufactured.

“From a clinical development standpoint, post-CD19 CAR failures are the biggest unmet clinical need in large B-cell lymphoma,” he said. “In these patients, none of the existing treatments really work well.”

Neelapu said one issue is that approximately 30% of patients with diffuse large B-cell lymphoma are CD19 negative following treatment with axi-cel.8 “[This] means that if we target different antigens, [we] could potentially overcome that mechanism of resistance,” he said. “We are fortunate in B-cell lymphomas, because there are so many targets we can choose from.”

One of the most interesting potential targets is CD22, Neelapu said.A phase 1 trial (NCT04088890) published in 2021 showed that patients who were refractory to CD19 CAR T-cell therapy and then were treated with a new CD22-targeted product experienced improvement.

“[Investigators] found a very high complete response rate, and a lot of them appear to be durable,” Neelapu said. “This is probably the most promising evidence that targeting a different molecule can be effective in the clinic in large B-cell lymphoma.” However, he also added that it’s not clear whether targeting CD22 will be more effective than other potential targets, such as CD20, CD79A, or CD79B. Those questions will require more research.

In the meantime, Neelapu said it may be wrong to think about the next step as choosing the best single target. “In the long term, we’d like to target multiple antigens at the same time,” he said. “And there are bispecific CARs and trispecific CARs that are in clinical trials now.”

Another suspected driver of resistance is suboptimal numbers of fit T-cells. Neelapu said experimental use of CAR T-cell therapies in a first-line setting led to the discovery that products derived from patients in an earlier line of therapy seem to lead to better results. “When we compared CAR T products in patients who were treated in the first line vs the third line, we found that the quality of the product was much better in terms of the T-cell phenotype and functionality,” he said.

In his presentation, Neelapu plans to review the ZUMA-12 trial (NCT03761056), a phase 2 trial that looked at axi-cel as part of first-line therapy in high-risk patients with large B-cell lymphoma. In that study, high-risk patients underwent 2 cycles of systemic chemotherapy. Patients who still had residual disease on a PET scan were then given an infusion of axi-cel. The study achieved an 89% objective response rate among the 40 patients treated. The response also appears to be durable; at 1 year, approximately three-quarters of patients were still in remission.

 “[This] is a lot higher than the 40% seen in second- and third-line settings,” he said.

Another strategy to improve the quality of CAR T-cell therapies is to optimize and accelerate the manufacturing of the therapies. For instance, Novartis has created a platform known as T-Charge, which dramatically speeds up the manufacturing process. YTB323 is a CD19-targeted CAR T product that uses the same design as tisagenlecleucel, but it is manufactured using a new, faster method.

“The production of CAR T cells used to require culturing the cells for [approximately] 10 to 14 days in the lab, but now with the T-Charge platform, it has been shortened to 2 days,” Neelapu said. “When they did that, they found that the function and the phenotype of the T cells [was] much better.”

A third apparent mechanism of resistance to CD19 CAR T-cell therapy is intrinsic tumor resistance. “[Essentially, for various reasons], the tumor cells resist CAR T–mediated killing,” he said.

Neelapu said several potential mechanisms for intrinsic resistance have already been identified, but strategies to overcome intrinsic resistance are still in the early phases of development. He expects to see significant progress in this area in the coming years. “We will probably uncover a lot more resistance mechanisms than what we currently know,” he said.

If 1 major focus of CAR T development is centered around evading resistance, Neelapu said another key strategy is finding ways to use allogeneic cells instead of autologous cells to derive therapies. Using allogeneic cells can allow something like an “off-the-shelf” approach to CAR T-cell therapy, rather than the time-consuming process of making patient-specific doses. It would also allow manufacturers to make many more doses from a single donor and would likely significantly reduce the cost of the therapy. But there’s 1 key problem, Neelapu said. “The main hurdle we are seeing right now in some of these early studies is that these cells don’t persist as long in the body,” he said.

Although autologous CAR T cells can persist for years in the body, the current allogeneic products do not come close to that level of durability. “With allogeneic CAR T products, most of the time they persist in the body for only 1 or 2 months, because once the host immune system recovers in a patient, they reject these allogeneic cells,” Neelapu said.

The ALPHA-2 study (NCT04416984) of ALLO-501A (Allogene Therapeutics, Inc) is 1 attempt to solve that problem. “One approach taken by the Allogene product is that they knock out this molecule called CD52, which allows them to give a better conditioning regimen with anti-CD52 antibody on top of cyclophosphamide and fludarabine to induce this prolonged lymphodepletion in the patient,” he said. “That way, the rejection may be delayed.”

Neelapu said many other approaches are currently being investigated or are soon to be the subjects of clinical trials. He thinks allogeneic therapies will likely win out over the long term. “They will likely be the future for cell therapies,” he said.

For community oncologists, Neelapu said chemotherapy remains the standard choice for first-line therapy for large B-cell lymphoma, as it cures 60% to 65% of patients. In the second-line setting CAR T therapy is now the standard of care. “If we ask the question, as a second line: What is the treatment that has the highest chance of achieving a cure in these patients? That’s CAR T,” he said.

As a practical matter, Neelapu said it is important for community oncologists to refer patients to a CAR T therapy center early, as there is some evidence that multiple prior therapies can diminish the effectiveness of autologous CAR T-cell products. “Early referral by the community oncologist at first relapse is key to achieve an optimal outcome and the best chance of cure,” he said.

In situations where economic or other barriers make it difficult for a patient to get treatment at a CAR T center, Neelapu said bispecific antibody therapies may soon be available. Such treatments could be a good bridging option, because unlike chemotherapy, they do not affect T-cell numbers or functions.

SOHO and the Return of In-Person Meetings

Reflecting on SOHO 2022 and the return to a fully in-person meetings, Neelapu said the virtual format necessitated by the COVID-19 pandemic had certain advantages. “I think Zoom has, in some ways, encouraged more people to attend,” he said. “And if it’s a live virtual presentation, we see a lot more people asking questions.”

However, he said he’s looking forward to something Zoom cannot provide. “With an in-person meeting, what’s appealing is to talk offline with colleagues and investigators from academia and industry,” he said. “[This] can generate a lot of interesting discussions, new ideas, and collaborations—that’s missing in a virtual meeting.”

1. Kite’s Yescarta (axicabtagene ciloleucel) becomes first CAR T therapy approved by the FDA for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy. News release. Gilead Sciences, Inc; October 18, 2017. Accessed August 21, 2022. https://bit.ly/3KfFvLi

2. FDA approves axicabtagene ciloleucel for second-line treatment of large B-cell lymphoma. News release. FDA; April 1, 2022. Accessed August 30, 2022. https://bit.ly/3wHlnME

3. Approved cellular and gene therapy products. FDA. August 17, 2022. Accessed August 30, 2022. https://bit.ly/2HhGlbl

4. Bristol Myers Squibb’s Breyanzi (lisocabtagene maraleucel) significantly improves outcomes, showing superiority over 20-year standard of care in second-line relapsed or refractory large B-cell lymphoma based on TRANSFORM study results. News release. Bristol Myers Squibb; December 11, 2021. Accessed August 21, 2022. https://bit.ly/3CsOPK3

5. Kymriah (tisagenlecleucel), first-in-class CAR-T therapy from Novartis, receives second FDA approval to treat appropriate r/r patients with large B-cell lymphoma. News release. Novartis; May 1, 2018. Accessed August 21, 2022. https://bit.ly/3QH1QUx

6. U.S. FDA approves Kite’s Tecartus, the first and only CAR T treatment for relapsed or refractory mantle cell lymphoma. News release. Gilead Sciences, Inc; July 24, 2020. Accessed August 21, 2022. https://bit.ly/3PRDpT8

7. Locke FL, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. 

. 2022;386(7):640-654. doi:10.1056/NEJMoa2116133

8. Spiegel JY, Dahiya S, Jain MD, et al. Outcomes of patients with large B-cell lymphoma progressing after axicabtagene ciloleucel therapy. 

. 2021;137(13):1832-1835. doi:10.1182/blood.2020006245

9. Frank MJ, Baird JH, Patel S, et al. CD22-CAR T-cell therapy mediates high durable remission rates in adults with large B-cell lymphoma who have relapsed after CD19-CAR T-cell therapy. 

. 2021;138(suppl 1):741. doi:10.1182/blood-2021-152145

10. Neelapu SS, Dickinson M, Munoz J, et al. Axicabtagene ciloleucel as first-line therapy in high-risk large B-cell lymphoma: the phase 2 ZUMA-12 trial. 

11. Flinn IW, Jaeger U, Shah NN, et al. A first-in-human study of YTB323, a novel, autologous CD19-directed CAR-T cell therapy manufactured using the novel T-Charge platform, for the treatment of patients (pts) with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL). 

. 2021;138(suppl 1):740. doi:10.1182/blood-2021-146268

12. Lekakis LJ, Locke FL, Tees M, et al. ALPHA2 study: ALLO-501A allogeneic CAR T in LBCL, updated results continue to show encouraging safety and efficacy with consolidation dosing. 

. 2021;138(suppl 1):649. doi:10.1182/blood-2021-146045

Articles

Sattva S. Neelapu, MD will discuss chimeric antigen receptor T-cell therapy will in lymphoma iduring a session at the SOHO 2022 Annual Meeting.

Many Challenges, Opportunities for CAR T-Cell Therapies in Lymphoma

A decade ago, a diagnosis of chronic lymphocytic leukemia (CLL) came with very few therapeutic options. “Chemoimmunotherapy was the standard of care,” Nicole Lamanna, MD, associate clinical professor of medicine in the Hematologic Malignancies Section of the Hematology/Oncology Division at Columbia University Herbert Irving Comprehensive Cancer Center in New York, New York, said in an interview with Targeted Therapies in Oncology™.

The only question was whether the patient was young and fit enough to be a candidate for stem cell transplant. Most patients were not, said Anthony Mato, MD, MSCE, director of the CLL Program at Memorial Sloan Kettering Cancer Center in New York, New York. “And they ended up dying of refractory disease or transformation of disease,” Mato said during an interview with

However, a lot can change in a decade. In the case of CLL, the change began in February 2014, with the FDA’s accelerated approval of ibrutinib (Imbruvica) to treat CLL in patients who had received at least 1 prior therapy.

 “That drastically changed things,” Lamanna said.

Ibrutinib was the first Bruton tyrosine kinase (BTK) inhibitor to be granted FDA approval for CLL in November 2013.

 Later, in the RESONATE trial (NCT01578707), the therapy had a 6-month progression-free survival (PFS) rate of 88% and a 12-month overall survival (OS) rate of 90% in previously treated patients with CLL. In this trial, the control group received ofatumumab (Arzerra), and at 12 months, the OS rate was 81% and the PFS was 8.1 months.

In an accompanying editorial in the New England Journal of Medicine, Robin Foà, MD, professor of hematology and head of the Division of Hematology at the Sapienza University of Rome in Italy, asserted that oncologists were “witnessing a new mechanism-driven era” associated with “the development of compounds capable of targeting the B-cell receptor signaling pathway” in the treatment of CLL.

 That assertion has stood the test of time.

The 8 years since that publication have seen a steady pipeline of new targeted therapies for CLL. The result is that clinicians and patients now have a vastly different range of therapeutic options to choose from. However, with those options have come new questions about how best to choose, sequence, and combine those agents to achieve the best long-term results. Experts such as Lamanna and Mato say the answers to those questions will only come with signifi cantly more research.

A Wave of Approvals Ibrutinib, which was approved as a first-line therapy in 2016, was the first targeted therapy approved for CLL,

 but it was not the last. That same year, the FDA approved idelalisib (Zydelig), an inhibitor of the delta isoform of PI3K, in combination with rituximab (Rituxan) for use in patients with relapsed CLL.

 In 2018, duvelisib (Copiktra) gained FDA approval.

Meanwhile in 2016, the agency approved venetoclax (Venclexta), initially for patients with 17p deletions whose cancers had progressed after previous treatment with at least 1 other therapy. The drug targets BCL2, which is a protein that promotes tumor cell survival.7 That approval was later expanded to include patients without 17p deletions.

 In 2019, the drug was approved as a first-line CLL therapy in combination with the anti-CD20 monoclonal antibody, obinutuzumab (Gazyva).

Even as PI3K and BCL2 inhibitors were beginning to hit the market, drug developers were working on second-generation BTK inhibitors, including acalabrutinib (Calquence), which was approved for CLL treatment in 2019,

and zanubrutinib (Brukinsa), which Lamanna said is likely to gain FDA approval later this year.

The days of chemoimmunotherapy as the major treatment for CLL are over, Lamanna said. “Chemoimmunotherapy is not used very often, if at all,” she said. “Now [oncologists choose] between a BTK inhibitor or venetoclax [plus] obinutuzumab in [the] front line.”

Although BTK inhibition has proven to be a major development in the treatment of CLL, this class of drugs carries a signifi cant risk of adverse events (AEs) and treatment resistance. Newer BTK inhibitors are more selective and have improved the safety profi les for patients with comorbidities.

For instance, results from the phase 3 ELEVATE-RR trial (NCT02477696) published in 2021 showed acalabrutinib had a lower risk of cardiovascular AEs compared with ibrutinib.

 Interim results from the ALPINE study (NCT03734016) showed zanubrutinib had a signifi cantly better overall response rate (ORR) compared with ibrutinib (78.3% vs 62.5%;

 = .0006) and led to lower rates of atrial fi brillation or flutter.

Lamanna noted that historically, patients with significant cardiovascular issues would be considered poor candidates for BTK inhibitors, but that is not necessarily the case anymore. “For somebody who had bad hypertension, bad cardiac issues, and was on anticoagulation, we would avoid ibrutinib and go to venetoclax,” she said. “Now with the second generation, you can challenge that a little. It [depends] on how severe their cardiac issues are.” Lamanna also said the decision can in part depend on the physician’s comfort level with the different therapeutic options.

Mato said comorbidities and fi tness are important to consider when deciding on a treatment regimen. The molecular genetic profile of the malignancy is somewhat less important than it used to be, he said, as BTK inhibitors and venetoclax are “equally useful” options for patients who are standard or high risk. Another factor to consider is patient preference, according to Mato. “The limiting factor of the BTK inhibitors is that they’re continuous therapies,” he said. “People tend to want to stop at some point.”

Noncovalent BTK Inhibitors in the Pipeline 

The evolution of BTK inhibition is continuing with noncovalent BTK inhibitors, such as pirtobrutinib and nemtabrutinib. Unlike earlier BTK inhibitors, they do not bind covalently to C481 of the BTK protein, making them a meaningful option, even for patients with acquired resistance to earliergeneration agents.

In phase 1/2 data published in 2021, investigators, including Lamanna and Mato, found that pirtobrutinib produced strong ORR results, even in patients who had previously been treated with BTK inhibitors. ORRs of 67%, 52%, and 71% were found in patients with previous resistance to covalent BTK inhibitors, previous intolerance to BTK inhibitors, and BTK C481 mutations, respectively.

 Those data suggest pirtobrutinib may be another treatment option for patients with BTK C481 mutations who have become resistant to ibrutinib.

Trials are also under way for other noncovalent BTK inhibitors, including nemtabrutinib. In results presented the European Hematology Association 2022 Congress, investigators found the therapy had an acceptable safety profi le and an ORR of 57.9% in heavily pretreated patients.

 Another drug, fenebrutinib, was the subject of a recently completed phase 1 study (NCT01991184).

 Twenty-four patients were enrolled in this study and 8 patients had an ORR. Best responses included 3 patients with partial response with lymphocytosis, 4 with a partial response, and 1 with a complete response (TABLE

Meanwhile, Sunesis Pharmaceuticals, Inc, terminated a phase 1b trial of vecabrutinib, yet another noncovalent BTK inhibitor. In that case, investigators found the drug was well tolerated but did not appear to have sufficient evidence of antitumor activity.

For Lamanna, the big picture is that these third-generation BTK inhibitors have the potential to further expand the treatment landscape, thereby increasing the range of therapeutic strategies for patients and their physicians. “The point is we’ll have [more drugs] in our armamentarium,” she said. “Of course, our goal would be to cure CLL, but if we can’t cure CLL, you’re always thinking, ‘How do I keep these patients going? How do I go from one drug to another drug and really make it a chronic disease?’”

Combining Targeted Therapies The new CLL therapies have also created the opportunity for new fixed-duration combination regimens, including those studied in the GLOW and CAPTIVATE trials. In December 2021, results from the phase 3 GLOW trial (NCT03462719) showed that combining ibrutinib with venetoclax led to fewer fi rst-year relapses in treatment-naïve patients who were elderly or unfit, compared with chlorambucil (Leukeran) plus obinutuzumab. At 30 months, patients in the ibrutinib plus venetoclax cohort had a PFS rate of 80.5% compared with 35.8% for patients receiving chlorambucil plus obinutuzumab. The trial did not include patients with 17p deletions or known TP53 mutations.

Findings from the CAPTIVATE trial (NCT02910583) of ibrutinib plus venetoclax have also been promising.

 This trial produced an ORR of 96% in treatment-naïve patients who were 70 years or younger at a 3-year follow-up. That study was notable in part because the response data were consistent, even for patients who were highrisk and including those with 17p deletions, 

 mutations, unmutated IGHV, and/or complex karyotypes.

Beyond evaluating the efficacy of the treatment combination, this study is also important because it could help investigators better understand the role minimal residual disease (MRD) can play in tracking patient responses to therapy. Lamanna noted that CAPTIVATE is designed so that after a prerandomization phase, patients who are MRD positive will continue treatment with ibrutinib either alone or combined with venetoclax. Those who have confi rmed undetectable MRD will continue with ibrutinib or be switched to placebo. The results could help oncologists better understand whether and how MRD can be used to guide therapy.

“Patients and specialists want to use MRD to guide exposure,” Mato said. “There has not been a lot of use of MRD, but I think people are ready to go in that direction. I really do.” He also added that, so far, no CLL therapies have been approved based on trials with an MRD end point; however, an MRD assay has been approved.

Another combination therapy, venetoclax plus rituximab, was the subject of the MURANO trial (NCT02005471), which found superior OS and PFS at 5 years compared with bendamustine (Treanda) plus rituximab. The estimated 5-year OS was 82.1% for the venetoclax regimen vs 62.2% for the bendamustine regimen.

In addition, a phase 1 trial (NCT03328273) evaluating the second-generation BTK inhibitor acalabrutinib plus the ataxia telangiectasia and RAD3-related inhibitor ceralasertib (also known as AZD6738) is currently ongoing.

Investigators are also examining how best to sequence therapies and what strategy to take when a patient experiences relapse or needs to discontinue a medication. Lamanna said patients who start with a BTK inhibitor can be easily retreated with venetoclax and rituximab or venetoclax plus a monoclonal antibody. “There’s no doubt that we have very good data that [show] the venetoclax-based regimens can salvage patients who either have intolerance to a BTK [inhibitor] or who have progressed,” she said. In such cases, patients can take fixed-duration venetoclax-based regimens, and if all goes well, they may be able to completely go off therapy for months or even years.

A 2020 study showed that, in cases where patients discontinued venetoclax, BTK inhibitors were the most effective choice for their next therapy, provided the patient was either BTK inhibitor naïve or had previously responded to a BTK inhibitor.

 Yet another study found that patients with venetoclax-based regimens can benefit from retreatment with venetoclax following remission, particularly if they achieved a complete response from their initial therapy.

Lamanna said the optimal treatment remains to be determined for patients who receive a doublet or triplet combination and eventually relapse. “Hopefully some of these studies will help tell us,” she said. The trials could also answer questions about whether fixed-duration therapies are appropriate for all patients, including patients who are high-risk, according to Lamanna.

Another potential option for patients is cellular therapies, such as lisocabtagene maraleucel (Breyanzi), which was approved in 2021 in combination with ibrutinib to treat relapsed or refractory large B-cell lymphoma. Lisocabtagene-maraleucel is an autologous, CD19-directed chimeric antigen receptor (CAR) T-cell therapy.

Lamanna noted that the idea of using CAR T cells to treat CLL has been around for more than a decade, but the AEs associated with the therapy required a signifi cant learning curve. However, she noted that significant progress has been made in terms of curbing AEs. “That’s the good news,” she said. The bad news is that CAR T has yet to achieve wide adoption within the CLL oncology community because of the steady stream of other therapies that have become available, Lamanna explained.

“It’s still being relegated a little bit to specialty places [that] could do CAR T,” Lamanna said. She believes CAR T-cell therapy will eventually be approved for CLL, but in a crowded field of therapies, she does not expect it to become a prominent component of CLL care.

Mato said he believes cellular therapies will have a role in the future of CLL therapy. “It’s a question about what line [of therapy],” he said. “Current patients are referred after they’re out of options. Sometimes that probably limits the success of the cellular therapy, because not only do you need to be able to harvest T cells, but you [also] need to have functional T cells.” Mato also said it will be important to have studies that examine the ideal candidates and sequence to offer CAR T-cell therapy.

The need for more research is a major theme in Mato’s assessment of the current CLL treatment picture. Although he is excited about the new therapies, he also thinks drug developers need to do a better job of carrying out relevant trials that will help oncologists better understand which of the new therapies work best in which situations. “The limitations are that they’re never compared [with] one another,” he said.

Most of the studies still compare the newer therapies with older, less-relevant regimens. Mato said a more helpful approach would be to test these new targeted therapies against other targeted therapies. “What we really need to move the fi eld forward are headto-head comparisons of relevant classes of drugs, and we need studies that allow us to understand sequencing,” he said.

Part of the reason such studies are rare is that drug developers are reticent to do competitions among “winners,” because the results might mean their product goes from being a go-to therapy to being a therapy that is less sought after, Mato explained. Thus, it is hard to fi nd industry support for the kinds of large-scale, head-to-head studies that are necessary. “If you’re not going to have that support, then the ability to fund a meaningful randomized clinical trial is really hard to come up with,” he said

On a smaller scale, Lamanna said there is also a need for clinicians to expand the knowledge of these new therapies by being strategic about how they use them. She cautioned that clinicians should not be too quick to change from one therapy to the next when patients experience AEs. Although patient status and toxicities may warrant a change in therapy, she said not every AE requires stopping the drug. “Sometimes a little diarrhea [or] nausea—you can work through them,” she said, noting that careful patient counseling ahead of time and thoughtful management of AEs during treatment can allow patients to continue on a therapy in many cases.

Doctors and patients who can stick with a regimen despite relatively minor AEs will ultimately have more options later in the treatment journey, which could then lead to better long-term outcomes. “It takes more time and effort, but it’s worth it, because these drugs are going to be the mainstay of our treatment for CLL for quite some time,” she said.

1. Imbruvica (ibrutinib) now approved in the U.S. for patients with chronic lymphocytic leukemia who have received at least one prior therapy. News release. Johnson & Johnson; February 4, 2014. Accessed August 4, 2022. https://bit.ly/3SpAJPe

2. Byrd JC, Brown JR, O’Brien S, et al; RESONATE Investigators. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia.

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3. Foà R. Changes in the treatment landscape for chronic lymphoid leukemia. 

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4. Imbruvica (ibrutinib) approved by the U.S. FDA for the first-line treatment of chronic lymphocytic leukemia. News release. AbbVie; March 4, 2016. Accessed August 4, 2022. https://bit.ly/3byT9fQ

5. U.S. Food and Drug Administration approves Gilead’s Zydelig (idelalisib) for relapsed chronic lymphocytic leukemia, follicular lymphoma and small lymphocytic lymphoma. News release. Gilead; July 23, 2014. Accessed August 4, 2022. https://bit.ly/3zYfDAf

6. Duvelisib (Copiktra, Verastem, Inc.) for adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). News release. FDA; September 24, 2018. Accessed August 4, 2022. https://bit.ly/2Zmrl2f

7. FDA approves new drug for chronic lymphocytic leukemia in patients with a specific chromosomal abnormality. News release. FDA; April 11, 2016. Accessed August 4, 2022. https://bit.ly/3zUXVxA

8. FDA approves new treatment option for previously treated chronic lymphocytic leukemia. News release. Genentech; June 8, 2018. Accessed August 4, 2022. https://bit.ly/2l0fuVD

9. AbbVie announces US FDA approval of Venclexta (venetoclax) as a chemotherapy-free combination regimen for previously untreated chronic lymphocytic leukemia patients. News release. AbbVie; May 15, 2019. Accessed August 4, 2022. https://bit.ly/2OGvJJp

10. Project Orbis: FDA approves acalabrutinib for CLL and SLL. News release. FDA; November 21, 2019. Accessed August 4, 2022. https://bit.ly/3BCs6ee

11. Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. 

. 2021;39(31):3441-3452. doi:10.1200/JCO.21.01210

12. Hillmen P, Eichhorst B, Brown JR, et al. First interim analysis of ALPINE study: results of a phase 3 randomized study of zanubrutinib vs ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Presented at: European Hematology Association 2021 Congress; June 9-17, 2021; virtual. Abstract LB190.

13. Lewis KL, Cheah CY. Non-covalent BTK inhibitors-the new BTKids on the block for B-cell malignancies. 

. 2021;11(8):764. doi:10.3390/jpm11080764

14. Mato AR, Shah NN, Jurczak W, et al. Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. 

. 2021;397(10277):892-901. doi:10.1016/S0140-6736(21)00224-5

15. Woyach J, Flinn IW, Awan FT, et al. Nemtabrutinib (MK-1026), a non-covalent inhibitor of wild-type and C481S mutated Bruton tyrosine kinase for B-cell malignancies: efficacy and safety of the phase 2 dose-expansion BELLWAVE-001 study. Presented at: European Hematology Association 2022 Congress; June 9-12, 2022; Vienna, Austria. Abstract P682. https://bit.ly/3HDw2fC

16. Byrd JC, Smith S, Wagner-Johnston N, et al. First-in-human phase 1 study of the BTK inhibitor GDC-0853 in relapsed or refractory B-cell NHL and CLL. 

. 2018;9(16):13023-13035. doi:10.18632/oncotarget.24310

17. Allan JN, Patel K, Mato AR, et al. Ongoing results of a phase 1b/2 dose-escalation and cohort-expansion study of the selective, noncovalent, reversible Bruton’s tyrosine kinase inhibitor, vecabrutinib, in B-cell malignancies. 

. 2019;134(suppl 1):3041. doi:10.1182/blood-2019-126286

18. Kater A, Owen C, Moreno C, et al Fixed-duration ibrutinib and venetoclax (I+V) versus chlorambucil plus obinutuzumab (CLB+O) for first-line (1L) chronic lymphocytic leukemia (CLL): primary analysis of the phase 3 GLOW study. Poster presented at: European Hematology Association 2021 Congress; June 9-17, 2021; virtual.

19. Wierda WG, Barr PM, Siddiqi T, et al. Fixed-duration (FD) ibrutinib (I) + venetoclax (V) for first-line (1L) treatment (tx) of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): three-year follow-up from the FD cohort of the phase 2 CAPTIVATE study. 

. 2022;40(suppl 16):7519. doi:10.1200/JCO.2022.40.16_suppl.7519

20. Kater AP, Kipps TJ, Eichhorst, B, et al. Five-year analysis of Murano study demonstrates enduring undetectable minimal residual disease (uMRD) in a subset of relapsed/refractory chronic lymphocytic leukemia (R/R CLL) patients (Pts) following fixed-duration venetoclax-rituximab (VenR) therapy (Tx). Presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020; virtual. Abstract 125. Accessed August 1, 2022. https://bit.ly/3d8OCRu

21. Jurczak W, Elmusharaf N, Fox CP, et al. Phase 1/2 results of ceralasertib (Cerala) as monotherapy or in combination with acalabrutinib (Acala) in high-risk relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Presented at: American Association for Cancer Research Annual Meeting 2022; April 8-13, 2022; New Orleans, LA. Abstract CT532. Accessed April 8, 2022. https://bit.ly/3JvBzpz

22. Mato AR, Roeker LE, Jacobs R, et al. Assessment of the efficacy of therapies following venetoclax discontinuation in CLL reveals BTK inhibition as an effective strategy. Clin Cancer Res. 2020;26(14):3589-3596. doi:10.1158/1078-0432.CCR-19-3815

23. Thompson MC, Allan JN, Sail K, et al. Venetoclax re-treatment of chronic lymphocytic leukemia (CLL) patients after a previous venetoclax-based regimen. Presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020; virtual. Abstract 3136. Accessed August 1, 2022. https://bit.ly/3OZwzKT

24. U.S. FDA approves Bristol Myers Squibb’s CAR T cell therapy Breyanzi for relapsed or refractory large B-cell lymphoma after one prior therapy. News release. Bristol Myers Squibb; June 24, 2022. Accessed August 12, 2022. https://bit.ly/3C0lEOa

Doctors and patients who can stick with a regimen despite relatively minor adverse event will ultimately have more options later in the treatment journey, which could then lead to better long-term outcomes in chronic lymphocytic leukemia.

As CLL Approaches Expand, Sequencing Questions Arise

When patients with locally advanced or metastatic soft tissue sarcoma (STS) do not respond to standard chemotherapy, they face a difficult situation.

“There are very few FDA-approved treatments for patients with soft tissue sarcoma,” Scott Michael Schuetze, MD, PhD, a clinical professor for the University of Michigan Health at Michigan Medicine, said.

Doxorubicin (Lipodox) is generally the first chemotherapy offered. Other drugs, such as trabectedin (Yondelis) and eribulin mesylate (Halaven), are also approved for certain patients, but such therapies come with significant risk of adverse effects. Although it’s a short list, it may soon grow.

“Over the past 10 to 20 years, researchers have identified molecular abnormalities in sarcomas that may be vulnerable to disruption by drugs targeting specific growth pathways, and pharmaceutical companies have done a remarkable job in developing pharmaceuticals to target these pathways,” Schuetze explained.

Of course, developing such drugs is one thing, getting them to patients who need them can be quite another.

TAPUR Design First launched in 2016, TAPUR (NCT02693535) is a phase 2, open-label, basket study sponsored by the American Society of Clinical Oncology (ASCO) that allows investigators to evaluate how small cohorts of patients with tumors having the same or similar genetic variations will respond to targeted therapies already approved for other indications. The study uses next- generation sequencing (NGS) to match patients with potentially actionable mutations to promising therapies and study cohorts. Cohorts begin with up to 10 patients who have the same cancer type, genomic alteration, and study drug. If 2 or more patients appear to respond to the therapy, the cohort can be expanded to 28 enrollees.

Currently, TAPUR is enrolling patients at 141 sites, and 19 drugs are accessible through partnerships with drug developers (

One of those drugs is palbociclib (Ibrance), a therapy approved for the treatment of hormone receptor–positive, HER2-negative breast cancer. At 2021 ASCO Annual Meeting, Schuetze and colleagues reported on the use of palbociclib in patients with STS and CDK4 amplification.

 Each of the patients in the study had either not responded to or progressed following treatment.

“Most of the patients treated in this cohort had a life expectancy of less than a year, and identification of more effective and better-tolerated treatments for these patients is a priority,” Schuetze said.

Earlier work has identified CDK4 and MDM2 as overexpressed and pathologically important for the tumor type, Schuetze said. TAPUR gave investigators the ability to determine responses in a small group of patients with STS.

In their TAPUR study, 1 patient had a partial response and 12 patients had stable disease at 16-plus weeks (SD16+). That translated to a disease control rate (DCR) of 48% (95% CI, 31%-62%) and an objective response rate (ORR) of 3.7% (95% CI, 0.1%-19%). Schuetze and colleagues said 9 of the 13 patients with disease control continued on treatment for more than 32 weeks.

“Most of the patients who enrolled in the study had dedifferentiated liposarcoma, and the results in this group were in line with expectations and results from prior studies, although it was disappointing that we did not see objective tumor responses in this sarcoma subtype,” Schuetze said. “The objective response in a patient with soft tissue sarcoma that was not a dedifferentiated liposarcoma was a bit of a pleasant surprise.”

Further, adverse events (AEs) were consistent with previous studies, he said.

Ajjai Alva, MBBS, another TAPUR investigator from Michigan Medicine, noted that TAPUR is not the first time a trial has attempted to use NGS sequencing to identify patients for quick entry into trials. The National Cancer Institute (NCI) launched the NCI-MATCH trial (NCT02465060) in 2015 using a similar model of matching patients via genetic mutations. However, Alva said that study had some limitations that TAPUR does not. For instance, in NCIMATCH, the sequencing was done at a single center to ensure uniformity in the sequencing.

“They really placed an importance on the stringency of the sequencing, which is good for science,” he said. However, it also resulted in procedural bottlenecks. “So logistically, it was very difficult.” TAPUR offers more flexibility in terms of where sequencing is done and which platforms are used. That makes the process of enrolling patients and beginning therapy significantly faster, something that is key for patients who often face progressing disease.

Schuetze’s study was not the only news to come out of the ASCO meeting. As TAPUR reached its 5-year anniversary, a number of new results were presented, including reports on head and neck cancer and uterine cancer.

In another palbociclib study, Evan Pisick, MD, of Cancer Treatment Centers of America, and colleagues evaluated the drug in a cohort of patients with head and neck cancer and CDKN2A mutation (8 patients) or loss (20 patients).

 Like the patients in Schuetze’s study, these patients had no standard treatment options and advanced disease.

 loss achieved SD16+, and 1 patient with a 

 mutation achieved the same. The DCR was 37% (95% CI, 21%-50%).

Half the patients (14) experienced at least one grade 3 to 5 AE or serious AE, the most common of which was low white blood cells/platelets. One patient experienced grade 5 respiratory failure, which investigators said was most likely due to extensive lung metastases and aspiration, although they noted that palbociclib-related pneumonitis could not be ruled out.

Additionally, Hussein Moustapha Ali- Ahmad, MD, of the Michigan Cancer Research Consortium, reported on a cohort of patients with uterine cancer who had 

 amplification, overexpression, or mutations.4 The 28 patients all had measurable disease and no standard treatment options. Most of the patients (21) had 

 amplification. They were treated with pertuzumab (Perjeta) and trastuzumab (Herceptin).

 amplification had partial responses, and 7 achieved SD16+. One patient with 

 8421 mutation but without amplification also achieved SD16+. That translated to a DCR of 37% (95% CI, 21%50%) and an ORR of 7.1% (95% CI, 0.8%-24%). Just 1 patient experienced a grade 3 AE (muscle weakness), which investigators said was possibly related to the therapy.

The combination of pertuzumab and trastuzumab was also the subject of research presented last year at the ASCO Gastrointestinal Cancers Symposium. That report evaluated the combination therapy’s ability to treat patients with colorectal cancer and 

 One patient in the study also had a mutation of the gene. The results of the trial produced better DCR (50%) and ORR (25%) versus Ali-Ahmad’s and colleagues’ new uterine cancer study.

Other 2020 results included promising outcomes for patients with prostate cancer and 

/2 inactivating mutations who were treated with olaparib (Lynparza).

 That study found 68% of patients achieved disease control and 36% of patients had an objective response.

However, olaparib did not perform as well in patients with pancreatic cancer and

1/2 inactivating mutations. In that study, 31% and 4% of patients achieved disease control and objective response, respectively.

Alva’s research involved looking at pembrolizumab (Keytruda) in patients with metastatic breast cancer who had high tumor mutational burden (TMB). The study found TMB was a meaningful biomarker predictive of response to pembrolizumab, leading to a DCR of 37% and ORR of 21%.

 Median progression-free survival was 10.6 weeks, and median overall survival was 30.6 weeks.

Alva said that before TMB was identified, the protein PD-L1 was used as a biomarker, but it was imprecise.

“A lot of patients in every cancer type do not express or do not have detectable PD-L1 and still respond,” he said. “And the other way around also is true: Sometimes there is high PD-L1 expression, and those tumors also do not respond.”

The TAPUR study showed TMB, although not a perfect biomarker, could help identify a cohort of patients in whom a significant proportion would respond to the therapy.

A similar study of pembrolizumab found DCR and ORR of 28% and 4%, respectively, in patients with metastatic colorectal cancer and high TMB.

Shortly after those studies were released, the FDA approved pembrolizumab for patients across cancer types if they have high TMB, progressed despite treatment, and have no other available treatment options.

The expanded approval was based on the KEYNOTE-158 trial.

 Alva noted that the TAPUR studies are not designed to lead to FDA action—with just 28 patients they generally are too small—but they can quickly generate data sufficient to trigger larger studies.

“The study was never designed to back FDA regulatory approval,” he said. “It was merely to find signals, quick signal checking—does TMB hold promise?”

Schuetze added that TAPUR allows for the investigation of therapies for cancer types that might otherwise be too rare to be the subject of a major study.

“These cancers studied in TAPUR are, for the large part, too rare for study in larger randomized phase 2 or phase 3 trials, and TAPUR is an innovative mechanism to collect treatment data from patients with very rare cancer subtypes,” he noted.

Schuetze said because the trials are not randomized makes it difficult to determine the impact of what the TAPUR study will be, but he added that it is already serving a meaningful opportunity “to gain knowledge about new treatment options and further medical care for patients with rare cancers.”

As for what it all means long term, Alva said he is a big believer in NGS as a tool that will play a major role in the future of cancer care.

“Biology wise, it gives us a lot of clues about prognostic markers, for example, that some things are going to work, some things are more likely to work, and some things are never going to work,” Alva said. “Those kinds of information—the more information, the better for us.”

1. News & updates. ASCO TAPUR. Updated April 26, 2021. Accessed July 1, 2021. https://bit.ly/2VfDolw 

2. Schuetze S, Rothe M, Mangat PK, et al. Palbociclib (P) in patients (pts) with soft tissue sarcoma (STS) with CDK4 amplification: results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study. 

Clin Oncol. 2021;39(suppl 15):11565. doi:10.1200/JCO.2021.39.15_suppl.11565

3. Pisick EP, Rothe M, Mangat PK, et al. Palbociclib (P) in patients (pts) with head and neck cancer (HNC) with CDKN2A loss or mutation: results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study. 

When patients with locally advanced or metastatic soft tissue sarcoma do not respond to standard chemotherapy, they face a difficult situation.

Jared Kaltwasser | Authors

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