Ongoing and new developments in chimeric antigen receptor (CAR) T-cell therapies were covered at the 63rd American Society of Hematology (ASH) annual meeting.
Coming into the 2021 American Society of Hematology (ASH) Meeting & Exposition, Gilead Sciences had already announced that axicabtagene ciloleucel (axi-cel), sold as Yescarta, offered an event-free survival (EFS) rate more than 60% higher than that of the current second-line standard of care (SOC) for patients whose initial treatment for large B-cell lymphoma (LBCL) failed or whose cancer returned within a year.1
For Frederick L. Locke, MD, of Moffitt Cancer Center in Tampa, the lead study author of the phase 3 ZUMA-7 trial that studied the use of axi-cel in these patients,2 the question was: What now?
The answer is clear, he said. Axi-cel, with years of data behind it, will quickly become the new SOC for these patients.
“ZUMA-7 met its primary EFS end point, demonstrating statistically significant and clinically meaningful improvement in efficacy with axi-cel vs second-line SOC in relapsed/refractory [R/R] LBCL,” Locke said during the ASH plenary session. “Results from the ZUMA-7 trial herald a paradigm shift: Axi-cel should be a new standard for patients with second-line R/R LBCL.”
Locke presented the data for ZUMA-7 to a large crowd, many of whom had heard the main data points but had other questions—for instance, if patients treated with axi-cel in the second-line setting fail, what happens next? Could autologous stem cell transplant (ASCT), which has been the second-line SOC treatment, now follow axi-cel?
“We don’t know what the appropriate therapy would be for a patient in the third line if they receive CAR [chimeric antigen receptor] T-cell therapy in the second line,” Locke said during a press briefing held prior to the plenary session. “We don’t understand [whether] the resistance mechanisms overlap….I think that will be an area of intense study in the years to come.” He said that in ZUMA-7, patients could go on to transplant if they progressed after receiving axi-cel; 19 patients did so, and 9 are still alive.
And in response to a question, Locke acknowledged that minority patients had been underrepresented in ZUMA-7; across the conference, there were discussions of how to make these expensive therapies available to all patients, regardless of socioeconomic status.
Differences with TRANSFORM. Axi-cel reached the market in the fall of 2017, within months of the approval of the first CAR T-cell therapy, and it is now approved for several types of R/R LBCL.3 Clinicians have become much better at managing the most significant adverse events (AEs) arising from cytokine release syndrome (CRS), which occurs as the customized therapy attacks the cancer within the patient’s body.
ZUMA-7 has an important difference from TRANSFORM, which studied lisocabtagene maraleucel (liso-cel) in LBCL4: Patients in ZUMA-7 were given corticosteroids only, not chemotherapy, prior to axi-cel treatment. “By giving CAR T-cell therapy as an earlier line of treatment, we are able to reduce the amount of chemotherapy patients are exposed to and get them quickly to a definitive therapy that can eradicate lymphoma for many years, if not forever, without a stem cell transplant,” Locke said.
But, some oncologists wondered, will bridging therapy be given in a real-world setting?
Locke told Evidence-Based Oncology™ that this may occur, but the point of ZUMA-7 is that axi-cel can be manufactured quickly and patients can avoid added chemotherapy, which appears to have contributed to the study’s positive findings (see Clinical Spotlight, SP13).
Advantages of axi-cel. As City of Hope’s Alex F. Herrera, MD, noted in his plenary introduction, the question of using CAR T-cell therapy generally and axi-cel specifically arose quickly after clinicians saw its success in the third-line setting.
Locke noted that ZUMA-7 produced an advantage that is also seen with TRANSFORM: When the SOC for second-line R/R LBCL is salvage chemotherapy followed by a high-dose therapy and ASCT, the challenge is getting patients to the point of receiving the transplant in the first place. In ZUMA-7, 94% of those randomized to receive axi-cel were infused with treatment, while only 36% in the SOC group received a transplant.
Results from ZUMA-7 showed the following:
A separate abstract presented during the ASH meeting found that patients in ZUMA-7 who received axi-cel reported superior quality-of-life outcomes than those who received SOC.5 “The superior clinical outcomes and patient experience with axi-cel over SOC should help inform treatment choices in second-line R/R LBCL,” the authors wrote.
At the 2021 American Society of Hematology (ASH) Meeting & Exposition, a major phase 3 study using chimeric antigen receptor (CAR) T-cell therapy in second-line treatment of aggressive B-cell lymphoma failed to yield positive results. But it’s this trial, the BELINDA study, that may help inform clinicians about the importance of infusing patients quickly, according to the lead investigator.
BELINDA, presented in ASH’s late-breaking session, found that tisagenlecleucel (tisa-cel) had no advantage in event-free survival over standard of care for patients. However, Michael R. Bishop, MD, of the University of Chicago, said it still represents a landmark study that offers many important takeaways, particularly regarding trial design.
Tisa-cel, sold as Kymriah by Novartis, represented an historic breakthrough when it was approved in August 2017. Thus, the news that BELINDA failed to meet its end point—unlike ZUMA-7—was extremely disappointing, Bishop acknowledged in a press briefing.
Could he explain the apparent lack of benefit? “It’s an extremely important question. And if I’m completely honest, I lay awake at night thinking about it,” Bishop said.
He went through possible explanations for gap in results between the 2 trials, starting with their definitions of event-free survival. But the more important differences, he said, have to do with BELINDA’s near doubling in the mean number of days between the time patients were randomized and when they were infused with modified T-cells.
ZUMA-7 did not allow for bridging chemotherapy, only steroids. BELINDA did allow for chemotherapy, Bishop said. Sometimes patients had 2 rounds of bridging chemotherapy. As a result, the median time to infusion for BELINDA with tisa-cel was 52 days. With ZUMA-7 and axi-cel, Locke reported the median time was 27 days.
“There’s a number of variables that affected that,” Bishop said. “And we think this long infusion time, where you have an extremely progressive disease going on, did not permit the potential benefits of tisagenlecleucel. We hope that people will learn from that in the designing of future trials.”
But if the ZUMA-7 findings mean that second-line CAR T-cell therapy could soon be approved by FDA, what can be done to ensure patients are infused in a timely manner? Evidence-Based Oncology™ (EBO) asked Bishop to comment on this, given that the approval of 1 or more CAR T-cell therapies in the second-line setting could open the door to many more patients being eligible for treatment.
Bishop acknowledged that some patients and institutions still have challenges dealing with payers when administering CAR T-cell therapy in the third-line setting, 4 years after tisa-cel’s approval.
“I think it’s quite variable, relative to insurance approval,” he said. “In some situations, I’ll have insurance approval within 48 hours. It really depends upon the carrier. And then there’s other carriers who literally make patients jump through hoops. I think that’s inappropriate for an approved therapy, and especially when you have exactly that—a life-threatening situation. Time is of the essence, and getting that approval and moving forward is very, very important.”
Other oncologists have told EBO that payers delays have caused patients to miss the window of opportunity for CAR T-cell therapy. Bishop said in a real-world setting, multiple factors come into play, and payer delays are not helpful.
“Sometimes you can’t wait to get some chemotherapy before [patients] get referred to the [cancer] center,” he said. “And I think that’s also going to be our challenge among physicians who treat lymphoma on a regular basis, especially this patient population.”
Bishop MR, Dickinson M, Purtill D, et al. Tisagenlecleucel vs standard of care as second-Line therapy of primary refractory or relapsed aggressive B-cell non-Hodgkin lymphoma: Analysis of the phase 3 BELINDA study. Presented at: 63rd American Society of Hematology Meeting & Exposition; December 11-14, 2021; Atlanta, GA. Abstract LBA-6. https://ash.confex.com/ash/2021/webprogram/Paper155068.html
The anti–CD-19 therapy lisocabtagene maraleucel (liso-cel) offered significant benefits over standard of care (SOC) when given to patients whose large B-cell lymphoma (LBCL) returned or failed to respond (R/R) to the first treatment after 12 months, according to interim findings of the randomized phase 3 TRANSFORM study.1
“This is a breakthrough therapy which has shown superiority over SOC in terms of efficacy with an extremely favorable safety profile,” said Manali Kamdar, MD, of the University of Colorado, who presented the TRANSFORM results during the 2021 American Society of Hematology (ASH) Meeting & Exposition. “We are excited about the potential of this study to change the existing standard of care in these high-risk patients.”
All signs point to liso-cel and another chimeric antigen receptor (CAR) T-cell therapy, axicabtagene ciloleucel (axi-cel), becoming the new SOC options for second-line treatment of patients with LBCL, given the results for liso-cel and those for the phase 3 ZUMA-7 trial.2 Both trials were highlighted at a press briefing to open the ASH meeting. ZUMA-7 later headlined the ASH plenary session (see SP11).
Press briefing moderator Laurie H. Sehn, MD, MPH, a hematologist-oncologist at the British Columbia Cancer Centre for Lymphoid Cancer at the University of British Columbia, called both sets of results “remarkable” and said they would be welcomed by clinicians who feel limited by the current SOC.
“I think it’s inevitable that this will become the standard of care,” she said.
Liso-cel, sold as Breyanzi by Bristol Myers Squibb, was approved in 2021 for adults who have failed on 2 prior treatments for LBCL, based on results of the TRANSCEND-NHL study.3 Investigators have reported that its manufacturing process, which results in an equal balance of CD8+ and CD4+ CAR T cells, makes the product more consistent and less toxic for patients than the first CAR T-cell therapies approved for R/R LBCL.4
Use of CAR T-cell therapy earlier in a patient’s course of care was a major theme of this year’s ASH meeting. Kamdar’s press briefing just ahead of her presentation outlined how liso-cel offered significantly improved measures of survival over salvage chemotherapy followed by autologous stem cell transplant, along with better reported quality of life.
In TRANSFORM, 184 patients were randomized to receive liso-cel or SOC. Patients ranged in age from 20 to 75 years; the median ages of patients in the SOC and liso-cel arms were 58 and 60 years, respectively. Two-thirds of the SOC arm was male; the liso-cel arm was 52% female. Patients were well matched by type of non-Hodgkin lymphoma; no racial or ethnic breakdown was reported.
Median event-free survival, the study’s primary end point, was 2.3 months for SOC vs 10.1 months for liso-cel, for a risk reduction of 65% (HR, 0.349; P <.0001). Secondary end points all favored liso-cel:
Median progression-free survival was 5.7 months for SOC vs 14.8 months for liso-cel, for a 59% risk reduction (HR, 0.406; P = .0001).
The likelihood of complete response (CR) was 66% for patients treated with liso-cel, compared with 39% for SOC, for a CR rate that was 27% higher with liso-cel (P <.00001). Investigators reported that of the 92 patients given SOC, 50 later received liso-cel.
Overall survival data were not mature at the time of data cutoff, but the trend favored liso-cel.
“Despite a relatively short follow-up period of just over 6 months, the positive results of this study suggest that CAR T-cell therapy has the potential to become the new SOC for patients who do not respond to initial chemotherapy or who relapse within 12 months,” Kamdar said.
She pointed out that the patients in the study were very high risk; under current SOC, many do not make it to stem cell transplant. By contrast, in the second-line setting, most did receive liso-cel infusion. When patients are in the third-line or later stage of treatment, a major challenge is that they may be too ill to wait for the CAR T-cell manufacturing process to be complete.
“Of the patients who were randomized to SOC, only 46% were able to proceed to transplantation,” Kamdar said. “On the other hand…97% of patients were able to successfully receive liso-cel infusion.”
Adverse events. From a safety standpoint, liso-cel was comparable with SOC, and some patients were able to receive the CAR T-cell therapy in an outpatient setting. Although the well-known effects associated with CAR T-cell therapy of cytokine release syndrome (CRS) and neurological toxicity were seen, there were no grade 4 or 5 neurological events. No deaths were attributable to liso-cel treatment.
Investigators reported no new liso-cel safety signals when giving the treatment in the second-line setting. Roughly half (49%) of those receiving liso-cel had some level of CRS, with 37% reporting grade 1 and 11% grade 2; one patient reported grade 3 effects that started on day 9 after treatment and resolved in 2 days. Patients with CRS were treated with tocilizumab (24%) and corticosteroids (17%). The most common treatment-emergent adverse events were cytopenias, which were reported in 43% of patients.
Findings are logical. “For somebody who has to treat patients with LBCL like I do, it’s incredibly frustrating when patients [have] failed frontline therapy,” she said. For patients such as those in TRANSFORM and ZUMA-7, who are especially high risk—Sehn called them “the worst of the worst”—the current approach calls for doubling down with higher doses of chemotherapy. Patients continue to fail, she said.
So, “it’s not surprising that coming in [to the second-line setting] with a novel approach and a cellular therapy that has proven curative capacity [in the] third-line setting, you may have outperformed in with more chemotherapy,” Sehn said.
The word that comes to mind, she said, is that the findings are “logical.”