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of obecabtagene autoleucel (obe-cel; Aucatzyl) adding to the 2 other FDA-approved chimeric antigen receptor (CAR) T-cell agents in relapsed/refractory acute lymphoblastic leukemia (ALL), investigators are excited about the agent’s potential to offer a more manageable safety profile with similar efficacy to previously available options.

 However, considerations regarding toxicity management, supportive care, and CAR T-cell access must be weighed appropriately when selecting a CAR T-cell agent for patients with relapsed/refractory ALL.

“The [FDA]-approved CAR T-cell therapies in their current iteration are autologous CAR T-cell products,” 

explained. “In the case of ALL, the currently approved [agents] target CD19, which is expressed in nearly all of B-cell ALL, and there’s also a costimulatory domain that allows these CAR T cells to rapidly proliferate and expand. Tisagenlecleucel [tisa-cel; Kymriah] and brexucabtagene autoleucel [brexu-cel; Tecartus] have the same binder to CD19, whereas obe-cel has a different, more short-acting binder. Tisa-cel and obe-cel are also both 4-1BB costimulatory whereas brexu-cel is CD28 [costimulatory]. That’s important because the functional dynamics of CAR T-cell expansion and persistence are theoretically different based on costimulatory domain, with 4-1BB CARs being slower to peak and perhaps longer lasting than CD22, which tends to peak very quickly and expand very rapidly but then not persist quite as long.”

 Peer Exchange, investigators in the field of hematologic oncology offered their perspective on the current and potential future standing of CAR T-cell therapies in the relapsed/refractory ALL treatment landscape. The panelists discussed updated data from the phase 1/2 ZUMA-3 trial (NCT02614066) and findings from the ongoing phase 1b/2 FELIX study (NCT04404660). They also highlighted CAR T adverse effect (AE) and supportive care considerations and examined CAR T-cell therapy access and availability issues.

Brexu-Cel Demonstrates Long-Term Survival Benefit, Obe-Cel Offers Glimpse Into the Future

During the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, investigators presented long-term survival outcomes from ZUMA-3, which supported the 2021 FDA approval of brexu-cel in relapsed/refractory B-cell precursor ALL. At the time of the approval, efficacy-evaluable patients (n = 54) achieved a complete response (CR) within 3 months at a rate of 52% (95% CI, 38%-66%), and the median duration of CR was not reached. CR/CR with incomplete count recovery (CRi) rate was the primary end point of the study; overall survival (OS) was a key secondary end point.

At a median follow-up for OS of 53.6 months (95% CI, 44.7-82.3), the median OS among all patients who received brexu-cel in phases 1 and 2 (n = 78) was 25.6 months (95% CI, 16.2-60.4). The 48-month OS rate among these patients was 40% (95% CI, 28%-52%).

Notably, patients who received brexu-cel during phases 1 and 2 with a CR/CRi per independent review assessment (n = 57) achieved a median OS of 47.0 months (95% CI, 23.2-not estimable [NE]). Within this subgroup, patients who received no subsequent allogeneic stem cell transplantation (SCT; n = 43) achieved a median OS of 60.4 months (95% CI, 23.2-NE) and those who did receive subsequent allogeneic SCT experienced a median OS of 36.3 months (95% CI, 10.2-NE).

“It’s reassuring that we’re seeing a substantial [portion of] patients [who] are able to maintain remission beyond the 4-year mark,” 

said.“Hopefully we will [perform] a more detailed analysis [about] the role of a transplant. As a field, [we need] better answers as to [why] some patients are able to maintain long-term remission after CAR T-cell therapy without subsequent transplant. We don’t understand well who these patients are, which makes it challenging to make the decision of [whether] to perform a transplant when a patient has a relapse in month 1 or 3.”

Additional findings from the ZUMA-3 update demonstrated that patients who received prior blinatumomab (Blincyto; n = 38) experienced a median OS of 15.9 months (95% CI, 8.3-26.0) compared with 60.4 months (95% CI, 18.6-NE) among patients who did not receive prior treatment with blinatumomab (n = 40). Patients who did (n = 17) and did not (n = 61) receive prior inotuzumab ozogamicin (Besponsa) experienced a median OS of 8.8 months (95% CI, 2.2-34.1) and 38.9 months (95% CI, 18.6-NE), respectively.

“Most of the patients I see have been exposed to blinatumomab in my region of the country; almost every [patient in this setting] receives blinatumomab at some point,” Muffly noted. “I typically use brexu-cel as the second of these therapeutic options. I also [prefer] brexu-cel for patients who have a history of central nervous system [CNS] involvement, because CAR T-cell therapy penetrates the CNS. One of the [remaining] questions is when to not use CAR T-cell therapy. Data are now accumulating in the adult ALL setting—we haven’t had these therapies as long as the pediatricians have—but [in my opinion] it’s very difficult to give our current CAR T-cell therapies in patients with a very high disease burden.”

Obe-cel was evaluated for the treatment of adult patients with relapsed/refractory B-cell ALL in FELIX. Obe-cel is a novel anti-CD19 CAR T-cell agent with a fast off-rate that has shown the potential to improve T-cell persistence and lessen immune-mediated toxicities compared with currently available CAR T-cell therapies. The primary end point of the study is CR/CRi rate per independent response review committee; secondary end points include OS, event-free survival (EFS), duration of response, and safety.

At a median follow-up of 21.5 months (range, 8.6-41.4), findings from FELIX presented during the 2024 ASCO Annual Meeting and during the 2024 European Hematology Association Congress demonstrated that the CR/CRi rate among efficacy-evaluable patients (n = 99) was 78%. Among these patients, 40% were in ongoing remission without subsequent SCT or another therapy and 18% were negative for minimal residual disease (MRD) following SCT.

In the overall treated population (n = 127), the median EFS without censoring for SCT was 9.0 months (95% CI, 6.57-14.32), with a 12-month EFS rate of 44.0% (95% CI, 35.2%-52.5%). When censoring for SCT, these figures were 11.9 months (95% CI, 7.98-22.11) and 49.5% (95% CI, 39.6%-58.6%), respectively. All 18 patients who had SCT in remission were MRD negative, and 55.6% of these patients displayed ongoing CAR T persistence before SCT.

The median OS without censoring for SCT and with censoring for SCT was 15.6 months (95% CI, 12.91-NE) and 23.8 months (95% CI, 12.91-NE), respectively. The respective 12-month OS rates were 61.1% (95% CI, 52.0%-69.0%) and 63.7% (95% CI, 53.7%-72.0%).

“My conclusion [from this update] was that some responders can have a long-term remission without transplantation,”

who presented the findings during the 2024 ASCO Annual Meeting, commented.

Additional findings showed that ongoing CAR T persistence correlated with long-term EFS in FELIX (HR, 2.7; 95% CI, 1.4-5.3). Patients who received obe-cel and had ongoing CAR T persistence at month 6 (n = 42) experienced a median EFS that was NE, with a 12-month EFS rate of 87.3% (95% CI, 72.0%-94.5%). Comparatively, patients who had a loss of persistence by month 6 (n = 18) displayed a median EFS of 15.1 months (95% CI, 8.11-NE), with a 12-month EFS rate of 59.3% (95% CI, 33.0%-78.1%).

“There was an interesting relationship with regard to CAR T-cell persistence and long-term EFS,” 

said. “There was a clear stratification of outcomes along the lines of loss of CAR T-[cell] persistence in patients at 6 months, or those who had ongoing persistence, and their ultimate outcomes.”

Prior safety data from FELIX showed that obe-cel therapy was generally well tolerated; any-grade cytokine-release syndrome (CRS) was reported in 69% of patients, with 2% experiencing grade 3 or higher CRS. Any-grade immune effector cell–associated neurotoxicity syndrome (ICANS) was present in 23% of patients, with 7% experiencing grade 3 or higher ICANS. Notably, no grade 3 or higher CRS or ICANS were reported in patients with less than 5% bone marrow blasts at lymphodepletion.

“[The safety profile] is the most striking difference with [obe-cel] vs brexu-cel,” Park said. “Why not use a safer product with the same efficacy? You could probably make that argument, [and] for high-burden patients, it’s an easy, no-brainer switch [from brexu-cel to obe-cel].”

Data from FELIX supported the November 2024 FDA approval of obe-cel for the treatment of adult patients with relapsed/refractory B-cell precursor ALL.3 FDA approval “It’s reasonable for all of us to [consider] reaching for [obe-cel] as the first CAR T-cell therapy that patients receive,” Roloff added.

Navigating CAR T–Related AE Management and Supportive Care

The panelists transitioned their conversation to AE management and supportive care considerations when using CAR T-cell therapies for the treatment of patients with relapsed/refractory ALL. In the July 2024 edition of their Clinical Practice Guidelines in Oncology for ALL, the National Comprehensive Cancer Network (NCCN) noted that severe CRS and/or neurologic toxicities may accompany CAR T-cell therapy and that these events should be managed according to the manufacturers’ Risk Evaluation and Mitigation Strategies program. The NCCN recommends tocilizumab (Actemra) to mitigate CRS and prefers the use of steroids for the treatment of tocilizumab-refractory CRS and/or other neurologic toxicities.

“There’s variability in the way that we manage CRS and ICANS,” Roloff explained. “I will typically give a single dose of tocilizumab first, and if on the next vital check or next patient assessment the patient seems like they need continued therapy, I’m starting steroids with that second dose of tocilizumab.”

“Fever is usually the first sign [of CRS or ICANS],” Park added. “Brexu-cel is mostly performed as an inpatient [therapy], but if it were to be outpatient, we ask patients to measure their temperature routinely. If patients get that first fever, we usually give tocilizumab and steroids together if the patient is receiving brexu-cel.”

The NCCN guidelines also recommend that antiseizure medications be considered for prophylactic use during the first month after CAR T-cell therapy infusion. They also noted that growth factor therapy, prophylactic antimicrobial therapy, and intravenous immunoglobulin can be considered to combat the severe neutropenia, T-cell depletion, and B-cell aplasia that can occur with CAR T-cell therapy in ALL.

Muffly noted that in her practice she continues treatment with acyclovir (Sitavig) during prophylaxis as would be done during a bone marrow transplant. She also advocated for prophylaxis for continued 

 pneumonia and antibiotic prophylaxis for patients with neutropenia.

“We also have to keep in mind that every patient is not able to stay at the center [for toxicity monitoring],” Park said. “As patients are [return for treatment], I’ve struggled with [factors such as] the frequency [with which] I’m going to tell them to check IgG levels, what to do with [this information], and what to do [in terms of] growth factors. These are important factors because they may lead to late toxicities and late complications. Short-term toxicities [may be improved with obe-cel vs brexu-cel] because there is less CRS and ICANS. But as these T cells persist longer, we may see more B-cell aplasia and cytopenia. We don’t know [for sure], but we have to keep that in mind and keep monitoring these patients.”

Taking Steps to Address CAR T Access and Availability Issues

The panelists concluded their talk by discussing barriers to CAR T-cell therapy access. CAR T-cell agents often entail a long manufacturing period with a vein-to-vein time of several weeks and a high production cost that can limit their use in patients with disease that necessitates a faster response. Additionally, CAR T-cell therapies usually need to be administered in an inpatient setting at a large academic medical center, creating geographic, financial, and referral barriers for patients.

“One of the main logistical limitations [of CAR T-cell therapies] is time,” 

said. “Referral to our CAR T doctor and insurance approval is usually at least a week, then with apheresis and manufacturing it can be 3 to 4 weeks from the diagnosis of relapsed [disease] to the ability to start lymphodepletion. Having the disease under control during that time so that the patient can receive CAR T-cell therapy is a major challenge.”

Most young adult patients with ALL are not receiving their primary treatment for the disease at centers that can deliver CAR T-cell treatments, according to Muffly. Thus, a multipronged approach must be employed to educate patients and offer them solutions to access CAR T-cell therapies, she said. Roloff added that access to lodging for patients receiving CAR T-cell therapies can be pivotal to allow for closer monitoring. Muffly also highlighted that the addition of obe-cel to the CAR T treatment arsenal could eventually offer patients a more feasible outpatient option due to its lessened toxicity profile compared with brexu-cel.

“An easy thought would be, ‘Why don’t we set up CAR T centers all over the place?’” Muffly said. “[But data have shown] that if you treat [patients with] ALL in less experienced centers, they don’t do as well. The solution is not to just create more CAR T-cell centers at random or try to cover the scope of the country [with them]. These are extremely specialized therapies, and this patient population is so specialized. Some of that [expansion] is good, but that as a broadscale answer is not a good thing for patients with ALL.”

FDA approves tisagenlecleucel for B-cell ALL and tocilizumab for cytokine release syndrome. FDA. Updated September 7, 2017. Accessed October 11, 2024. bit.ly/3U9YSvB

FDA approves brexucabtagene autoleucel for relapsed or refractory B-cell precursor acute lymphoblastic leukemia. FDA. October 1, 2021. Accessed October 11, 2024. bit.ly/4eWFSIW

FDA approves obecabtagene autoleucel for adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia. FDA. November 8, 2024. Accessed November 21, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-obecabtagene-autoleucel-adults-relapsed-or-refractory-b-cell-precursor-acute

Oluwole OO, Ghobadi A, Cassaday RD, et al. Long-term survival outcomes of patients (pts) with relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) treated with brexucabtagene autoleucel (brexu-cel) in ZUMA-3. 

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Jabbour E, Tholouli E, Sandhu KS, et al. Obecabtagene autoleucel (obe-cel, AUTO1) in adults with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL): overall survival (OS), event-free survival (EFS) and the potential impact of chimeric antigen receptor (CAR)-T cell persistency and consolidative stem cell transplantation (SCT) in the open-label, single-arm FELIX phase Ib/II study. 

. 2024;42(suppl 16):6504. doi:10.1200/JCO.2024.42.16_suppl.6504

Autolus Therapeutics. Developing next generation programmed T cell therapies. September 2024. Accessed October 11, 2024. bit.ly/3XXCiaw

NCCN. Clinical Practice Guidelines in Oncology. Acute lymphoblastic leukemia, version 2.2024. Accessed October 11, 2024. https://www.nccn.org/professionals/physician_gls/pdf/all.pdf

Gajra A, Zalenski A, Sannareddy A, Jeune-Smith Y, Kapinos K, Kansagra A. Barriers to chimeric antigen receptor T-cell (CAR-T) therapies in clinical practice. 

. 2022;36(3):163-171. doi:10.1007/s40290-022-00428-w

Articles

The recent FDA approval of obecabtagene autoleucel (obe-cel) adds to the arsenal of CAR T-cell therapies for relapsed/refractory acute lymphoblastic leukemia (ALL), offering a potentially safer profile with comparable efficacy. The ZUMA-3 trial highlighted brexu-cel's long-term survival benefits, while the FELIX study showcased obe-cel's promising outcomes and reduced toxicity. Despite these advancements, challenges remain in managing adverse effects, ensuring supportive care, and improving access to CAR T-cell therapies. Addressing logistical barriers and optimizing patient education are crucial for broader adoption and effective treatment delivery.

Hematologic oncologists offer their perspective on the current and potential future standing of CAR T-cell therapies in the relapsed/refractory ALL treatment landscape. 

Obe-Cel Approval Expands CAR T-Cell Therapy Options in Relapsed/Refractory ALL

Despite the clear consensus that was reached regarding the unfavorable risk-benefit profile of PD-1 inhibitors in patients with certain PD-L1–negative gastrointestinal cancers in a recent Oncologic Drugs Advisory Committee (ODAC) meeting, the jury is still out regarding the appropriate use of a cutoff, according to Nataliya Uboha, MD, PhD.

 She added that questions must be addressed before a definitive answer can be given regarding the efficacy of these agents in patients with PD-L1 expression levels ranging from 1% to 10%.

The final votes from two September 26, 2024, FDA ODAC sessions determined that the risk-benefit profile of PD-1 inhibitors was not favorable for the frontline treatment of patients with PD-L1 expression less than 1% who have advanced HER2-negative microsatellite stable gastric/gastroesophageal junction (GEJ) adenocarcinoma or unresectable or metastatic esophageal squamous cell carcinoma (ESCC) (

In my practice, I offer immunotherapy to those with a PD-L1 combined positive score [CPS] of 1% or greater,” Uboha, an associate professor and researcher at the University of Wisconsin School of Medicine and Public Health in Madison, said in an interview with 

. “I have become less dogmatic about this—when the initial data with nivolumab [Opdivo] came out, my cutoff was 5%. However, I am seeing variability between PD-L1 expression between the primary [and] metastatic sites—[recently], I saw a PD-L1 score of 2.3%, so even with a decimal point. These patients have very serious illnesses, and they need better treatments. In the era of uncertainty, the benefits of the addition of immunotherapy outweigh the risks, especially when the testing for the biomarker is not very reliable.”

Determining whether the use of PD-1 inhibitors in patients with PD-L1 expression ranging from 1% to 10% is optimal remains especially critical as approval is pending for tislelizumab-jsgr (Tevimbra) in combination with platinum-containing chemotherapy in ESCC.

 The biologics license application (BLA) was submitted to the FDA on July 18, 2023, and cited data from the phase 3 RATIONALE-306 trial (NCT03783442) showing that the tislelizumab regimen produced a significant improvement in overall survival (OS) compared with placebo and chemotherapy in the overall patient population (n = 649) of the trial.

However, 3-year survival data presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting showed that the survival benefit was greater in patients with a PD-L1 tumor area positivity (TAP) score of 10% or greater vs in those with a TAP score less than 10%.

Among patients with a PD-L1 TAP score of 10% or greater, the median OS was 16.6 months (95% CI, 15.3-23.4) in the tislelizumab plus chemotherapy arm (n = 116) vs 10.0 months (95% CI, 8.6-13.3) in the placebo plus chemotherapy arm (n = 107; HR, 0.70; 95% CI, 0.52-0.95). Among those with a PD-L1 TAP score less than 10%, the median OS was 16.0 months (95% CI, 12.3-19.6) in the tislelizumab arm (n = 151) vs 10.4 months (95% CI, 9.0-13.4) in the placebo arm (n = 168; HR, 0.77; 95% CI, 0.60-0.99).

“The [ODAC] discussion was whether the committee should consider limiting the approval in biomarker-selected patient populations for both nivolumab and pembrolizumab [Keytruda]. Tislelizumab [plus chemotherapy in the frontline setting] is not approved yet, but we’re seeing similar efficacy of these agents across different studies in this patient population,” Uboha said. “I would anticipate that the committee will likely make a decision to approve tislelizumab in similar settings, since we’ve seen similar efficacy, but I also anticipate that there will be a limitation to indications of both nivolumab and pembrolizumab use based on lack of benefit in those with PD-L1–negative tumors.”

Tislelizumab is also pending approval in the locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma setting; the FDA accepted the BLA for tislelizumab plus fluoropyrimidine- and platinum-containing chemotherapy in February 2024 with a target action date expected in December 2024.

Testing for PD-L1: How Accurate Are Assessments and Should Approvals Be Restricted?

Uboha added that the original frontline approval of pembrolizumab plus trastuzumab (Herceptin), fluoropyrimidine, and platinum-containing chemotherapy was for all patients with locally advanced, unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma. However, the accelerated approval was restricted in November 2023 to include only patients whose tumors have a PD-L1 CPS of 1% or greater, as determined by an FDA-approved test.

“The [ODAC meeting] discussion about patients whose tumors have low PD-L1 expression, in the range of 1% to 10%, was much more nuanced. Primarily, the discussion was geared to how difficult it is to reliably identify the exact score,” Uboha said. “There’s a lot of heterogeneity in expression [and] the pathologists have commented on the heterogeneity [of] expression between the primary [and] metastatic sites. We don’t know what the different treatments, such as radiation, can change [regarding] expression of PD-L1 in these tumors; is expression of PD-L1 dynamic? Looking at patients with a low PD-L1 score and how they respond to immunotherapy treatment was not a primary end point in any of the studies that were discussed.”

Robert Albert Anders, MD, PhD, an associate professor of pathology at the Johns Hopkins University School of Medicine and a pathologist at Johns Hopkins Kimmel Cancer Center, presented the clinical perspective the on PD-L1 testing in clinical practice at the ODAC meeting. In an interview with 

, he noted that “There are a lot of very detailed portions of PD-L1 testing, [and] the thresholds are presented as all or none. It’s either above a percentage or below a percentage, but there are a lot of caveats that go into PD-L1 testing: The type of specimen, the stain that is used, and how the test is interpreted. I find these things are often overlooked in the discussion of clinical biomarkers.”

Anders added that PD-L1 should be an additional piece of evidence and not the only piece of evidence that determines whether a patient should receive treatment with PD-1 inhibitors. Uboha also noted that the simplification of testing, recommendations, and guidelines is necessary because discordance exists between the prescribing information of a drug, FDA approval, and ASCO as well as NCCN guidelines.

“We need to make it simpler. We need to have or at least attempt to make similar or uniform cutoffs for PD-L1 expression, so that these agents can be used interchangeably, and so that it’s easier for our pathologists and community partners to adopt them in clinical practice,” Uboha said.

“The threshold for positivity is an ongoing problem where we have different PD-L1 tests, and based upon which test is used, the cutoffs are different. Even based upon the tumor type, the cutoffs can be different,” Anders said. “[Therefore], the pathologist who’s scoring PD-L1 is left with almost an impossible task because the way the test is interpreted depends on which test was run and which tumor type it is. That’s not an impossible hurdle, but it’s something we’ve never faced before. The other issue about threshold for positivity is that it’s difficult to reproducibly determine PD-L1 positivity.”

Breaking Down ODAC’s Discussion: Not Enough Benefit for a PD-L1 Score Less Than 1%

Although the benefit of PD-1 agents in patients with PD-L1 scores ranging from 1% to 10% requires further elucidation, according to Uboha, the September 26, 2024, ODAC meeting discussion focused on patients with expression levels less than 1%.

The FDA noted concerns regarding the lack of benefit observed with PD-1 inhibitors for patients with ESCC who had lower or negative PD-L1 scores (

They also detailed concerns for patients with gastric/GEJ adenocarcinoma because of the modest efficacy that has been observed with the agents across patient populations defined by different PD-L1 thresholds (

 In both populations, the regulatory agency highlighted the potential for increased toxicities resulting from the addition of these inhibitors.

“These agents work in many of our patients, but I do believe we need to be more nuanced. We should offer these agents to patients where they are likely to work because they do have toxicities [and] patients can develop immune-mediated toxicities that could negatively affect their quality of life,” Uboha said.

Data from the phase 3 CheckMate 649 (NCT02872116), KEYNOTE-859 (NCT03675737), and RATIONALE-305 (NCT03777657) trials presented in the gastric/GEJ adenocarcinoma space all showed statistically significant primary OS results for patients who were randomly assigned to the PD-L1 agent-containing arm vs the control arm. All patients experienced an OS benefit when treated with a nivolumab plus chemotherapy regimen vs chemotherapy (HR, 0.79; 95% CI, 0.70-0.89), a pembrolizumab plus chemotherapy regimen vs chemotherapy (HR, 0.77; 95% CI, 0.69-0.86), and a tislelizumab plus chemotherapy regimen vs chemotherapy (HR, 0.80; 95% CI, 0.69-0.92).

However, exploratory results the FDA highlighted showed that the benefits were greatest in patients with a PD-L1 score of 10% or higher treated with the nivolumab regimen vs chemotherapy (HR, 0.65; 95% CI, 0.55-0.78), pembrolizumab regimen vs chemotherapy (HR, 0.64; 95% CI, 0.52-0.77), and tislelizumab regimen vs chemotherapy (HR, 0.57; 95% CI, 0.43-0.76). Respective HRs for patients with PD-L1 expression less than 1% were 0.92 (95% CI, 0.70-1.23), 0.92 (95% CI, 0.73-1.17), and 0.98 (95% CI, 0.64-1.50). Patients with PD-L1 expression less than 10% experienced respective HRs of 0.94 (95% CI, 0.80-1.1), 0.86 (95% CI, 0.75-0.98), and 0.91 (95% CI, 0.77-1.07).

“Everybody agreed that PD-L1 is a predictive biomarker of response,” Uboha said. “Everybody also agreed that it has been a challenging biomarker to use [and] adopt. Across all members, there was strong agreement that patients with a higher PD-L1 score, particularly a PD-L1 CPS score of 10% or greater, derive benefit from the addition of immunotherapy to their treatment. There was also general agreement that those who have no expression of PD-1 in their tumors do not derive much benefit.”

“The problem is the biomarker isn’t particularly perfect,” Anders said. “That makes determining whether an individual will respond [difficult].”

In ESCC, findings from the phase 3 KEYNOTE-590 (NCT03189719), CheckMate 648 (NCT03143153), and RATIONALE-306 trials were discussed. The FDA noted that primary OS data were statistically significant in favor of the anti–PD-L1-containing arm vs chemotherapy alone arm in all the trials, but the point estimates for the treatment effect did not appear to be favorable in patients with PD-L1 expression less than 1% and appeared intermediate in patients with a PD-L1 expression of less than 10%.

“One distinction that’s important to make is that most ESCCs will express PD-L1, and so the use of anti–PD-1 agents will probably be broader in patients with ESCC,” Uboha noted.

All patients with ESCC experienced an OS benefit when treated with nivolumab plus chemotherapy vs chemotherapy (HR, 0.73; 95% CI, 0.60-0.88), pembrolizumab plus chemotherapy vs chemotherapy (HR, 0.72; 95% CI, 0.59-0.87), and tislelizumab plus chemotherapy vs chemotherapy (HR, 0.68; 95% CI, 0.56-0.82).

FDA OS analyses showed that patients with a PD-L1 expression of 10% or higher experienced respective HRs of 0.62 (95% CI, 0.46-0.84), 0.57 (95% CI, 0.44-0.75), and 0.66 (95% CI, 0.48-0.92) with nivolumab, pembrolizumab, and tislelizumab, respectively. Respective HRs for those with PD-L1 expression less than 1% were 0.93 (95% CI, 0.46-1.91), 1.00 (95% CI, 0.54-1.85), and 1.34 (95% CI, 0.73-2.46). Furthermore, patients with PD-L1 expression of less than 10% experienced respective HRs of 0.77 (95% CI, 0.60-1.01), 0.95 (95% CI, 0.71-1.26), and 0.76 (95% CI, 0.58-0.99).

Future Directions for Care Amid Paradigm Considerations

Another test will soon be incorporated into practice following the October 18, 2024, approval of zolbetuximab-clzb (Vyloy) plus fluoropyrimidine- and platinum-containing chemotherapy for the frontline treatment of adults with locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma whose tumors are CLDN18.2 positive, as determined by an FDA-approved test.

“I am planning to incorporate reflexive CLDN18.2 testing into our treatment paradigms as well, but this will be applicable only to adenocarcinomas in the advanced setting,” Uboha said.

As targeted agents such as zolbetuximab join the treatment landscape, and the approval of tislelizumab plus chemotherapy for ESCC and gastric cancer indications is pending, clarification has come regarding the optimal approach for patients with a PD-L1 expression of less than 1%.

“The ODAC committee voted to recommend restricting the use of these [anti–PD-1 antibody] agents to patients whose tumors have PD-L1 expression, and I’m hoping that the FDA will further refine the label going forward,” Uboha said. “I’m [also] hoping for more of a unified label across different immunotherapy agents. It will not only make it easier for us to use these agents in clinical practice, but it will potentially simplify future trial designs [in] knowing how to use the appropriate control arm.”

“PD-L1 is a reasonably good biomarker to enrich for patients more likely to respond in a population,” Anders added. “However, the power of its predictive value falls off significantly, almost to being not useful, when applied to an individual patient. Part of that difficulty in being a useful biomarker stems from the inability to uniformly and reproducibly score PD-L1 expression on a given patient.”

Editor’s Note: This interview occurred prior to the approval of zolbetuximab.

Meeting of the Oncologic Drugs Advisory Committee. FDA. September 26, 2024. Accessed October 21, 2024. https://www.youtube.com/live/ELA3JDqtcFw

Immune checkpoint inhibitors in patients with metastatic or unresectable esophageal squamous cell carcinoma. Oncologic Drugs Advisory Committee Meeting. FDA. September 26, 2024. Accessed October 21, 2024. bit.ly/3UjNvS1

Immune checkpoint inhibitors in patients with metastatic or unresectable HER2-negative gastric adenocarcinoma. Oncologic Drugs Advisory Committee Meeting. FDA. September 26, 2024. Accessed October 21, 2024. bit.ly/4ferVGm

Yoon HH, Kato K, Raymond E, et al. Global, randomized, phase III study of tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced/metastatic esophageal squamous cell carcinoma (RATIONALE-306 update): minimum 3-year survival follow-up.

. 2024;42(suppl 16):4032. doi:10.1200/JCO.2024.42.16_suppl.4032

BeiGene’s biologics license application for Tevimbra (tislelizumab) for first-line gastric or gastroesophageal junction cancers accepted by FDA. News release. BeiGene Ltd. February 27, 2024. Accessed October 21, 2024. bit.ly/3YfqoJx

FDA amends pembrolizumab’s gastric cancer indication. FDA. Updated November 8, 2023. Accessed October 21, 2024. bit.ly/3YwRX27

FDA approves zolbetuximab-clzb with chemotherapy for gastric or gastroesophageal junction adenocarcinoma. FDA. October 18, 2024. Accessed October 21, 2024. bit.ly/3YvZuOE

The recent FDA ODAC meeting highlighted the unfavorable risk-benefit profile of PD-1 inhibitors for certain PD-L1–negative gastrointestinal cancers, yet questions remain about their efficacy in patients with PD-L1 expression levels between 1% and 10%. The discussion emphasized the variability and challenges in PD-L1 testing, which complicates treatment decisions. While PD-L1 is a predictive biomarker, its reliability is questioned due to heterogeneity in expression. Future directions include refining treatment paradigms with new agents like zolbetuximab and standardizing PD-L1 testing to improve clinical practice.

Nataliya Uboha, MD, PhD, and Robert Albert Anders, MD, PhD, unpack the unfavorable risk-benefit profile of PD-1 inhibitors in patients with certain PD-L1–negative gastrointestinal cancers and discussions from a recent ODAC meeting.

Discussions Swirl on the Role of PD-1 Inhibitors for Gastric/GEJ/ESCC Cancers With 1%-10% PD-L1 Expression

Despite having the option of cancer care through the Veterans Affairs (VA) health network, veterans with cancer still experience economic, social, and geographic barriers to receiving high-quality care. This has prompted investigators to develop several interventions to better serve these patients.

“Veterans have higher rates of lung cancer [compared with] civilian populations; prostate and bladder cancer [rates] are also pronounced [among] veterans, [and we also see] higher rates of melanoma, [all] largely due to exogenous exposure risk,” Manali I. Patel, MD, MPH, MS, said in an interview with 

. “One of the biggest barriers [to cancer care] for veterans is the lack of system level resources that can ensure veterans understand the diagnosis and treatment options, such that veterans receive care that is concordant with their goals, preferences, and values. Cancer care is quite complex and trying to not only coordinate care but explain the nuances in plain language is challenging. Having resources [available] that proactively assist veterans in their understanding and support them through cancer care is what is most needed to improve patient outcomes.”

Patel is an associate professor in the Division of Oncology at Stanford University School of Medicine, a staff oncologist at the VA Palo Alto Health Care System in Palo Alto, California, and directs the Partnerships to Advance Cancer Care lab.

Beyond these issues that Patel identified, which are also prevalent among nonveteran patient populations, she explained that veteran patients with cancer face unique barriers to receiving high-quality cancer care, especially when receiving care in non-VA community settings where appropriate and tailored health care, including mental health care, may be lacking, as well as other veteran-directed resources. This is especially challenging for veterans who may lack social support to help them advocate and navigate through the system.

“Many veteran [patients with cancer] have limited social support, which we know is important in helping people navigate through their cancer care, advocate for treatments that are aligned with their goals, and help to manage aspects of their care, especially as they’re nearing the end of life. The VA is especially aware of these issues in their approach to deliver cancer care. Specifically in the VA setting, there are many interventions that address these key barriers,” Patel noted.

In a qualitative study of veteran patients with lung cancer published in 

, Patel et al interviewed 24 patients with lung cancer who were receiving cancer treatment at the VA Palo Alto Health Care System. The median one-way distance to the facility for the study population was 82 miles (range, 45-300), and patients had stage I (12.5%), II (12.5%), III (37.5%), or IV (37.5%) disease at diagnosis. The study objective aimed to “assess veterans’ perspectives regarding their lung cancer care with a specific focus on identifying modifiable barriers to evidence-based care delivery.”

Findings from the study showed that social and economic disadvantages were hindering the delivery of cancer care, fragmented care delivery was contributing to diminished mental health and emotional well-being, and there was a lack of health system–level interventions to address limited health literacy. Patients noted that this lack of health literacy negatively impacted shared decision-making regarding treatment options and end-of-life care.

Respondents cited long commute times, travel-related financial concerns, job retention, and wage loss as social and economic disadvantages limiting their access to care. Although VA transportation options such as shuttle buses and fuel mileage reimbursements were available and utilized, patients often found these stressful.

Furthermore, as Patel noted, mental health concerns, which are prevalent among veteran patients, have been associated with increased mortality among people with cancer. But interventions have been shown to have a positive impact on outcomes for these patients. For example, findings from a retrospective population-based cohort study of patients in the Veterans Affairs Central Cancer Registry with newly diagnosed non–small cell lung cancer (n = 55,315) showed that patients with a preexisting mental health disorder (n = 18,229) experienced a lower likelihood of being diagnosed with cancer in a late stage when they participated in a mental health treatment program vs when they did not (OR, 0.62; 95% CI, 0.58-0.66; 

 < .001). Patients who participated in a mental health treatment program also experienced an increased likelihood of receiving stage-appropriate treatment (OR, 1.55; 95% CI, 1.26-1.89; 

 < .001), lower all-cause mortality (adjusted HR, 0.74; 95% CI, 0.72-0.77; 

 < .001), and lower lung cancer–specific mortality (adjusted HR, 0.77; 95% CI, 0.74-0.80; 

 < .001) compared with those who did not.

Patel noted that care administered within the VA setting has been associated with better outcomes among veterans than care received in non-VA settings. This is largely due to the tailored and veteran-specific care that veterans receive in VA settings.

 Thus, interventions are being developed to ensure that veteran patients can more easily access this care as well as better collaboration with non-VA settings where veterans may seek care.

“Our studies and others have consistently shown that when veterans receive care in non-VA settings for cancer, their outcomes, including survival, are not as [favorable]. Also, [in terms of] end-of-life [care], there are significant hospitalizations and acute care use that occur for veterans [who] may receive care in non-VA settings,” Patel added.

To address the barriers to quality precision care that veteran patients with cancer may face, Patel and other investigators have employed several interventions, with many more in the development and rollout phases. During the 2024 American Society of Clinical Oncology Annual Meeting, investigators presented findings from an interventional study (NCT05795959) that examined the impact of a multilevel intervention led by a community health worker or veteran volunteer.

 During the 1-month program, the community health worker or veteran volunteer provided veteran-tailored education regarding molecular testing in adult patients with newly diagnosed lung cancer and alerted physicians via a secure messaging system if tumor samples were not tested.

All patients included in the study completed baseline and 1-month follow-up assessments via a 3-question validated precision medicine knowledge questionnaire and a 13-question validated patient activation measure. Molecular testing was measured via chart review at 6-month follow-up. The primary objective was patient knowledge of precision medicine; patient activation in their care and receipt of molecular testing were secondary objectives.

At 1 month of follow-up, data from the randomized clinical trial revealed that patients who received the intervention (n = 23) experienced increased mean knowledge scores with a mean score of 2.30 (+/– 0.97) compared with 1.16 (+/– 1.15) among patients in the control group who received usual care alone (n = 23; 

 = .014). Additionally, patient activation scores increased more in the intervention group (46.7 +/– 11.3) compared with the control arm (37.6 +/– 9.26, 

 = .002). Patients in the investigational arm experienced a molecular testing rate of 95.6% vs 86.9% in the control arm; this difference was not deemed statistically significant (

“We had high rates of molecular testing overall across both the intervention and the usual care group. However, veterans had a better understanding of the tests that should have been performed before they started treatment, and they were trained on how to advocate for care that matched their goals,” Patel said. “Patients reported education, satisfaction, and activation changes, and we saw a statistically significant reduction in the time to first course of treatment.”

Telehealth interventions have also been a key factor in improving cancer care for patients, according to Patel. Approximately 38% of Veterans Health Administration patients reside in rural areas, and just 44% of rural counties have an oncologist, prompting the Veterans Health Administration to establish the National TeleOncology Service.

“We have a lot of provider shortage areas across the US that impact all patient populations,” Patel said. “What’s unique for veteran populations is that they can still access the VA through these new initiatives developed through the National TeleOncology Program.”

To better determine how social determinants of health affect the use of telehealth services, the National Cancer Institute–funded center Telehealth Research and Innovation for Veterans with Cancer (THRIVE) was established in 2023. THRIVE consists of 4 core areas that act synergistically to research telehealth equity: the Administrative Core, Research and Methods Core, Clinical Practice Network, and Pragmatic Trial. As of October 2023, THRIVE reviewed 20 pilot studies and funded 3 studies to address telehealth access for patients in rural communities and veterans experiencing homelessness, as well as the effects of automated texting protocols on cancer screening adherence.

Another strategy to reduce the burden of travel for patients with cancer while ensuring they have the option to receive care from the VA is the Close to Me Novel Infusion Care Delivery service, launched in 2022 by the VA’s National Oncology Program. The service offers anticancer therapy at community-based outpatient clinics, mobile infusion units, and patients’ homes. The program was initiated at community-based outpatient clinics in the Pittsburgh, Pennsylvania area, with 12 VA facilities nationwide being selected to implement 8 community-based outpatient clinic care models, 3 home care models, and 1 mobile infusion site in early 2023.

In July 2024, the VA announced that the program had expanded to 22 new sites. A planned expansion will provide services for an additional 9000 patients with cancer across 30 locations by the end of October 2025.

Approximately 500 patients with cancer have been treated across the community-based outpatient clinic locations, reducing their travel by a total of over 200,000 miles. Notably, the treatment adherence rate for patients treated via the Close to Me Novel Infusion Care Delivery service is 99%.

“This is better overall for veterans who may not want or have the ability to travel long distances for care,” Patel said. “This helps to keep care within VA settings while also improving their experiences.”

Lopez C, Murillo A, Das M, Patel MI. Understanding barriers and facilitators to high-quality cancer care among veterans with lung cancer: a qualitative study. 

 2023;19(12):1153-1159. doi:10.1200/OP.23.00228

Berchuck JE, Meyer CS, Zhang N, et al. Association of mental health treatment with outcomes for US veterans diagnosed with non-small cell lung cancer. 

. 2020;6(7):1055-1062. doi:10.1001/jamaoncol.2020.1466

Thomas M, Gonzalez H, Agrawal M, Das M, Patel MI. Ensuring precision medicine for veterans with lung cancer: a randomized clinical trial. 

. 2024;42(suppl 16):1501. doi:10.1200/JCO.2024.42.16_suppl.1501

Zullig LL, Makarov D, Becker D, et al. Telehealth Research and Innovation for Veterans with Cancer: the THRIVE Center. 

. 2024;2024(64):70-75. doi:10.1093/jncimonographs/lgae019

Franchio C. VA launches Close to Me Novel Infusion Care Delivery service. VA News. March 16, 2023. Accessed October 22, 2024. bit.ly/40eblSI

Shields J. Advancing cancer treatment access with 22 new ‘Close to Me’ sites

VA News. July 18, 2024. Accessed October 22, 2024. bit.ly/4eKoiZ3

VA National Oncology Program. Accessed October 22, 2024. bit.ly/3NBmfuh

Manali I. Patel, MD, MPH, MS, details several interventions developed to better serve veterans with cancer who are experiencing economic, social, and geographic barriers to care. 

Education, Telehealth, and Access Initiatives Aim to Improve Cancer Care for Veterans

Over the past 15 years, colorectal cancer (CRC) diagnoses have risen among men and women aged 40 years and older, and even among younger individuals.

 Currently, people born after 1990 are twice as likely to be diagnosed with CRC— and 4 times as likely to develop rectal cancer—as those born in 1950, according to the American Cancer Society (ACS). The ACS estimates about 107,000 new cases of colon cancer and 46,220 new cases of rectal cancer in the US in 2024. It is the third-leading cause of cancer-related deaths in men and fourth-leading cause in women; more than 53,000 deaths from colorectal cancer are expected this year (

Although genetic drivers of CRC are sometimes inherited, more often they develop and accumulate over an individual’s lifetime. One of the prime risk factors for CRC is the consumption of a high-risk, Western-style diet high in processed foods, refined grains, red meat, and sugar, which increases the frequency of CRC nearly 10-fold.

Dietary modifications hold the promise of having a major impact on incidence, morbidity, and mortality of CRC. This has been supported by several studies on human populations, with rapid changes in tumor incidence in migrant populations. The historic data on migrants from Japan to Hawaii developing a higher incidence are particularly informative.

 These data suggest healthier dietary patterns may reduce CRC incidence in the US and other developed countries by more than 80% to 90%.

The gut microbiome, which includes naturally occurring microbes such as bacteria, viruses, and fungi, is a key player in the interplay between cancer and our diets. Although diet mediates the gut microbiome and an enormous diversity of chemical transformations, the microbiome/ diet interactions are a poorly understood component of CRC risk.

Bacteria in the gut have a symbiotic relationship with gut epithelial cells that absorb nutrients from food in the intestines and exchange information, keeping the system balanced and minimizing the probability of a tumor developing. This complex ecosystem is continuously modified by ongoing nutritional exposures, determining which cells dominate in either increasing or decreasing probability of a tumor developing.

The presence of genetic alterations in epithelial cells that will cause these cells to form tumors involves the interaction of the epithelial cells with many other cell types. This includes host immune and supporting cells, as well as the enormous and diverse population of bacteria in the gut that exceed the number of human cells in the body. Thus, the microbiome is a major influence on how many other cell types in the gut function.

The enormous impact of diet on the formation and growth of tumors also provides insight into the complex interplay of cell types and signals that determine probability of tumor development. The Augenlicht and Kelly labs at Montefiore Einstein Comprehensive Cancer Center and Albert Einstein College of Medicine have a strong collaboration that brings together complementary expertise of 8 investigators to provide unique insight into fundamental mechanisms of how the gut maintains its normal functions that are compromised in causing tumors to develop. Together, our labs are investigating how stem cells influence the maintenance of normal intestinal functions and how modulating the composition and biochemical functions of the intestinal microbiome influence normal functions that alter probability of disease (

Our research uses a mouse model system that reflects nutrient levels that humans are exposed to and helps us understand how dietary exposures alter probability of human tumor development. This is a simple idea, but it is rarely incorporated in scientific literature, leading to many observations in mice that may not be directly relevant to humans. The experimental system we use, termed new Western diet 1 (NWD1), is formulated to accurately reflect exposure to macronutrients, such as fat, vitamin D, fiber, and others, that are consumed by humans at higher risk for colon cancer.

Feeding mice NWD1 yields important results. NWD1 causes sporadic tumors in mice, meaning they have no genetic predisposition; such tumors are, by far, the major form of human CRC.

 Additionally, in mice that harbor gene mutations that can cause tumors, feeding NWD1 always causes much earlier appearance of tumors.15-19 This reflects a major clinical problem that has become alarming over the last decade: Development of CRC at a younger age in the US and other industrialized countries coincides with greater consumption of unhealthy Western-style diets that are likely the underlying cause of this shift. The Augenlicht lab has shown that the NWD1 causes numerous alterations in the function of cells in normal-appearing intestinal tissue long before tumors are detected.

As a result of these findings, our research is now focused on understanding how the higher-risk diet alters the function of intestinal stem cells, the cells in the gut tissue that are responsible for producing all the other cells that maintain intestinal functions and that also form tumors when their DNA mutates.

 Surprisingly, we found that alternate stem cells in the intestine are recruited to function in mice fed NWD1, but with the caveat that these cells, and all the daughter cells they produce, are reprogrammed to cause tumors to develop over time. Moreover, these reprogrammed stem cells and the differentiated cells they produce are also involved in many of the fundamental alterations that occur during aging or in patients with inflammatory bowel disease—2 other conditions that have been shown to elevate the risk for CRC.

The Kelly and Augenlicht labs recently discovered that metabolism of xenobiotics—foreign compounds in the gut that are ingested—can be driven by microbial community production of sulfide (H

S), a highly reactive chemical compound that reduces structurally diverse azo compounds, including drugs and other xenobiotics.

 This novel, nonenzymatic mechanism of drug metabolism in the gut overturns the standard enzymatic paradigm for how microbes interact with xenobiotics. It also indicates that gut chemistry, derived from microbial community function, has been a missing component that shapes metabolism in the gut.

S production is a core feature of human gut microbiomes and showed that H

S concentrations in the gut are adjustable by diet in mouse models. As a highly reactive molecule that chemically reduces many molecules that are either produced in the gut or ingested, H

S can be toxic, and diets containing a high level of sulfur, in particular sulfur containing amino acids, have been associated with CRC risk.

S levels in the gut by 2 mechanisms: by providing higher levels of sulfur-containing amino acids and by increasing the number of bacteria capable of producing H

 Further, the human stem cells of the gut sense this increased production of H

S, elevating the activity of a pathway that can eliminate H

S. This is of major interest, since this pathway exists in the mitochondria of the human cells—a subcellular organelle—and disruption of the structure and function of the mitochondria has been identified by the Augenlicht lab as a key to how the NWD1 diet alters the stem cells, causing the recruitment of alternate stem cells that increases risk for tumors to form.

 Recent data from our collaboration have shown that this mediated biochemical alteration may precede the appearance of tumors. Thus, these changes in the microbiome can be a marker to indicate elevated tumor risk and a signal for intervention to reduce risk.

Building on our research findings that highlight the complex biology of the gut, several research goals remain. First, we must understand details of the biochemistry and alterations in gene and cell function that tie the effects of the diet on the intestinal bacteria and the intestinal stem cells that determine the chance of tumor development. A second goal is to identify dietary patterns, or individual nutrient interventions, that can reduce the detrimental impact of bacteria-epithelial cell interaction. A third goal is to harness the detailed understanding of this ecosystem to identify individuals who are at elevated risk for tumor development and to closely monitor those at higher risk for tumors in earlier stages when tumors can be readily removed for cure, and, better yet, perhaps motivate those identified to be at risk to alter their lifestyle so that the tumors never arise.

Leonard Augenlicht, PhD, is a professor of medicine and cell biology; Ziv Cohen, PhD, is part of the Department of Systems and Computational Biology; Sarah Wolfson, PhD, is a staff scientisit in the Department of Systems and Computational Biology; Jiahn Choi, PhD, is an instructor in cell biology; and Libusha Kelly, PhD, is an associate professor of Systems and Computational Biology, all at the Montefiore Einstein Cancer Center. 

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Fodde R, Schmitt M, Schewe M, Augenlicht LH. Modelling western dietary habits in the mouse: easier said than done. 

. 2017;6(2):138-140. doi:10.21037/hbsn.2017.01.20

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Augenlicht LH. Environmental impact on intestinal stem cell functions in mucosal homeostasis and tumorigenesis. 

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Li W, Zimmerman SE, Peregrina K, et al. The nutritional environment determines which and how intestinal stem cells contribute to homeostasis and tumorigenesis. 

. 2019;40(8):937-946. doi:10.1093/carcin/bgz106

Peregrina K, Houston M, Daroqui C, Dhima E, Sellers RS, Augenlicht LH. Vitamin D is a determinant of mouse intestinal Lgr5 stem cell functions. 

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Wang D, Peregrina K, Dhima E, Lin EY, Mariadason JM, Augenlicht LH. Paneth cell marker expression in intestinal villi and colon crypts characterizes dietary induced risk for mouse sporadic intestinal cancer. 

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Colorectal cancer (CRC) incidence has increased, particularly among those born after 1990, with dietary factors playing a significant role. A Western-style diet, high in processed foods and red meat, elevates CRC risk by influencing the gut microbiome and intestinal stem cells. Research using mouse models shows that such diets lead to early tumor development, highlighting the microbiome's role in CRC risk. The microbiome's production of hydrogen sulfide (H2S) is linked to tumorigenesis, suggesting dietary interventions could mitigate CRC risk by altering gut microbiome dynamics.

One of the prime risk factors for CRC is the consumption of a high-risk, Western-style diet high in processed foods, refined grains, red meat, and sugar.

Vol. 25/No. 15 | Oncology Live®

Obe-Cel Approval Expands CAR T-Cell Therapy Options in Relapsed/Refractory ALL

Discussions Swirl on the Role of PD-1 Inhibitors for Gastric/GEJ/ESCC Cancers With 1%-10% PD-L1 Expression

Education, Telehealth, and Access Initiatives Aim to Improve Cancer Care for Veterans

The Microbiome and Colon Cancer: Dietary Influence on Incidence, Morbidity, and Mortality

Adding an HPK1 Inhibitor to Immune Checkpoint Inhibition May Be Effective in Solid Tumors

An Era of Firsts in CML: Asciminib Challenges SOC TKIs

Cancer Clinical Trials: A Relevant Need to Clearly Define the Value to Individual Patients