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Up to 40% of patients with diffuse large B-cell lymphoma (DLBCL) are refractory to or relapse after first-line treatment.

Although CD20 once served as a promising target, patients with DLBCL often developed resistance or did not respond to targeted frontline treatments, which led investigators to uncover other pan–B cell targets in the first- and later- line settings.

 The likelihood of cure decreases with each relapse, and disease refractory to second- or later- treatment lines is associated with a survival of less than 5 years.

 For most patients, high-dose chemotherapy and stem cell transplantation remain the standard of care in the second line. However, treatment options are expanding with CD19-directed chimeric antigen receptor (CAR) T-cell therapies and monoclonal antibodies (mAbs), several of which have been approved by the FDA in the past 5 years.

“We’ve gone from a disease where the curve kept dropping and patients kept relapsing and dying of their cancer to where we’re curing at least a subset,” Jason Westin, MD, said during a recent 

. “It’s very gratifying to see these novel approaches begin to bear fruit, and the idea of adding our amazing new targeted therapies to 1970s chemotherapy. I’m hopeful that we can start having novel-novel combinations in the front line [and] I’m quite intrigued by the potential for moving CAR T cells to even earlier lines.”

Westin was joined by a panel of hematology cancer experts to discuss CD19-directed CAR T-cell therapies, including clinical and real-world data for these agents. The panel also discussed several CD19-directed mAbs that are helping to move treatment in the second line away from chemotherapy, a shift that they hope will eventually reach the frontline setting. “Years ago, [Dr Westin] was proposing chemotherapy-free approaches in frontline therapy of DLBCL,” Grzegorz S. Nowakowski, MD, said. “At that time this was heretical, and all of us had a fast heartbeat just listening to him talk about it. It’s very rewarding to see that the mindset is changing. There’s an ongoing discussion of chemotherapy- free approaches in frontline [management of] large cell lymphoma—how we can select the right population, how we can design those studies, and how we can slowly go away from R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] therapy. That’s exciting to see because, ultimately, replacing this fairly antiquated therapy would be a goal if we can achieve it.”

Three CD19-directed CAR T-cell therapies are approved by the FDA for patients with relapsed or refractory (R/R) DLBCL: axicabtagene ciloleucel (axi-cel; Yescarta), tisagenlecleucel (tisa-cel; Kymriah), and lisocabtagene maraleucel (lisocel; Breyanzi).

 These agents all bind to CD19 via a monoclonal antibody called FMC63 but have some differences in how they are produced (eg, standard retrovirus vs lentivirus), their underlying mechanisms, and their approved indications.

“All 3 were desperately needed by patients to bring forward a therapy with enough capacity for individual cell manufacturing and personalized care across what was estimated to be 10,000 to 15,000 patients with R/R DLBCL annually,” David Miklos, MD, PhD, said (TABLE 1

Axi-cel received FDA approval in April 2022 for adult patients with LBCL who are refractory to first-line chemoimmunotherapy or who experience disease relapse within 12 months of f irst-line chemoimmunotherapy, making it the f irst CAR T-cell therapy to receive a second-line treatment indication.

 It is also approved after at least 2 lines of systemic therapy.

Approval in the second-line setting was based on data from the phase 3 ZUMA-7 trial (NCT03391466), which randomly assigned 359 patients to receive axi-cel (n = 180) or standard care (n = 179).

 After a median follow-up of approximately 25 months, the median event-free survival (EFS) was 8.3 months (95% CI, 4.5-18.3) in the axi-cel group and 2.0 months (95% CI, 1.6-2.8) in the standard-care group, with a 24-month EFS rate of 41% and 16%, respectively (HR, 0.40; 95% CI, 0.31-0.51; P < .001). The percentage of responders was 1.66 times as high in the axi-cel group as in the standard-care group at 83% (95% CI, 77%-88%) vs 50% (95% CI, 43%-58%), respectively (P < .001), with a complete response (CR) observed in 65% vs 32% of patients. An interim analysis estimated the OS rate at 2 years to be 61% in the axi-cel group vs 52% in the standard care group.

Initial approval of axi-cel as a third- or subsequent-line treatment was based on data from the phase 2 ZUMA-1 study (NCT02348216), which showed an objective response rate (ORR) of 72% with a CR rate of 51% (95% CI, 41%-62%).

 Longterm overall survival (OS) and safety data from ZUMA-1, which now has more than 5 years of follow-up, were reported at the 63rd American Society of Hematology Annual Meeting and Exposition (2021 ASH).10 The 5-year OS rate was 42.6% (95% CI, 32.8%-51.9%); among those alive at 5 years, 92% received no additional treatment following axi-cel.

“One thing I’d like to highlight from the long-term follow-up from ZUMA-1 [and other studies] is that we’re seeing what I consider to be a plateau, so I use the word cure when I talk to my patients,” Westin said. “When patients are more than 6 to 12 months out, we don’t have a lot of events that occur at those late time points.” 

Tisa-cel received FDA approval in May 2018 for adult patients with R/R DLBCL previously treated with at least 2 lines of systemic therapy based on data from the phase 2 JULIET trial (NCT02445248).11 In the study, 93 patients received a tisacel infusion.

 The best overall response rate was 52% (95% CI, 41%-62%), with CRs in 40% of patients and partial responses (PRs) in 12% of patients. Twelve months following the initial response, the relapse-free survival rate was an estimated 65% in the total population and 79% among patients with a CR.

Investigators are exploring the efficacy of tisacel in the second-line setting in the ongoing phase 3 BELINDA trial (NCT03570892).13 A total of 322 patients were randomly assigned to tisa-cel with optional bridging therapy (ie, tisa-cel group) or salvage chemotherapy and autologous stem-cell transplantation (ASCT; ie, standard-care group). A response occurred in 46.3% of patients in the tisa-cel group and 42.5% of patients in the standard-care group; however, the trial did not meet its primary end point of EFS, which was 3 months in both groups (HR, 1.07; 95% CI, 0.82-1.40; P = .61).

The panelists noted 2 key challenges that may have led to the suboptimal results seen in the BELINDA trial—a longer product manufacturing time with tisa-cel vs the other CD19-directed CAR T-cell therapies and the use of bridging therapies, which made it difficult to tease out how much was attributable to tisa-cel. “On the BELINDA trial, the median time to infusion was 52 days,” Westin said. “That comes down to that late time point and the need to get 2 different types of platinum chemotherapy in the standard-care arm. Everybody was apheresed, but the products weren’t made until [an individual] had shown response to the first type of platinum chemotherapy, hence the need to give another one, because the long time frame to make the product started after the 6 weeks of chemotherapy.” He noted that 12% of patients in the CAR T-cell arm received 2 different types of bridging therapy. “This is a very complicated trial design,” he said.

Liso-cel received FDA approval in February 2021 for adult patients with R/R DLBCL previously treated with at least 2 lines of systemic therapy based on data from the phase 1 TRANSCENDNHL-001 study (NCT02631044).

 In the study, 269 patients received at least 1 dose of liso-cel.

 Among the 256 who were efficacy evaluable, the ORR was 73% (95% CI, 66.8%-78.0%), with 53% of patients experiencing a CR (95% CI, 46.8%-59.4%) and 20% having a PR (95% CI, 14.9%-24.9%).

The median time to first response was 1 month, which is also the time frame in which most patients achieved their best response. At a median of 3 months, investigators observed that patients with an initial PR achieved a CR (n = 28), and a small proportion of patients who had an initial response of stable disease achieved a CR or PR (n = 7). Of the patients who achieved a response, 60% had remission lasting at least 6 months and 55% had remission lasting at least 12 months. The median OS was 21 months (95% CI, 13.3-not reached [NR]), with 75% of patients alive at 6 months and 58% alive at 12 months.

Two-year follow-up data from TRANSCENDNHL-001 were reported at 2021 ASH.16 At 24 months, the probabilities of continued response, PFS, and OS were 49.5% (95% CI, 41.4%-57.0%), 40.6% (95% CI, 34.0%-47.2%), and 50.5% (95% CI, 44.1%-56.5%), respectively.

In the phase 3 TRANSFORM trial (NCT03575351) investigators evaluated the efficacy of liso-cel in the second-line setting. Individuals were randomly assigned to receive liso-cel or standard of care.

 The median EFS was 10.1 months in the liso-cel arm vs 2.3 months in the standard-care arm (HR, 0.349; P < .0001), and the median PFS was 14.8 months vs 5.7 months, respectively (HR, 0.406; P = .0001). In the lisocel arm, 66% of patients achieved a CR compared with 39% of patients in the standard-care arm (P < .0001). OS data were immature at the time of the analysis, which had a median follow-up of 6.2 months (range, 0.9-20.0), but were trending toward favoring liso-cel (HR, 0.509; 95% CI, 0.2581.004; P = .0257).

Miklos noted that, as shown with axi-cel in the ZUMA-7 trial, results from the TRANSFORM study again showed an improved CR rate in the second vs third line. “That might be due to fresher T cells, more fit immune systems, and less exposure to prior chemotherapy—arguing again that these therapies, which are good in the third line, might be even better in the second line,” he said. “In fact, when we look at the publications, we’re all struck by how if you [received] the ASCT and if you got the CAR T-cell [therapy], there was a remarkable plateau in the patients who received both therapies.” 

Recently, a considerable amount of realworld data for CAR T-cell therapy has emerged. For example, investigators of a small single-center Italian study who treated 18 patients with axi-cel and 12 with tisa-cel reported best ORR and CR rates of 73.3% and 40% among the entire population, respectively, showing the high response rates of these agents maintained outside of a clinical trial.

 When available CAR T-cell treatments have been compared, no significant differences in efficacy or safety have been observed. In a matching-adjusted indirect comparison of tisa-cel and liso-cel, investigators found no differences in OS, PFS, or CR.

“What we’ve seen are remarkably striking similar outcomes from the clinical trials, both in terms of the efficacy—the long-term PFS and OS— as well as the toxicity profile in an increasingly diverse population in terms of their comorbidities and functional status,” Westin said. He emphasized that CD19-directed CAR T-cell therapies appear safe and efficacious even in populations not eligible for pivotal clinical trials. 

Based on these real-world findings, the panelists indicated that some changes to clinical trials might be warranted. “We need to think about eligibility and who we’re including and not including in these trials,” Kami J. Maddocks, MD, said. “But there’s also another important aspect to the real-world data: making sure we’re collecting and reporting [the data] so that we know what’s going on in patients who weren’t eligible or weren’t able to access trials.”

Two of the most recently FDA-approved CD19directed mAbs include tafasitamab (Monjuvi) and loncastuximab tesirine (Zynlonta), both of which are given intravenously (TABLE 2

). An advantage of these treatments is that they do not have production times, making them treatments that community practices can readily adopt. “This therapy is available off the shelf and [can be beneficial] for patients who sometimes are not candidates for escalated therapies,” Nowakowski said. 

In July 2020, tafasitamab received accelerated FDA approval in combination with the oral immunomodulatory compound lenalidomide (Revlimid) for adult patients with R/R DLBCL not otherwise specified, including DLBCL arising from low grade lymphoma, and who are not eligible for autologous stem cell transplant.

 “[Tafasitamab is] engineered to increase direct cytotoxicity of the antibody and activation of effector cells,” Nowakowski explained. “The antibody by itself showed an approximate 25% to 30% response rate in patients with R/R DLBCL [but] what really made a difference is this additional antibody with lenalidomide.”

Approval of the combination was based on data from the phase 2, open-label L-MIND study (NCT02399085), in which 80 patients received tafasitamab 12 mg/kg intravenously with lenalidomide (25 mg orally on days 1 to 21 of each 28-day cycle) for a maximum of 12 cycles, followed by tafasitamab as monotherapy.

 After a median follow-up of 13.2 months, 48 patients had a response for an ORR of 60% (95%, CI 48%-71%); 34 responders had a CR, and 14 had a PR. The median duration of response was 21.7 months (95% CI, 21.7-NR). Responses lasted at least 12 months in 72% of patients, with the median duration of response not reached in those who had a CR. 

In September 2021, long-term outcomes with at least 35 months of follow-up from L-MIND were published,

 which confirmed the long duration of response, meaningful OS, and well-defined safety profile of tafasitamab plus lenalidomide followed by tafasitamab monotherapy in patients with R/R DLBCL ineligible for ASCT. The ORR was 57.5%, with 40.0% being CRs and 17.5% being PRs. The median duration of response was 43.9 months (95% CI, 26.1-NR), the median OS was 33.5 months (95% CI, 18.3-NR), and the median PFS was 11.6 months (95% CI, 6.3-45.7).

More recently, at 2021 ASH data were presented from RE-MIND2 (NCT04697160), a retrospective cohort study comparing outcomes from L-MIND with matched patients who were treated with National Comprehensive Cancer Network/ European Society for Medical Oncologyrecommended therapies.

 Tafasitamab plus lenalidomide improved survival outcomes vs polatuzumab vedotin-piiq (Polivy) plus bendamustine/rituximab (Rituxan) and rituximab plus lenalidomide in closely matched patient populations.

"The results were comparable to what we have seen with CAR T-cell [therapies],” Nowakowski said. “The number of patients in the CAR T-cell comparison is limited. We’d like to see more data and more mature data. But this prototype targeting CD19 in the right patients is important. You can do it in many different ways, and antibody IMiD [immunomodulatory imide drug] combinations could be one of those ways."

Loncastuximab tesirine-lpyl (Zynlonta) is a CD19-directed antibody and alkylating agent conjugate. It received accelerated FDA approval in April 2021 for adult patients with R/R DBCL after at least 2 lines of systemic therapy.

 Approval was based on data from the phase 2, open-label, single-arm LOTIS-2 trial (NCT03589469). In the study, 145 patients received at least 1 dose of loncastuximab tesirine. The study included patients at high risk for a poor prognosis, such as those with double- or triple-hit, transformed, or primary refractory DLBCL.

 The ORR was 48.3% (95% CI, 39.9-56.7) with CRs and PRs each occurring in approximately 24% of patients.

“What I found particularly exciting about this study is that it included a fair share of patients who were post–CAR T-cell therapy, and in the signal of activity in those patients, although that number was limited, it showed that the response rate was maintained, which is very encouraging,” Nowakowski said, adding that a benefit of mAbs is that they can be combined with other therapies to improve their efficacy. “There’s this whole revolution of different concepts and ways that we can now sequence or combine those therapies to improve outcomes of patients with R/R DLBCL,” Nowakowski said. 

Morrison VA, Shou Y, Bell JA, et al. Evaluation of treatment patterns and survival among patients with diffuse large B-cell lymphoma in the USA. Future Oncol. 2019;15(9):1021-1034. doi:10.2217/fon-2018-0788 

Abramson JS. Anti-CD19 CAR T-cell therapy for B-cell non-Hodgkin lymphoma. Transfus Med Rev. 2020;34(1):29-33. doi:10.1016/j. tmrv.2019.08.003

Yescarta. Prescribing information. Kite Pharma; 2022. Accessed April 18, 2022. bit.ly/3KWfSyG 

Kymriah. Prescribing information. Novartis; 2020. Accessed April 18, 2022. bit.ly/3D4fkmN

Breyanzi. Prescribing information. Juno Therapeutics; 2021. Accessed April 18, 2022. bit.ly/382N3SU 

Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020;396(10254):839-852. doi:10.1016/S0140-6736(20)31366-0 

FDA approves axicabtagene ciloleucel for second-line treatment of large B-cell lymphoma. FDA. April 1, 2022. Accessed April 12, 2022. bit.ly/3ObiTxq

FDA approves axicabtagene ciloleucel for large B-cell lymphoma. FDA. Updated October 25, 2017. Accessed April 12, 2022. bit.ly/3xxCiTn 

Locke FL, Miklos DB, Jacobson CA, et al; All ZUMA-7 Investigators and Contributing Kite Members. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386(7):640654. doi:10.1056/NEJMoa2116133 10. 

Jacobson C, Locke FL, Ghobadi A, et al. Long-term (≥4 year and ≥5 year) overall survival (OS) by 12- and 24-month event-free survival (EFS): an updated analysis of ZUMA-1, the pivotal study of axicabtagene ciloleucel (axi-cel) in patients (pts) with refractory large B-cell lymphoma (LBCL). Blood. 2021;138(suppl 1):1764. doi:10.1182/ blood-2021-148078

FDA approves tisagenlecleucel for adults with relapsed or refractory large B-cell lymphoma. FDA. Updated May 3, 2018. Accessed April 12, 2022. bit.ly/3uD3RIW 12. 

Schuster SJ, Bishop MR, Tam CS, et al; JULIET Investigators. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380(1):45-56. doi:10.1056/NEJMoa1804980

Tisagenlecleucel in adult patients with aggressive B-cell non-Hodgkin lymphoma (BELINDA). ClinicalTrials.gov. Updated March 7, 2022. Accessed April 12, 2022. https://clinicaltrials.gov/ct2/show/ NCT03570892 

Bishop MR, Dickinson M, Purtill D, et al. Second-line tisagenlecleucel or standard care in aggressive B-cell lymphoma. N Engl J Med. 2022;386(7):629-639. doi:10.1056/NEJMoa2116596 

FDA approves lisocabtagene maraleucel for relapsed or refractory large B-cell lymphoma. FDA. February 5, 2021. Accessed April 12, 2022. bit.ly/3rrR1eq 

Abramson JS, Palomba ML, Gordon LI, et al. Two-year follow-up of TRANSCEND NHL 001, a multicenter phase 1 study of lisocabtagene maraleucel (liso-cel) in relapsed or refractory (R/R) large B-cell lymphomas (LBCL). Blood. 2021;138(suppl 1):2840. doi:10.1182/ blood-2021-148948

Kamdar M, Solomon SR, Arnason JE, et al. Lisocabtagene maraleucel (liso-cel), a CD19-directed chimeric antigen receptor (CAR) T cell therapy, versus standard of care (SOC) with salvage chemotherapy (CT) followed by autologous stem cell transplantation (ASCT) as second-line (2L) treatment in patients (pts) with relapsed or refractory (R/R) large B-cell lymphoma (LBCL): results from the randomized phase 3 Transform study. Blood. 2021;138(suppl 1):91. doi:10.1182/ blood-2021-147913 

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Schuster SJ, Zhang J, Yang H, et al. Comparative efficacy of tisagenlecleucel (tisa-cel) and lisocabtagene maraleucel (liso-cel) in patients with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). J Clin Oncol. 2021;39(suppl 15):7535. doi:10.1200/JCO.2021.39.15_suppl.7535

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Zynlonta. Prescribing information. ADC Therapeutics; 2021. Accessed April 18, 2022. bit.ly/3JQxpqP 

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Articles

Oncology Live®

Up to 40% of patients with diffuse large B-cell lymphoma are refractory to or relapse after first-line treatment.

New Treatment Options Are  in Play for Relapsed/ Refractory DLBCL 

Following in the footsteps of the cytokine interleukin (IL)-2, IL-15 affords investigators similar qualities as a target without the associated toxicities of its immunotherapeutic predecessor.

Because IL-15 represents a potential potent immune modulator, leveraging its ability to activate effector T and natural killer (NK) cells may rely on the development of immune cytokines with additional antibodies to enhance antibody-dependent cellular cytotoxicity.

IL-15 and IL-2 activate downstream JAK/ STAT signaling pathways through shared β and γ receptor subunits; however, distinctions between IL-2 and IL-15 become more evident in adaptive immune response and their role in the immunomodulation of T and NK cells in the tumor microenvironment (FIGURE).

 IL-15 has demonstrated similar receptor binding, biologic activity, and signaling as IL-2, but without the adverse effect (AE) profile, including the induction of severe capillary leak syndrome.

One of the shortcomings with IL-15, however, is the short half-life because of its small molecular size. Investigators sought to optimize IL-15 with the development of fusion proteins with IL-15Rα bound by flexible linkers that enhance the affinity for IL-15βγ.1,2 This circumvents the need for dendritic cells expressing the subunit receptors for IL-15 to be in proximity for maximum efficacy.

Investigational superagonists have demonstrated preclinical effects in murine models including increased half-life from 7 to 20 hours, increased IL-15 potency, and serum stability, with detectability in patient serum up to 7 days after subcutaneous injection. Further, restricted tumor growth and improved median overall survival were also observed in breast and colon cancer tumors, with improved efficacy observed when combined with anti-CTLA or anti–PD-L1 therapies. In terms of hematologic models, when IL-15 was combined with anti-CD20 antibodies, NK cell responses were improved in murine B cell lymphomas.

Investigators have observed preclinical efficacy of IL-15–directed therapies in combination with other targeted therapies has paved the way for investigators to evaluate IL-15 superagonists in phase 1 and phase 2 trials.

N-803 (Anktiva) is a first-in-class IL-15 superagonist consisting of 3 key structural components: the cytokine (IL-15N72D), the cytokine fusion (IL-15Rα), and the antibody (IgG1 Fc). Specifically, the cytokine and antibody work in tandem to proliferate endogenous NK cells/CD8-positive T cells without inducing T-regulatory stimulation in the tumor microenvironment. Additionally, the IgG1 Fc has demonstrated the ability increase the agent’s half-life and increase honing to the CD16 receptors expressed on NK cells and macrophages.

Preliminary data from the phase 2 QUILT 3.055 trial (NCT03228667) demonstrated the tolerability of the IL-15 superagonist across multiple cohorts of patients who received N-803 in combination immune checkpoint inhibitors (ICIs) after prior treatment with ICIs.3 Specifically, among the 140 patients who received therapy, serious treatment-related AEs (TRAEs) were observed in 8% of patients, including respiratory failure in 1 patient that was grade 5 and attributed to N-803 and the ICI.

Investigators also reported that compared with standard chemotherapy-containing regimens, the investigative approach had lower rates of AEs. In terms of efficacy, 49% of individuals on the trial had stable disease (SD), with 36% having SD more than 2 months and 16% having SD more than 6 months. Overall, 13 patients had a partial response to therapy.

N-803 received a breakthrough therapy designation from the FDA in December 2019 for the treatment of patients with BCG-unresponsive non–muscle invasive bladder cancer following promising results from a phase 1/2 study (NCT02138734) of the agent in combination with BCG.

Data from the ongoing phase 2/3 QUILT-3.032 trial (NCT03022825) of the combination have met the primary end point. In updated data from cohort A of the trial presented at the 2021 American Urological Association Annual Meeting, the complete response (CR) rate was 72% (95% CI, 61%-81%) among the 81 patients enrolled.

 Additionally, investigators reported that patients who had a response had a 58.6% (95% CI, 43.1%-71.2%) probability of maintaining a CR for at least 12 months. At a median follow-up of 20.4 months, the median duration of CR was 19.9 months (95% CI, 7.8–not reached). As of data cutoff of May 19, 2021, 30% of patients had a durable response at 18 months.

Investigators aimed to curb the incidence of patients progressing to radical cystectomy. In the trial, 85% of patients were able to avoid cystectomy following administration of 50 mg of BCG plus 400 mg of intravesical N-803 weekly for 6 weeks. Of note, the patient population was heavily pretreated, with patients having received a median of 12 prior BCG instillations and a median of 5 prior transurethral resections of bladder tumors, as well as 42% of patients having received prior treatment with chemotherapy in addition to BCG.

In terms of safety, the combination was well tolerated, with no grade 4/5 AEs. Two patients experienced grade 3 TRAEs (urinary tract infection and arthralgia). The most frequent grade 1/2 AEs were dysuria (22%), hematuria (16%), and pollakiuria (19%).

Combinations Fuel Progress in Pancreatic Cancer

Pancreatic cancer is notoriously difficul to treat. Investigators in the phase 2 QUILT-88 trial (NCT04390399) are hoping to elicit the activation of a patient’s entire immune system with a unique combination of low-dose chemoradiation, cytokine-induced NK-cell and T-cell activation, and PD-L1–targeted high-affinity NK cell (t-haNK) infusion. The QUILT-88 trial leverages N-803 in combination with standard-of-care chemotherapy, aldoxorubicin hydrochloride (a type II DNA topoisomerase inhibitor), stereotactic body radiation therapy, and an off-the-shelf PD-L1 t-haNK.

The study protocol was designed to evaluate the treatment across 3 cohorts stratified by line of the therapy (first, second, and third or later), with a primary end point of progression-free survival. Data from the cohort of 61 patients who received therapy in the third or later line were presented at the 2022 American Society of Clinical Oncology Gastrointestinal Cancers Symposium.

The median overall survival (OS) in the overall cohort was 5.8 months (95% CI, 3.9-6.9). For those who received treatment with the investigational combination in the third line, the median OS was 6.8 months (95% CI, 5.0-9.8), which investigators noted more than doubled the median OS vs historical standards after second-line therapies. TRAEs were uncommon and occurred in 8% of patients, with no treatment-related deaths reported. Additionally, investigators noted that all treatments were administered in an outpatient setting.

Forward-Looking Prospects Include Lung and Breast Cancers

In patients with stage IIIB or IV non–small cell lung cancer (NSCLC), investigators hope to build on early synergistic effects of N-803 plus PD-1 inhibitors.

 Investigators of the phase 3 QUILT 2.023 trial (NCT03520686) will assess N-803 in combination with anti–PD-1 standard-of-care regimens pembrolizumab (Keytruda) with or without chemotherapy vs standard of care alone.

Additionally, in October 2021, the combination of N-803 and pembrolizumab was selected for investigation as part of the Lung Cancer Master Protocol, or Lung-MAP.9 The precision medicine trial is a collaboration between the National Cancer Institute, Southwestern Oncology Group Cancer Research, Friends of Cancer Research, the Foundation for the National Institutes of Health, and private companies. Investigators of the phase 2/3 trial (NCT05096663) will evaluate the safety and efficacy of the investigative combination vs investigator’s choice of docetaxel, gemcitabine, or pemetrexed in combination with ramucirumab (Cyramza). The trial is expected to enroll approximately 478 patients with advanced NSCLC.

Investigators also seek to capitalize on retreatment efficacy of N-803 by including it as a component of a chemoimmunotherapy backbone in the ongoing QUILT 3.058 trial (NCT04927884) in combination with sacituzumab govitecan-hziy (Trodelvy) for patients with triple-negative breast cancer who have had at least 2 prior therapies. N-803 will administered subcutaneously at 15 μg/kg with cyclophosphamide (25 mg) and PD-L1 t-haNK (approximately 2 × 109).

Knudsin KM, Hodge JW, Schlom J, Gameiro SR. Rationale for IL-15 superagonists in cancer immunotherapy. Expert Opin Biol Ther. 2020;20(7):705-709. doi:10.1080/14712598.2020. 1738379

Yang Y, Lundqvist A. Immunomodulatory effects of IL-1 and IL-15; implications for cancer immunotherapy. Cancers (Basel). 2020;12(12):3586. doi:10.3390/cancers12123586 

Wrangle JM, Awad MM, Badin FB, et al. Preliminary data from QUILT 3.055: a phase 2 multicohort study of N803 (IL-15 superagonist) in combination with checkpoint inhibitors (CPI). J Clin Oncol. 2021;39(suppl 15):2596. doi:10.1200/JCO.2021.39.15_ suppl.2596

ImmunityBio granted FDA breakthrough therapy designation for N-803 IL-15 superagonist in non-muscle invasive bladder cancer. News release. ImmunityBio. December 4, 2019. Accessed April 21, 2022. bit.ly/38XruU4

Chamie K, Chang S, Gonzalgo M, et al. Phase 2/3 clinical results of IL-15RAFC superagonist N-803 with BCG in BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) carcinoma in-situ (CIS) patients. J Urol. 2021;206(suppl 3):e120-e121. doi:10.1097/JU.0000000000001977.05

Seery TE, Nangia CS, McKean HA, et al. Promising survival and disease control in third-line or greater metastatic or locally advanced pancreatic cancer patients following chemo-radiation and novel combination of aldoxorubicin, N-803 IL-15 superagonist, and PDL1- NK cell therapy. J Clin Oncol. 2022;40(suppl 4):582. doi:10.1200/JCO.2022.40.4_suppl.582

Wrangle JM, Velcheti V, Patel MR, et al. ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with metastatic non-small cell lung cancer: a non-randomised, open-label, phase 1b trial. Lancet Oncol. 2018;19(5):694-704. doi:10.1016/ S1470-2045(18)30148-7

QUILT 2.023: a study of N-803 in combination with current standard of care vs standard of care as first-line treatment for patients with stage 3 or 4 NSCLC. ClinicalTrials.gov. Updated April 4, 2022. Accessed April 21, 2022. https://clinicaltrials.gov/ct2/ show/NCT03520686

National Cancer Institute selects ImmunityBio’s N-803 IL-15 receptor agonist to combine with Keytruda in 700-site Lung-MAP clinical trial of a chemo-free therapy. News release. ImmunityBio. October 4, 2021. Accessed April 21, 2022. bit.ly/36z5Swq

Testing the use of combination immunotherapy treatment (N-803 [ALT-803] plus pembrolizumab) against the usual treatment for advanced non-small cell lung cancer (a Lung-MAP treatment trial). ClinicalTrials.gov. Updated October 27, 2021. Accessed April 21, 2022. https://clinicaltrials.gov/ct2/show/ NCT05096663

FDA authorizes ImmunityBio study of Anktiva and PD-L1 t-haNK to increase effectiveness of Trodelvy in triple-negative breast cancer. News release. ImmunityBio. June 15, 2021. Accessed April 21, 2022. bwnews.pr/3v5IekS

Following in the footsteps of the cytokine interleukin-2, IL-15 affords investigators similar qualities as a target without the associated toxicities of its immunotherapeutic predecessor.

Superagonists Pull IL-15 Into Focus  in Oncology Care

Complex in their development, diagnosis, and treatment, neuroendocrine tumors (NETs) present a challenge to clinicians who may only see a few cases during their career. NETs are slow growing with a symptom burden that may be attributable to other disease states. Delayed diagnoses result in patients presenting with late-stage disease.

“NETs are what I call an unusual disease,” Eric Liu, MD, FACS, said in an interview with 

. “NETs used to be considered quite rare [and] it’s one of those diseases where we do not receive that much education on it in medical school or in our training process. So, it’s kind of an unusual, unknown disease, but it affects a lot of [individuals].” Liu is surgical director of the Neuroendocrine Institute at Rocky Mountain Cancer Centers in Denver, Colorado.

As a community oncologist with a specialty in NETs, Liu highlighted the most important aspect of the disease: awareness. “The neuroendocrine system is [one] that no one ever talks about. We talk about the respiratory tract and the digestive tract and the central nervous system and even the endocrine system. But the neuroendocrine system is more like what we call the diffuse endocrine system that controls a lot of things in the background. There are tiny little cells scattered all throughout the body—in the lungs, through the digestive tract— called neuroendocrine cells, and they can turn into cancers,” he said.

In a discussion of the disease state, Liu reviewed treatment options chronic [disease]; some of my colleagues call it “cancer in slow motion.” (

), pitfalls of diagnoses, and the importance of involving specialists and advocates early. “NETs are a disease for which, luckily, we have many clinicians who are experts in and really specialize in them,” he said. “Unfortunately, it is not a well-known disease that [all practitioners] can take care of. I always encourage [colleagues], if they see this unusual diagnosis, to seek expert opinions.”

Please discuss the diagnostic approach for these tumors. What are the common traits that patients present with in the clinic? 

The diagnosis of neuroendocrine cancer is very complicated, and the reason is because the symptoms can be extremely mild. Neuroendocrine cancers tend to be more of a chronic [disease]; some of my colleagues call it “cancer in slow motion.”

Because it can linger for a long time, the diagnosis can be tough to make [and] in lots of cases [individuals] have mild symptoms [including] abdominal pain, a little flushing here and there, maybe some diarrhea, and [they] come and go in some cases. For example, a patient will present with abdominal pain in the emergency department and an x-ray will look normal, and [a clinician] won’t see [any sign of NETs]. This pain will come again [and] eventually, the patient may get a CT scan, and [receive a] diagnosis of NETs. [Other times], there are no symptoms at all, and the patient can present all out of the blue with sudden abdominal pain or NETs can even be found incidentally on a CT scan for another reason, or possibly even [during] an endoscopy or a colonoscopy.

It is a tough diagnosis to make. [Let’s take an example of] a 50-year-old woman who presents with flushing, a very common symptom for NETs. If that is the situation, a gynecologist may present a diagnosis of menopause. [What if a] patient has persistent diarrhea? A gastroenterologist may prescribe a colonoscopy and results may not show anything but the symptom persists. The gastroenterologist may give a diagnosis of irritable bowel syndrome. You can see how these mild symptoms can very easily be misinterpreted, and the diagnosis of NETs is not made for a long time.

Unfortunately, the treatments for irritable bowel syndrome and menopause do not treat cancer and so as the symptoms persist, the disease persists. Thankfully, it’s a slow growing disease in general and individuals can live with it for a long time. It is a very challenging diagnostic dilemma. But once the diagnosis is made, thankfully there is a lot we can do to help patients.

Luckily, we do have good diagnostic techniques to [confirm NETs]. The easiest one is a CT scan, [which is] quick, standard, lots of [individuals] can get it, it’s not very expensive, and it provides a survey of the lungs, stomach, and pelvis. That is frequently how we make the diagnosis of NETs by seeing a mass either in the intestines, the pancreas, or the liver.

We also have different blood tests as well; however, they are not quite as good. Unfortunately, [because] NETs are slow growing, and individuals can have them for many years without any symptoms, [they] frequently [are] diagnosed very late, usually stage IV. Stage III [disease] tends to include spread to the local lymph nodes, but stage IV is when it spreads far, for example to the liver, bones, or lungs.

NETs typically start in the lungs, pancreas, or small intestine, which are the 3 most common points of origin [and] even though it has a reputation for being a very slow disease, it is aggressive in the way that it spreads. Neuroendocrine disease is not benign; it is a highly metastatic disease that can be life threatening.

How do you decide whether to pursue looking for NETs? 

We must consider comorbidities and age [at the time of diagnosis], which is usually 60 years, but can be seen in a patient who is age 40 or 50 years. Treatments can be quite varied and include medicines, surgery, special kinds of radiation, and different kinds of therapies for the liver…. [We must] take into consideration the overall general health of the patient.

For example, if the patient has many comorbidities, such as diabetes, or a history of stroke, and they are elderly and very frail, maybe the treatment for the neuroendocrine disease needs to take a back seat to something else, because if a patient is going to die, for example due to a stroke or a heart attack, NETs may not be the most life-threatening aspect of their health. But if a patient is quite healthy, they don’t smoke, and are doing well, my goal is always to keep the patient healthy. And our goal, as it should be for everything, is to heal the patient so that they can live a high quality of life. If I can help improve quality of life, that’s always my No. 1 priority.

What are the typical treatments that you are looking to initiate once a patient has received a diagnosis of NETs? 

Despite neuroendocrine [disease] being a relatively unusual and rare, we have many different types of therapies. And the reason that I encourage patients to see specialists is because choosing the tools in the toolbox can be very challenging. We need to decide what is best for the patient and one tool clinicians forget is surveillance. Then we have other types of medicines, because neuroendocrine [cancer] is a hormonal disease, and one of the unusual things is that NETs may affect blood sugar [and] they may cause pain. And so, getting those hormones under control is very important.

But there’s no question that up front one of the most powerful therapies that we have for neuroendocrine disease is surgery. If we can remove a lot of the bulk of the tumor, we can remove a fair amount of the hormone burden, which is not usually the case for other cancers.

However, a lot of the times the disease goes to the liver, and we can use embolization. Additionally, one of the most exciting therapies we have is called PRRT, or peptide receptor radionuclide therapy, which combines hormonal therapy with radiation that goes straight to the tumor and the radiation treatment [is delivered] from the inside out. It’s very effective in helping to control the disease. It is not a cure, but it can help patients with symptoms and can help slow down the growth of their tumors.

Are there any other unmet messages you would like to convey to the community oncologist regarding NETs? 

I always say, have a buddy. Have a friend who specializes in neuroendocrine disease who you can talk to. I should stress that I am community physician, so I understand what it is to be out there working with patients in their community. I’ve seen 2000 cases of NETs and I’ve learned how vastly complicated the disease really is. What I always tell clinicians is, don’t be shy, order all the tests, gather all the information up front so you can have all the correct data and can make the best decision.

One of the problems I see frequently as a specialist who receives referrals is that sometimes the patient did not have a complete workup. [In some cases] the clinicians jumped to [one type of] surgery, when in fact maybe you could have done a little better surgery if you had more information. Or in other cases, the wrong therapy was administered because the pathology was misinterpreted. There are lots of different ways that the devil is in the details.

I always encourage my colleagues across the United States [to see this as] a team effort. I am happy that the patient always has their [primary oncologist] at home because they get their treatments, shots, and their scans [locally] and they don’t have to fly to Denver, Colorado to see me every single month; that would be ridiculous. If we can work together, and I can share some of my experience with you, we can come up with the best plan for the patient. That is always the best that we can do.

I don’t know everything about brain cancer, bone cancer, or bladder cancer but I know a lot about neuroendocrine cancer. And so, I am happy to rely on my colleagues who really specialize in those other things.

There is one other thing I do want to share, neuroendocrine disease really isn’t that rare, and there is a lot we can do to help patients. Unfortunately, the information is not readily and easily available, which means that individuals need to advocate for themselves—either the patient needs to advocate, or the physician needs to advocate—get the right tests, seek second opinions, don’t worry about having to travel because you might have to do that.

Luckily, if anything has come from the COVID-19 pandemic, it is that we do a lot more telemedicine now. Reach out and see [whether] some of the experts in the United States would be willing to see you through telemedicine and review your case. A lot of the time, a physician at home can conduct the physical exam and with the advanced scans that we have, I can see right into their bodies. So, most of the time, they just need me to think about the case.

Think about getting a second opinion, think about working with a specialist, make sure you get a comfortable team around you. If they say something is impossible, that might not always be true.

Zhang JY, Kunz PL. Making sense of a complex disease: a practical approach to managing neuroendocrine tumors. 

. 2022;18(4):258-264. doi:10.1200/OP.21.00240 

Lutathera. Prescribing information. Advanced Accelerator Applications USA, Inc; 2020. Accessed April 20, 2022. bit.ly/3EyZxOn 

Afinitor. Prescribing information. Novartis; 2022. Accessed April 20, 2022. bit.ly/3K1NBpd 

Sutent. Prescribing information. Pfizer; 2021. Accessed April 20, 2022. bit.ly/3xP9wgO

Eric Liu, MD, FACS, reviews treatment options, pitfalls of diagnoses, and
the importance of involving specialists and advocates early in neuroendocrine tumors.

Unmasking NETs Requires a Multifaceted Approach to Care

Immunotherapy agents represent a transformational advance in our ability to treat many cancers. Rather than introducing a therapy that kills both healthy and malignant cells, immunotherapy agents harness the body’s natural ability to recognize and control the invasive cells that can form tumors.

Most patients who receive immunotherapies will experience few, if any, treatment-related adverse effects (AEs). But some patients receiving these treatments can experience serious AEs caused by an overactivation of the immune system and its effects on healthy cells. 

It is important for clinicians to identify AEs quickly and assign such toxicities an appropriate grade using the standard Common Terminology Criteria for Adverse Events 5.0 grading system. Based on that grading, treatment should be designed using standard guidelines developed by oncology societies, including the Society for Immunotherapy of Cancer and American Society of Clinical Oncology (ASCO). Most of the toxicities caused by immunotherapy drugs are reversible by using steroid or other immunosuppressive therapies.

It is critical to ensure clinicians recognize and know how to manage these treatment-emergent AEs so patients can seek appropriate medical attention quickly and continue to take advantage of the benefits of immunotherapy.

Several immunotherapy drugs have been approved by the FDA to treat various types of advanced cancers. Approved immunotherapies include CTLA-4 inhibitor ipilimumab (Yervoy); PD-1 inhibitors pembrolizumab (Keytruda), nivolumab (Opdivo), and cemiplimab (Libtayo); and PD-L1 inhibitors atezolizumab (Tecentriq) and avelumab (Bavencio) (TABLE 1

Immunotherapy AEs can be difficult to identify because they can cause symptoms that are associated with common ailments and infections. Some of these adverse reactions might resemble another medical issue but require a very different course of action. For example, pneumonitis, which a small number of patients on checkpoint inhibitor immunotherapy may experience, can cause some of the same symptoms as viral or bacterial respiratory infection but should be treated with steroids instead of antibiotics. The primary immunotherapy-related AEs patients and clinicians should be aware of include flu-like symptoms, asthenia, arthralgias, and rash. Endocrinopathies such as thyroiditis, hypophysitis, adrenal insufficiency, and type I diabetes must be recognized quickly, as these complications may lead to the need for lifelong hormonal replacement therapy.

There have been reports of inflammation of organs, including pneumonitis, pancreatitis, hepatitis, nephritis, colitis, dermatitis (redness, itchiness, or rash), neuritis, uveitis, and myocarditis. Although myocarditis occurs in fewer than 1% of patients receiving immunotherapy, it is likely the most serious adverse reaction that can occur because of these agents.

 Early detection of this potentially fatal AE, which carries a 40% to 50% risk of death, is critical, but there are currently no clear ways to accurately predict or identify this type of immunotherapy-associated toxicity.

I was recently part of a multidisciplinary team at Roswell Park Comprehensive Cancer Center (Roswell Park) that identified troponin, a protein that enters the bloodstream only when the heart is damaged, as an early and reliable predictor of myocarditis in patients with cancer receiving immunotherapy with immune checkpoint inhibitors.

Findings of this retrospective study, which reviewed the records of 1001 patients with cancer who were treated with 1 or more immunotherapy agents at Roswell Park from 2016 to 2020, suggested that weekly troponin monitoring during the first 6 weeks of treatment could help physicians detect this rare but potentially fatal AE of immunotherapy. Any patient showing an elevation in troponin levels or signs of cardiotoxicity, such as angina or arrhythmia, should be referred to a cardio-oncology team for complete evaluation, including electrocardiogram, echocardiogram, or cardiac MRI.

Although immunotherapy-related myocarditis is extremely rare, it occurs with greater frequency and severity when immunotherapy drugs are given in combination, and early recognition is critical. For example, in a multicenter analysis, my colleagues and I identified 2 cases of myocarditis that developed in patients with metastatic melanoma following treatment with a combination of ipilimumab and nivolumab, which are 2 commonly used immune checkpoint inhibitors.

Reduction of immunotherapy-related AEs relies heavily on corticosteroids and other immunomodulatory agents, which should be prescribed to reduce the potential for short-term and long-term complications. It remains unclear whether prophylactic antibiotics should routinely be prescribed to reduce the potential for opportunistic infection in patients receiving steroids. Treatment should be individualized depending on each patient’s medical history, comorbidities, and underlying disease status, as well as the type, number, and severity of AEs.

Because immunotherapy is a relatively new treatment option, many of these agents have AEs that have not been previously observed. AEs stemming from immunotherapy use can affect the skin, lungs, gastrointestinal and endocrine systems, joints, heart, and other organs. Some of these AEs are just beginning to be described, therefore clinicians need guidance on how to recognize early signs, how to treat AEs, and when to refer a patient to a disease specialist.

For this reason, I have been helping to create guidance for medical professionals who care for patients receiving immunotherapy drugs. Along with other experts in this field, I helped write the first consensus guidelines on how to recognize and respond to immunotherapy-related AEs and am contributing to similar resources to be issued by ASCO and the National Comprehensive Cancer Network (TABLE 2

Information is key in identifying and managing any AEs of immunotherapy. It is critical for medical professionals to give patients clear written guidance before a course of immunotherapy is started and to keep that flow of information going back and forth during clinic visits and between appointments.

When my patients on immunotherapy ask me about possible AEs, I stress that immunotherapy is an incredibly important and effective option for treating many cancers and that AEs are rare. I also strongly encourage my patients to become active participants in their treatment by learning about these possible AEs, monitor for these adverse reactions, and respond to any symptoms that develop. Together, we can help to ensure these new and advanced treatments are as effective as possible.

Yervoy. Prescribing information. Bristol Myers Squibb; 2022. Accessed April 7, 2022. bit.ly/38px6Go

Keytruda. Prescribing information. Merck Sharp & Dohme Corp; 2022. Accessed April 7, 2022. bit.ly/3ul9M52

Opdivo. Prescribing information. Bristol Myers Squibb; 2022. Accessed April 7, 2022. bit.ly/3Klihmx

Libtayo. Prescribing information. Regeneron Pharmaceuticals Inc; 2021. Accessed April 7, 2022. bit.ly/3DSfK0D

Tecentriq. Prescribing information. Genentech; 2022. Accessed April 7, 2022. bit.ly/3Kof1GP

Bavencio. Prescribing information. EMD Sereno, Inc; 2019. Accessed April 7, 2022. bit.ly/3raRCBe

Puzanov I, Subramanian P, Yatsynovich YV, et al. Clinical characteristics, time course, treatment and outcomes of patients with immune checkpoint inhibitor-associated myocarditis. 

. 2021;9(6):e002553. doi:10.1136/jitc-2021-002553

Tawbi HA, Forsyth PA, Algazi A, et al. Combined nivolumab and ipilimumab in melanoma metastatic to the brain. 

. 2018;379(8):722-730. doi:10.1056/NEJMoa1805453

Puzanov I, Diab A, Abdallah K, et al; Society for Immunotherapy of Cancer Toxicity Management Working Group. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. 

. 2017;5(1):95. doi:10.1186/s40425-017-0300-z

Igor Puzanov, MD, MSCI, FACP, discusses the adverse effects associated with immunotherapy and how to manage them.

Tackling the Adverse Effects  of Immunotherapy

With improvements in electronic medical records (EMRs), telemedicine, and other digital health solutions, clinicians have access to more data than ever to help inform decisions. New metrics such as patient volume, location, and details of treatment trajectory can help practices improve their care from a clinical standpoint, according to Lalan Wilfong, MD. But how best to leverage the economic influence of these data on clinical practice and patient outcomes remains an area of exploration.

“Practices [must] figure out how to better understand the economics of what they do, especially as the field moves to more total cost of care models and more valuebased care models, where we are more accountable for the cost we give [to the patient] and how we spend the [associated] revenue,” Wilfong said in an interview with 

Wilfong, a medical oncologist and hematologist with Texas Oncology and vice president for payer relations and practice transformation at McKesson Specialty Health, both in Dallas, Texas, said using data to retain patients from time of diagnosis through completion of therapy is a key factor in a practice’s financial stability. Data-driven health economics and outcomes research offers clinicians effective methods for improving quality of life and outcomes for patients and optimizing economic benefits for the practice.

“Quality metrics have influenced the way that we measure and perceive cancer care by focusing us more on what means most to patients, and how do we improve the outcomes that we provide vs just managing patients as we see is best,” Wilfong said. “Things [such as] metrics in the Oncology Care Model for reducing hospitalizations and reducing ED [emergency department] visits makes us think through the entire patient care continuum vs focusing on just what’s happening that day with a patient.”

Health economics research has grown tremendously in community oncology over the past few years. Wilfong attributes that growth to the shift toward value-based care. “We had to show the benefit of the services we provided and really start thinking about the entire patient journey vs just individual data points, like we do in clinical research,” he said. “Health economic outcomes [helps us] understand risk profiling and what is the true value of the therapies we provide, not just monetarily, but also the patient’s quality of life and outcomes.”

The incorporation of machine learning and/or artificial intelligence in standard practice procedures may afford clinicians the chance to evaluate and optimize treatment economics. The SHIELD-RT study (NCT03775265) was among the first randomized prospective studies to implement machine learning as part of an interventional clinical application. The study used an EMR-based algorithm to identify patients at high risk of emergency department (ED) visits or hospitalizations during radiotherapy or chemotherapy.

The machine learning algorithm identified 311 patients with a greater than 10% risk of an acute care visit during radiotherapy at Duke University Hospital in Durham, North Carolina, between January 2019 and June 2019. Patients were randomized to receive a weekly evaluation during treatment (n = 157) or a twice-weekly evaluation during treatment (n = 154).

Overall, a reduction in acute care visits for the total population was observed from 22% to 12%. Patients evaluated twice weekly experienced fewer hospitalizations and ED visits compared with patients in the once-weekly arm: 29 vs 41 and 18 vs 33, respectively. From an economic perspective, the study authors noted that costs were reduced across revenue centers and that machine learning has shown potential to enhance quality of care in addition to keeping costs down. Specifically, the overall mean cost of acute care during radiotherapy was reduced by $2063 (95% CI, 4-4119; 

 = .03) when patients were evaluated twice weekly. The largest mean difference was observed in inpatient costs ($1815; 95% CI, –129 to 3760; 

 Next steps include incorporating physician and intervention costs into the analysis.

Another potentially helpful data point clinicians may consider involves patient-reported outcomes (PROs), which can be added into the EMR and other digital health solutions to better inform treatment decisions. Data obtained at the patient level provides investigators with real-world insight that may help in understanding outcomes not observed in patients enrolled in clinical trials and assessing the unmet needs in preventing and treating adverse effects. Leveraging digital health solutions that can collect these data may improve the following:

Communication between patients, providers, and their communities 

Clinical assessment improvements for patient outcomes 

Self-monitoring education and uptake of self-management practices

In a qualitative review, Aapro et al sought to better understand the effect of PROs in oncology collected via electronic methods on routine supportive care in terms of clinical and health economic end points. In the analysis, investigators reviewed 66 studies that included data from 38 unique digital health systems used to collect PROs via remote monitoring. Of note, 21 of the systems provided patients with self-management symptom support tactics.

Highlighting one of the pillars for improvement—communication—digital solutions that allow for self-reporting of symptoms can lead to a reduction in unexpected cost for the patient, greater use of hospital resources, and improved completion rates of treatment. For example, a single-center study cited in the analysis assessed outcomes of 766 patients who were randomized to receive email alert prompts to report symptoms experienced during their chemotherapy treatment at Memorial Sloan Kettering Cancer Center in New York, New York. Severe symptoms were reported by 63% of patients during the study and in response to email alerts of these symptoms, nurses initiated clinical action.

The authors also cited a decrease in ED and hospital admissions when digital health solutions were used to monitor patient outcomes. Specifically, among those who received the alert (n = 441), 34% were admitted to the ED compared with 41% of patients who received standard care (n = 325; P = .02).

Despite the observed benefits with PROs, the uptake of such solutions in practice present clinicians, patients, and supportive staff with additional hurdles. For example, integration of solutions in established systems takes time and adds an initial cost up front, not to mention that training and potential clinical trials evaluating efficacy may present delays in execution (TABLE).

Data-driven health economics and outcomes research offers clinicians effective methods for improving quality of life and outcomes for patients and optimizing economic benefits for the practice.

Vol. 23/No. 9 | Oncology Live®

New Treatment Options Are in Play for Relapsed/ Refractory DLBCL

Superagonists Pull IL-15 Into Focus in Oncology Care

Unmasking NETs Requires a Multifaceted Approach to Care

Tackling the Adverse Effects of Immunotherapy

Data-Driven Health Economics Research Can Improve Clinical, Economic Outcomes

Genomic Testing Challenges Persist

Nivolumab Plus Chemotherapy Moves Into Neoadjuvant Setting in NSCLC

Second-Line Axi-Cel Offers a “Practice-Changing” Indication for LBCL

We Must Improve Communication With the Public