Budde Considers Multiple Regimens for a Patient With DLBCL

During a Targeted Oncology Case-Based Roundtable event, Elizabeth Lihua Budde, MD, PhD, a hematologist-oncologist, and associate professor in the Division of Lymphoma, Department of Hematology and Hematopoietic Cell Transplantation at City of Hope in Duarte, CA, discussed the case of a 75-year-old patient with diffuse large B-cell lymphoma (DLBCL).

Targeted Oncology^TM: Can you discuss the NCCN (National Comprehensive Cancer Network) guidelines for chimeric antigen receptor (CAR) T-cell therapies in DLBCL?

BUDDE: The NCCN guidelines [give indication] for use of CAR T-cell therapies in patients with DLBCL after 2 or more lines of systemic therapy. All centers that offer the CAR T-cell therapies must be enrolled and comply with the Risk Evaluation and Mitigation Strategy requirements because of the cytokine release syndromes and neurologic toxicities. The center would be able to manage the toxicities.¹

One-quarter to one-third of these patients can have prolonged cytopenia. This means that 4 to 6 weeks after the CAR T-cell infusions, some of these patients will still be quite cytopenic [4 to 6 weeks after the CAR T-cell infusions], and that cannot just be attributed to the chemotherapy that was used as part of the lymphodepletion regimen. B-cell aplasia and hypogammaglobulinemia can be common [because of the targeting of CD19]. These patients need to have their IgG monitored periodically and have intravenous immunoglobulin replacement.¹

Can you discuss the choice of loncastuximab tesirine-lpyl (Zynlonta)?

Loncastuximab tesirine-lypl [Lonca-T] obtained an FDA approval on April 23, 2021.2 This approval is for adult patients with at least 2 prior lines of therapy for relapsed or refractory [R/R] DLBCL. It’s an antibody-drug conjugate [ADC], first in its class of PBD [pyrrolobenzodiazepine]-based ADCs. PBD is the payload. Essentially, when it gets infused in the patient, it will bind to the target CD19 on the surface of the lymphoma cells, which then will undergo internalization; then the payload, the PBD, will be released. The PBD is a cytotoxic DNA minor groove interstrand cross-linking agent; it’s an alkylator. Compared with other payloads, PBD has an improved preclinical therapeutic index.3

What are the data behind using Lonca-T in this population?

Approval of Lonca-T was based on the single-arm phase 2 LOTIS-2 study [NCT03589469] for adult patients with R/R DLBCL. The study patients had at least 2 prior lines of therapy, and if they had a prior CD19 therapy, they needed to have a biopsy to prove the tumor still expressed CD19. ECOG performance status was 0 to 2. This study allowed patients with prior allogeneic or autologous stem cell transplant [SCT]. The drug was given in a 30-minute infusion every 3 weeks. The first 2 cycles were the loading doses at 150 μg/kg. It was given every 3 weeks for 6 weeks; then the dose was cut back to half, so 75 μg/kg. This is after cycle 2 until 1 year. After 1 year, if the patient was still in remission, or at least had stable disease, they could get maintenance for up to 3 years. Maintenance was given as 1 dose every 12 weeks.^4,5

The primary end point for this study is overall response rate [ORR], and there are quite a few secondary end points: duration of response [DOR], event-free survival, progression-free survival [PFS], overall survival [OS], and, of course, complete response [CR]. The primary antitumor activity and safety data analysis was done for any patient who received at least 1 dose of Lonca-T infusion. This analysis was done when all responders had at least a 6-month follow-up, after initial documented response.^4,5

The baseline characteristics of the patients treated in the study [showed] the median age was 66 years, with a range of 56 to 71. Most patients had DLBCL, but the study also included patients with high-grade B-cell lymphoma, double-hit or triple-hit [double/triple] lymphomas, and primary mediastinal B-cell lymphoma. Fourteen percent of patients had a double/triple expressor, and the median prior lines of therapy was 3, ranging from 2 to 4. Over half the patients had refractory disease to their last line of therapy, and a few patients had prior SCT.^4,5

How did patients respond in the LOTIS-2 study?

The efficacy is based on the ORR. There were 145 patients enrolled in the study. The ORR was 48.3% [95% CI, 39.9%- 56.7%] and the CR rate was 25% [95% CI, 17.4%-31.9%]. The time to response was pretty fast; most responded after 2 cycles. Again, it was given 1 dose every 3 weeks. The median time to a first response was only 41 days, so that’s between cycle 1 and cycle 2. The mean number of cycles of Lonca-T given was 4.6, and the median was 3.^5,6

Let’s breakdown the efficacy data by subgroups. A pretty encouraging ORR was seen in high-risk subgroups, including patients with the double/triple hit lymphomas. Now in comparing with and without double/triple hit, you see the ORR without double/triple hit is 50%, and with double/triple hit, it’s about 33%. One-third of those patients responded to the treatment. Whether the patient had transformed or de novo DLBCL didn’t seem to make a huge difference. Whether the patient had prior SCT—I wouldn’t say the difference is significant, but it’s interesting. In patients with prior SCT, 14 of 24 patients responded, so it was an ORR of 58%. In patients who did not have a prior SCT, 56 of 121, that’s 46%. We can see responders across different high-risk subgroups. The median [m]DOR is 13.4 months, so the response is longer than a year.^5-7

The mPFS for all comers was around 5 months, and mOS was around 9.5 months. It’s interesting to look at the data on subsequent treatment, after the patients received Lonca-T. Fifteen patients went on to receive CD19 CAR T-cell therapies with an ORR of around 46.7%. Six patients had CR; 1 patient had partial response [PR]. Nine patients, when they achieved a response to Lonca-T, moved on to SCT as consolidation.

Can you describe the safety of Lonca-T in this study? What are the common adverse events (AEs)?

Given the nature of the payload, the PBD, there was peripheral edema. It was seen in patients both younger and older than 65, with a similar incidence. For all comers, the most common grade 3 and above treatment-emergent AEs [TEAEs] were neutropenia, thrombocytopenia, increased γ-glutamyltransferase [GGT], and anemia. Around 17.9% of patients discontinued their treatment because of TEAEs. Most of them discontinued treatment because of GGT elevation; that’s only 16 patients, so 11%. Four patients, which is 2.8%, discontinued treatment because of peripheral edema, and 3 patients [2.1%] discontinued treatment because of localized edema.^5,7

There was no increased toxicity seen in patients who were older than 65, in comparison with patients who were younger than 65. All patients received oral dexamethasone as premedication, and they were also counseled on sun exposure. Treatment delays of up to 5 weeks and dose reductions were allowed to manage toxicities. Patients who had weight gain due to fluid retention over 1 kg, from day 1 of cycle 1, or who had edema or pleural effusions, received standard doses of spironolactone [Aldactone].

Some practical information regarding Lonca-T: It’s a pretty short, 30-minute intravenous infusion, [administered on] day 1 each cycle; so, it’s 1 dose every 3 weeks. The first 2 cycles are the loading doses, and subsequent cycles use half of that dose. All patients are recommended to have premedication with dexamethasone for 3 days, starting the day before Lonca-T use. If dexamethasone was not started prior to the day of Lonca-T, it’s recommended to be given at least 2 hours prior to Lonca-T infusion. [In the prescribing information, there is] a table available that tells you how to do dose delays and dose modifications, and this was tested in the clinical trial.⁸

There’s currently a confirmatory, phase 3, randomized, 2-part, open-label trial [NCT04384484] comparing Lonca-T plus rituximab—a CD19 and CD20 chemotherapy-free regimen—vs R-GemOx [rituximab plus gemcitabine/ oxaliplatin], which we usually use in the R/R setting for DLBCL. This is for patients who are not suitable for transplant after at least 1 prior line of therapy.⁹

What are other treatment options for patients with DLBCL?

Another novel combination, which received FDA approval in July 2020, is tafasitamab [Monjuvi] in combination with lenalidomide [Revlimid]. Again, this is for patients who are not eligible for autologous SCT. Approval was based on a pivotal trial, the L-MIND study [NCT02399085].²

Tafasitamab is an Fc-enhanced anti-CD19 monoclonal antibody; so, compared with the wild-type Fc structures, it has increased antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis activities, and it also has direct cell-killing activity. As a single agent, there’s some activity in patients with B-cell non-Hodgkin lymphoma; some of the patients have a pretty long duration of remission.¹⁰

Lenalidomide, which I think most physicians have used in practice, is a neuromodulator. It can enhance T and natural killer cell activation and expansion, and it has demonstrated activity both as a single agent and in combination with other agents. It is currently approved for treatment of mantle cell lymphoma, follicular lymphoma, and marginal zone lymphoma. A preclinical study looking at a combination of tafasitamab and lenalidomide found a synergistic effect.

What was the design and baseline characteristics of the phase 2 L-MIND trial?

In this study, patients with 4 or more prior lines of therapy were not allowed. Study patients had only 1 to 3 prior lines of therapy and were not eligible for transplant. Patients with primary refractory disease were also excluded. That’s based on the study’s language.^10,11

Tafasitamab was given weekly each cycle, for cycle 1 to cycle 3; each cycle is 28 days. From cycle 4 to cycle 12, tafasitamab was given 1 dose every 2 weeks. Lenalidomide was given from day 1 to day 21; so, 3 weeks on, 1 week off in each cycle, at 25 mg per day. If the patient continued to do well after the initial 12 cycles, they went on to maintenance with tafasitamab alone—1 dose every 2 weeks until disease progression. The benchmark for this study to be a success was to detect at least a 15% or higher absolute increase in ORR, and this is in comparison with using lenalidomide as monotherapy.¹¹

The median age was 72 years; the oldest patient treated on the study was 76 years old. For International Prognostic Index [IPI] risk score, it’s a pretty good split; 0 to 2 or 3 to 5. Around half the patients have a higher IPI score. Looking at the number of prior therapies, half the patients on this study had only 1 prior line of therapy. Although the protocol intended to exclude patients with primary refractory disease, in the end, they were relenting; patients with primary refractory disease were enrolled and treated in this clinical trial. Half of the patients had refractory disease to the last known therapies, and 11% of patients had prior SCT.

Can you describe the response to tafasitamab and lenalidomide in the L-MIND study?

At a median follow-up of 17 months, 43% of patients achieved CR, and this continued to hold true when the median follow-up was 2 years or longer, so there was durable remission at 24 months. The objective response is 60% at 17-months median follow-up, and 58.8% at 24 months. The response is quite durable.11,12

For PFS rate, by 12 months, 50% of patients relapsed, but 50% remained in remission. Looking at the OS rate at the end of 18 months, 64% of patients were still alive.11 At the 2-year follow-up, the mPFS was 16 months for the responders [95% CI, 6.3–not reached (NR)] and mOS is 31.6 months [95% CI, 18.3-NR].¹³

What was the toxicity profile in L-MIND?

The most common hematologic-related toxicities were neutropenia, anemia, and thrombocytopenia. Around 10% of patients had febrile neutropenia, and 2% of patients had grade 4 febrile neutropenia. In nonhematologic toxicities, the most common were fatigue, diarrhea, cough, pyrexia, peripheral edema, respiratory tract infection, and decreased appetite.^11,13

Half of the patients had serious AEs, and they were suspected to be treatment related in around 19% of the patients. Around 12% of patients discontinued treatment because of AEs. [As I mentioned before, discontinuation with] Lonca-T was around 17% to 19%. Treatment-related deaths occurred in 13% of patients. Around half of the patients, 45.7%, had at least 1 dose reduction of lenalidomide, and most patients were able to receive the lenalidomide dose of more than 20 mg per day over the duration of treatment. That was quite remarkable, because in practice, we usually use a lower dose of lenalidomide for patients with lymphoma.

[There was a difference in TEAEs by treatment phase]. The combination therapy was given up to 12 cycles, then patients moved on to tafasitamab monotherapy. It was apparent that patients had fewer AEs with monotherapy of tafasitamab; but neutropenia, including grade 4, continued to be reported, even in the monotherapy arm. Ten patients discontinued the combination therapy because of AEs.¹⁰

A study called RE-MIND [NCT04150328] used a matched comparison of tafasitamab/lenalidomide data from the L-MIND clinical trial and real-world data using lenalidomide monotherapy in transplant-ineligible patients. They matched 76 patients from the L-MIND study and 76 patients from the real world. If you look at the ORR with the combination, it’s 67.1% with close to 40% CR rate; and lenalidomide monotherapy led to a 34.2% of ORR, 13% of patients had a CR. The combination therapy seems to have a higher ORR, CR rate, and OS rate in the transplant-ineligible patient.¹⁴

Can you give us some data about polatuzumab vedotin-piiq (Polivy) plus rituximab?

Another regimen was approved in June 2019, [referred to as] pola-BR. The study included adult patients who had at least 1 prior line of therapy, had good ECOG performance status, and were ineligible for transplant or had failed prior transplant [NCT02257567]. The study excluded any patient who had prior allogeneic SCT, transformation to DLBCL, or greater than grade 1 peripheral neuropathy. This is due to the neurological AEs from polatuzumab, which is an ADC; it’s anti-CD79b conjugated to a monomethyl auristatin E payload, so it’s similar to brentuximab [Adcetris].¹⁵

The study had 2 parts, which looked at follicular lymphoma and DLBCL. Both parts had pola-BR as the treatment arm and BR as the comparable arm. The stratification is based on response to prior treatment and disease burden. The schedule is each cycle is 28 days, for a total of 6 cycles. Polatuzumab is given 1 dose each cycle, bendamustine is given at 90 mg/m² on day 1 and day 2, and rituximab is given on day 1. The primary end point was to look at the CR rate 6 to 8 weeks post end of treatment.

For patient characteristics, the age is a little older than the previous 2 studies; patients as old as 86 years were enrolled onto the pola-BR arm. Median prior lines of therapy is 2 for both arms, and most patients had refractory disease to the last known therapy. Around one-quarter of patients in the pola-BR arm had a prior STC with relapsed disease; 37.5% of DLBCL were a germinal center B-cell-like subtype.

The ORR was 45% for the pola-BR arm, and most responders had CR [40%]. For the BR arm, which is used as a comparator arm, ORR was 17.5%; pola- BR has a significantly higher response rate in both ORR and CR rate.

[The study included data on PFS that were analyzed both] by an independent review committee and by the study investigators. The data favored the pola-BR over the BR arm. There was longer mPFS for the pola-BR arm— around 9.5 months.¹⁷ The OS also favored the pola-BR arm at 12.4 months vs 4.7 months.

What kind of toxicities did patients experience with pola-BR?

As we predicted, the pola-BR arm had higher hematologic toxicities, including anemia, neutropenia, and thrombocytopenia. There was a bit higher incidence of diarrhea in the pola-BR arm. One important AE that is much higher in the pola-BR arm is peripheral neuropathy, but all the peripheral neuropathies were grade 1 or grade 2, overall around 43.6%, so these are related to polatuzumab.

_REFERENCES:

_{1. NCCN. Clinical Practice Guidelines in Oncology. B-cell lymphomas, version 4.2021. Accessed October 1, 2021. https://bit.ly/3geoS5N}

2. FDA grants accelerated approval to tafasitamab-cxix for diffuse large B-cell lymphoma. FDA. Updated August 3, 2020. Accessed June 6, 2021. https://bit.ly/3bodb9v

3. Zammarchi F, Corbett S, Adams L, et al. ADCT-402, a PBD dimer-containing antibody drug conjugate targeting CD19-expressing malignancies. Blood. 2018;131(10):1094-1105. doi:10.1182/blood-2017-10-813493Carlo-Stella C, Zinzani PL, Kahl B, et al. Initial results of a phase 2 study of loncastuximab tesirine, a novel pyrrolobenzodiazepine-based antibody-drug conjugate, in patients with relapsed or refractory diffuse large b-cell lymphoma. Presented at: European Hematology Association meeting; June 12, 2020; virtual. Accessed October 1, 2021. https://bit.ly/2VJiPhQ

4. Caimi PF, Ai W, Alderuccio JP, et al. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2021;22(6):790-800. doi:10.1016/S1470-2045(21)00139-X

5. Caimi PF, Weiyun ZA, Alderuccio JP, et al. Duration of response to loncastuximab tesirine in relapsed/refractory diffuse large B-cell lymphoma by demographic and clinical characteristics: subgroup analyses from LOTIS 2. J Clin Oncol. 2021;39(suppl 15):7546. doi:10.1200/JCO.2021.39.15_suppl.7546

6. Caimi PF, Weiyun ZA, Alderuccio JP, et al. Efficacy and safety of loncastuximab tesirine (ADCT-402) in relapsed/refractory diffuse large B-cell lymphoma. Blood. 2020;136(suppl 1):35-37. doi:10.1182/blood-2020-137524

7. Zynlonta. Prescribing information. FDA; 2021. Accessed October 1, 2021. https://bit.ly/2Y85CQo

8. Hamadani M, Linhares Y, Gandhi M, et al. Phase 3 randomized study of loncastuximab tesirine plus rituximab versus immunochemotherapy in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL): LOTIS-5. J Clin Oncol. 2021;39(suppl 15). doi:10.1200/JCO.2021.39.15_suppl.TPS7574

9. Salles G, Duell J, González Barca E, et al. Primary analysis results of the single-arm phase II study of MOR208 plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma (L-MIND). Hematol Oncol. 2019;37(suppl 2):173-174. doi:10.1002/hon.130_2629

10. Salles G, Duell J, González Barca E, et al. Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study. Lancet Oncol. 2020;21(7):978-988. doi:10.1016/S1470-2045(20)30225-4

11. Salles G, Duell J, González Barca E, et al. Long-term outcomes from the phase II L-MIND study of tafasitamab (MOR208) plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma. Presented at: 25th European Hematology Association Annual Congress; June 11-21, 2020; virtual. Abstract EP1201. https://bit.ly/3iAtrro

12. Monjuvi (tafasitamab-cxix). Prescribing information. MorphoSys US Inc; 2020. Accessed October 1, 2021. https://bit.ly/2S38ZW7

13. Nowakowski GS, Rodgers TD, Marino D, et al. RE-MIND study: a propensity score-based 1:1 matched comparison of tafasitamab + lenalidomide (L-MIND) versus lenalidomide monotherapy (real-world data) in transplant-ineligible patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). J Clin Oncol. 2020;38(suppl 15):8020. doi:10.1200/JCO.2020.38.15_suppl.8020

14. Sehn LH, Herrera AF, Flowers CR, et al. Polatuzumab vedotin in relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol. 2020;38(2):155-165. doi:10.1200/JCO.19.00172