Treatment with loncastuximab tesirine in patients with R/R DLBCL: Health-related QoL, symptoms, and tolerability data

While approximately 60% of patients with diffuse large B-cell lymphoma (DLBCL) respond to frontline chemoimmunotherapy, the prognosis for patients who relapse after first line (and subsequent) therapy is poor, highlighting an unmet need for patients with relapsed or refractory (R/R) DLBCL. The single-arm, phase II LOTIS-2 study investigated the antibody-drug conjugate loncastuximab tesirine in patients with R/R DLBCL following ≥2 systemic treatment regimens, including patients with high-risk disease types, and found antitumor activity and an acceptable safety profile in this patient population. Spira, et al.¹ recently published a study in Clinical Lymphoma Myeloma and Leukemia that analyzed the effect of loncastuximab tesirine on health-related quality of life (HRQoL), symptoms, and tolerability in patients with R/R DLBCL enrolled in LOTIS-2 (NCT03589469). Here we summarize the key findings.

Methods

The LOTIS-2 study was a multicenter, single-arm, open-label phase II trial that enrolled 145 patients aged ≥18 years (Table 1). Patients received loncastuximab tesirine as a 30-minute intravenous infusion on Day 1 of each 3 week treatment cycle at a dose of 150 μg/kg for two cycles and then 75 μg/kg for subsequent cycles.

Patient-reported outcomes were measured using the EQ-5D-5L and the Functional Assessment of Cancer Treatment–Lymphoma (FACT-Lym) instruments at baseline, Day 1 of each treatment cycle, and at the end-of-treatment visit.

The EQ-5D-5L is a self-assessed quality-of-life questionnaire. The scale measures quality of life on five dimensions including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each level is rated on the five-component scale that describes the degree of problems in that area (i.e. I have no problems walking about, slight problems, moderate problems, severe problems, or unable to walk). This tool also has the EQ visual analog scale (EQ VAS) which measures overall health, with a score of 100 representing “the best health you can imagine” and a score of 0 representing “the worst health you can imagine.”²

FACT-Lym and Lym S assessments

The FACT-Lym questionnaire is used to assess aspects of health-related quality of life for patients with lymphoma. It contains a generic core questionnaire called the Functional Assessment of Cancer Therapy–General (FACT-G) which is a compilation of 27 items to assess components including physical well-being, social/family well-being, emotional well-being, and functional well-being. The FACT-Lym also contains an additional 15 items specifically for evaluating response to treatment in patients with non-Hodgkin lymphoma called the Lymphoma Subscale (Lym S).³

Table 1. Patient characteristics*

BCL, B-cell lymphoma; CAR-T, chimeric antigen receptor; DLBCL, diffuse large B cell lymphoma. †Range 2–7.
Patient characteristics, % (unless otherwise stated)	N = 145
Histologies
DLBCL (not otherwise specified)	87.6
High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements	7.6
Primary mediastinal large B-cell lymphoma	4.8
Disease stage
Transformed disease	20
Double-hit or triple-hit disease	10.3
Advanced disease (stage IV)	64.1
Advanced disease (stage III)	13.1
Male	59
White	90
Age
Median age, years	66
≥65 years	55
≥75 years	14
Prior treatment
Median†	3
Stem cell transplant	16.6
CAR T-cell therapy	9

Results

• Of the 145 patients enrolled, 130 were analyzed.
• Patients had received a median of three cycles (range, 1–15 cycles) of loncastuximab tesirine as of the data cutoff, with eight patients continuing treatment.

Table 2. Results from mixed models for EQ VAS and FACT-Lym change scores*

CI, confidence interval; EQ VAS, EQ visual analog scale; Lym S, 15-item Lymphoma Subscale; MID, minimally important difference; TOI, Trial outcome index.   †This MID should be considered tentative, as it may be revised based on future research; higher scores indicate better quality of life. ‡Physical well-being + functional well-being + Lym S. *Adapted from Spira, et al.1
	MID prespecified threshold (range)	Change from baseline to C2D1		Change from baseline to C9D1		Change per cycle (slope)
		Est. (95% CI)	p value	Est. (95% CI)	p value	Est. (95% CI)	p value
EQ VAS	7	0.42 (−2.20 to 3.04)	0.749	5.00 (1.75–8.25)	0.003	0.65 (0.26–1.04)	0.001
FACT-Lym physical well-being	2.5 (2–3)	−0.24 (−0.95 to 0.46)	0.494	−0.03 (−0.93 to 0.86)	0.941	0.03 (−0.08 to 0.14)	0.606
FACT-Lym social/family well-being	—	−0.43 (−1.30 to 0.44)	0.330	−1.46 (−2.53 to −0.38)	0.008	−0.15 (−0.27 to −0.02)	0.025
FACT-Lym emotional well-being	(2†)	0.69 (0.12–1.25)	0.018	0.80 (0.08–1.52)	0.030	0.02 (−0.08 to 0.11)	0.738
FACT-Lym functional well-being	2.5 (2–3)	0.32 (−0.64 to 1.29)	0.506	−1.18 (−2.35 to −0.01)	0.049	−0.21 (−0.35 to −0.08)	0.002
FACT-Lym Lym S	3 (2.9-5.4)	1.36 (0.16–2.57)	0.027	1.33 (−0.15 to 2.81)	0.078	−0.004 (−0.18 to 0.17)	0.961
FACT-G Total Score	3 (3–7)	0.12 (−2.09 to 2.32)	0.917	−1.79 (−4.50 to 0.92)	0.194	−0.27 (−0.59 to 0.05)	0.094
FACT-Lym TOI‡	6 (5.5–11)	0.94 (−1.46 to 3.34)	0.439	−0.04 (−2.95 to 2.87)	0.979	−0.14 (−0.48 to 0.20)	0.413
FACT-Lym Total Score	7 (6.5–11.2)	0.93 (−2.10 to 3.95)	0.546	−0.91 (−4.57 to 2.76)	0.626	−0.26 (−0.68 to 0.16)	0.224

EQ VAS Scores (Table 2)

The EQ VAS overall health score improved over time:

• The adjusted improvement was 0.65 per cycle (95% confidence interval [CI], 0.26–1.04; p = 0.001).
• The adjusted mean change from baseline score was 5.00 (95% CI, 1.75–8.25; p = 0.003) at Cycle 9, Day 1.

At each visit during treatment, more patients experienced meaningful improvement compared to deterioration; 15% of patients experienced meaningful deterioration, compared with 40% that remained stable, and 45% who experienced meaningful improvement.

Starting from Cycle 3, Day 1, the mean changes from baseline in the EQ VAS were consistently higher than 0 and the minimally important difference improved by at least 40%. This indicates a positive improvement in overall health as early as two cycles into loncastuximab tesirine treatment. The mean change score continually increased to minimally important difference or greater after seven cycles of treatment, and all but one patient at Cycle 8 or later were responders.

Patients who remained at Cycle 9, Day 1 included elderly patients (40% of whom were aged 65 to <75 years, and 20% aged >75 years), and patients who were heavily pretreated (30% with >3 previous treatments).

FACT-Lym Scores (Table 2)

• Overall, the FACT-Lym total scores remained stable during treatment except for social/family wellbeing (WB), which was reported as having worsened at some visits.
  • A greater proportion of patients reported improvement compared to baseline in pain, lumps/swelling, and losing weight for most visits.
  • More than 60% of patients stated being “not at all” or “a little bit” bothered by treatment side effects at all treatment visits.
  • Subanalysis of the older patients was similar to the population as whole.
• No meaningful or statistically significant changes were noted in physical WB, Trial outcome index (sum of physical WB + functional WB + Lymphoma Subscale; Lym S), or FACT-Lym total scores when compared with baseline.
• Though there were improvements in emotional WB and Lym S scores, they were not statistically meaningful.
• There was a decline in social/family WB, and functional WB declined over time.
• The FACT-G total score (the sum total of physical, social/family, emotional, and functional WB) remained stable.
• While there was no detectable difference in baseline scores between responders and nonresponders:
  • There was an association between improvement in EQ VAS and clinical response.
  • There was an increase over time of mean change from baseline VAS score among responders.
  • Most FACT-Lym WB and composite scores remained constant in responders and reduced in nonresponders.

Symptoms

• The Lym S revealed that pain in certain parts of the body, being bothered by lumps/swelling, trouble sleeping at night, and fatigue (“get tired easily”) were the most common at baseline (33%–59% stated “somewhat” to “very much”).
• More than 80% of patients said “not at all” or “a little bit” at baseline for being bothered by fever, night sweats, losing weight, itching, and loss of appetite.
• Patients reported improvement during the course of treatment compared with baseline for pain, lumps/swelling, and weight loss at most visits.
• The reports for fever and night sweats remained the same for most patients.
• The only symptom that worsened over time was itching (p > 0.10 except one visit, where p = 0.06 at Cycle 7, Day 1).
• Some symptoms such as fatigue, trouble sleeping, and loss of appetite were inclusive because there was no clear trend for improvement or worsening.
• Results were consistent with loncastuximab tesirine’s identified toxicity profile: 43% of patients reported skin- or nail-related toxicities, most of which were mild to moderate in severity (only 4% had Grade ≥3 toxicity).
• Most patients stated that treatment-related toxicities were tolerable; this response was also seen among elderly patients.

GP5-Based Patient-Reported Tolerability to Treatment

Regarding patients’ responses to how much they were affected by side effects of treatment at baseline, 81% stated “not at all” or “a little bit,” and 5% claimed “quite a bit” or “very much,” reflecting residual side effects from prior treatments. During treatment with loncastuximab tesirine, >60% of patients reported being “not at all” or “a little bit” bothered by side effects of treatment.

Elderly Patients

• Greater than 50% of the study population were elderly patients aged ≥65 years. Results for HRQoL, symptoms, and tolerability were very similar to responses from the overall population.
• Treatment with loncastuximab tesirine had a greater number of patients that reported improvements in pain, lumps/swelling, and losing weight for most visits.
• Itching, as in the rest of the patient population, worsened.
• The EQ VAS overall health score and most FACT-Lym scores remained stable or improved in elderly patients.
• Most elderly patients were able to tolerate treatment with loncastuximab tesirine.

Conclusion

In summary, results from this analysis indicate a benefit in patients with R/R DLBCL who were treated with loncastuximab tesirine, including elderly patients, as the data show that patients remained stable or improved their overall HRQoL, particularly among responders. Most patients reported an improvement in symptoms of pain, lumps/swelling, and weight loss compared with baseline during most visits. Itching was the only symptom—in the whole cohort, including elderly patients—that worsened over time. The majority of patients said the treatment was tolerable. This study has some limitations, including recall bias, but overall, these findings seem promising for loncastuximab tesirine treatment for patients with R/R DLBCL.