Interim Safety Analysis of ALLG-Pacific (NHL35): An Open Label Phase II Study of Pembrolizumab and Chemo-Immunotherapy As First-Line Therapy for Primary Mediastinal B-Cell Lymphoma

Background: Primary mediastinal B-cell lymphoma (PMBL) comprises 10% of diffuse large B-cell lymphoma (DLBCL), primarily affecting young adults. Combination chemoimmunotherapy is effective, but there is no consensus on the optimal therapeutic regimen. The randomized IELSG37 study demonstrated no improvement to progression free survival (PFS) when consolidation radiotherapy was administered following chemoimmunotherapy. However, PFS was inferior for patients (pts) treated with R-CHOP-21 (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone every 21 days) compared with other regimens, supporting intensification of therapy beyond R-CHOP-21 in this entity. Programmed-death- (PD-1) ligands PD-L1/PD-L2 are frequently upregulated in PMBL, and the PD-1 inhibitor pembrolizumab (pembro) blocks interaction of PD-1 and PD-L1/2, and subsequent signalling. Pembro has encouraging activity in relapsed/refractory PMBL with an overall response rate of 43% (complete response 23%) and modest toxicity in a phase II study, and is predicted to be synergistic with rituximab. Therefore, there is compelling rationale for combining R-CHOP and pembro as first-line therapy for PMBL.

Methods: ALLG-PACIFIC (ACTRN12621001529831p) is a 35 patient, phase II, single arm, open-label study of R-CHOP in combination with pembro for pts with newly diagnosed PMBL. Pts receive 2 cycles of rituximab (375mg/m²) plus pembro (200mg) every 21 days ('window phase') followed by 6 cycles of R-CHOP plus pembro every 21 days ('induction phase') followed by 5 cycles of pembro 400mg every 42 days ('consolidation phase'). Adults (≥18 years) with treatment naïve histologically confirmed PMBL and adequate organ function, no contraindications to R-CHOP and with no active autoimmune disease are eligible.

The primary endpoint is 18-month event free survival. A key secondary endpoint is safety of treatment including rates of early discontinuation due to toxicity. Here, we present the results of a planned interim safety analysis.

Results: As of 10^th July 2024, 12 pts have completed ‘window’ and ‘induction’ treatment phases (ie. 8 cycles). Three pts have withdrawn consent; 1 due to rash during the first window cycle, one due to patient preference to receive treatment off study, and one due to alopecia and nausea following completion of window treatment, who has subsequently consented to remain on the study for efficacy and survival follow up. All 15 pts are included in this safety analysis. All pts had ≥1 adverse event (AE), with 7 pts (47%) experiencing AEs leading to dose delay. Eight pts (53%) experienced ≥1 possible immune related AE (irAE); rash (G2 n=3, G3 n=3) and alanine aminotransferase (ALT) elevation (G2 n=1, G3 n=3), all with alternate possible causative concomitant medications. Twenty five ≥G3 AEs occurred in 12 pts; rash (n=3), ALT elevation (G3 n=3, G4 n=1), sinus tachycardia (G3 n=2), lipase elevation (G3 n=2), infections (G3 n=3), neutropenia (G3 n=2, G4 n=1) febrile neutropenia (G3, n=2), fever (G3, n=1), and one each G3 of anemia, headache, syncope, chylothorax. There was 1 G3 disease related pericardial effusion. There were no G5 AEs or AEs leading to treatment discontinuation per protocol.

Conclusions: This interim analysis of ALLG-PACIFIC suggests that R-CHOP-21 in combination with pembro as first-line therapy for PMBL has a manageable safety profile consistent with that expected of the agents involved. There were no unexpected toxicities, however rates of rash and ALT elevation during ‘window’ phase have led to a recommendation to avoid concomitant administration of supportive medications during ‘window’ phase that may precipitate these AEs. (eg. Allopurinol, co-trimoxazole). Study enrolment, safety and efficacy analyses are ongoing.

Lewis:AstraZeneca: Consultancy, Honoraria, Patents & Royalties: Travel and accommodation for educational events/conferences; Roche: Consultancy, Honoraria; Merck/MSD: Consultancy, Other: Advisory Board; AbbVie: Consultancy, Other: Advisory Board; Janssen: Honoraria; Gilead/Kite: Honoraria; Loxo/Lilly: Other: Trial steering committee, Patents & Royalties: Travel and accommodation for educational events/conferences; IQVIA: Other: Advisory Board. Giri:Royal Adelaide Hospital: Current Employment. Keane:Astra Zeneca: Speakers Bureau; Takeda: Speakers Bureau; Roche: Consultancy; Merck: Consultancy, Speakers Bureau; Gilead: Consultancy. Cochrane:Beigene: Research Funding. Cheah:MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Menarini: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau; Dizal: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sobi: Consultancy, Honoraria; Lilly: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Consultancy, Honoraria, Other: travel expenses, Speakers Bureau; Regeneron: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding, Speakers Bureau; Genmab: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding.

Pembrolizumab is a type of targeted therapy drug called an immune checkpoint inhibitor (a type of immunotherapy). It is a monoclonal antibody that binds to the protein PD-1 on the surface of immune cells called T cells. It works by keeping cancer cells from suppressing the immune system. This allows the immune system to attack and kill the cancer cells. Many cancers, including PMBL, demonstrate up-regulation and over-expression of programmed-death-1 (PD-1) ligands PD-L1 and PD-L2. This is prominent in PMBL, and in this setting is largely due to genetic alterations at 9p24,including PD-L1/PD-L2 copy gain, amplification and translocations leading to the PD-L1/PD-L2 locus being placed next to the IgH locus. Binding of PD-L1/2 to PD-1 (receptor on T-cells)provides a way for the tumour cells to evade the T-cell immunologic response, by negatively regulating T-cell mediated immune events. Inhibition of the PD1-L1/L2 pathway has been an effective treatment strategy across a range of malignancies. Within haematological malignancies, the most promising results have been noted in Hodgkin lymphoma and PMBL The PD-1 inhibitor pembrolizumab binds PD-1, therefore blocking PD-1 and PD-L1/2interaction and subsequent signalling. Pembrolizumab has encouraging activity in patients with relapsed/refractory PMBL. In the phase II KEYNOTE-170 study, among 53 patients with relapsed/refractory PMBL and a median of 3 prior lines of therapy, the ORR was 43% (CR 21%) with median PFS 5.5 months. Toxicity was relatively modest, with grade ÃÆ'ѢÂâ⑬°Ã‚Ã'Â¥3 adverse events observed in23% of patients, uncomplicated neutropenia being the mostcommon.8 As of September 2020, pembrolizumab is subsidised on the PBS in Australia for patients with relapsed/refractory PMBL on the basis of these encouraging data.