Evening with the Experts �New Updates in the Management of Lymphomas�A Patient Perspective

Ranjana Advani M.D.

Saul Rosenberg Professor of Lymphoma

18th Annual Indy Hematology Review

DISCLOSURES

• Advisory Board: Roche, Celgene, Takeda, Seattle Genetics, Epizyme, Sanofi, Kura, ADCT, Karyopharm, Merck, BMS, Daichi Sanyo, Incyte

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• Institutional research funding: Seattle Genetics, Regeneron, Pharmacyclics, Merck, Forty-Seven, Cyteir, Millennium, ADCT, Kura

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• Speaker’s Bureau: none
• Stockholder: none
• Employee: none

What is lymphoma?

• Lymphocytes normally fight viruses, bacteria, fungi, and foreign organisms
• Lymphocytes travel in lymphatic system
• These cells can grow in nodal and extranodal locations

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Lymphoma is a family of blood cancers derived from mature lymphocytes

B-cells

T-cells

NK-cells

Courtesy Dr Smith

How common is lymphoma?

Hodgkin and non-Hodgkin lymphoma affect both genders, all ages, all races

662,789 people living with lymphoma

80,000 new cases/year

20,000 deaths/year

https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2020/cancer-facts-and-figures-2020.pdf

Courtesy Dr Smith

It was simple in the old days of chemotherapy

In the past, chemotherapy targeted

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1. DNA
2. Topoisomerase
3. Microtubules

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Rational combinations = using non-cross resistant chemotherapy agents

Courtesy Dr Ansell

It has become a lot more complicated!

Aberrant signaling targets

Somatic mutation targets

Immunological targets

Courtesy Dr Ansell

Immunotherapy of Lymphoma 2021

• Target The Tumor
• Engineered Antibodies
• CAR T Cells
• Antibody-Drug Conjugates
• Bispecific Antibodies

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• Target The Host
• Enhance ADCC
• Remove Checkpoints on the Immune System

Outcomes in Relapsed/Refractory (R/R) DLBCL – SCHOLAR-1

• Patients must have received Rituximab
• Pooled ORR 26%, CR 7%
• Response rates consistently low across subgroups (age, refractory status, Stage, IPI)

Chimeric Antigen Receptor (CAR) modified T cells

FDA/EMA

FDA

FDA/EMA

Efficacy of CARTs in R/R DLBCL

Median follow-up

27.1 months

14 months

18.8 months

Ai ICML 2021

Grade 3 AEs of special interest: CRS (2-20%) and neurological (10-28%)

Interim Analysis of ZUMA-12: A Phase 2 Study of Axicabtagene Ciloleucel (Axi-Cel) as First-Line Therapy in Patients With High-Risk DLBCL [ASH 2020 Neelapu et al, # 405]

Median DOR, PFS and OS not reached at median follow up of 9.5 months

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6/10/21: Bristol Myers Squibb Announces Positive Topline Results from Phase 3 TRANSFORM Trial Evaluating Breyanzi (lisocabtagene maraleucel) Versus Chemotherapy Followed by Stem Cell Transplant in Second-line Relapsed or Refractory Large B-cell Lymphoma

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6/28/21: Kite Announces Yescarta^® CAR T-cell Therapy Improved Event-Free Survival by 60% Over Chemotherapy Plus Stem Cell Transplant in Second-Line Relapsed or Refractory Large B-cell Lymphoma

Axi-Cel approved for R/R Mantle Cell and Follicular Lymphoma

Wang NEJM 2020

Jacobsen EBMT 2021

What are Antibody Drug Conjugates (ADCs)?

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ADCs are monoclonal antibodies to which potent cytotoxic drug is conjugated

Improved therapeutic window

ADC: Loncastuximab

Carlo-Stella ICML 2021

ADC: Loncastuximab (LOTIS-2 Results)

Caimi Lancet Oncol 2021

Med DOR 10.3 mo

For CR pts: 13.4 mo

Randomized Phase III Trials with Loncastuximab

LOTIS- 5: R/R DLBCL

LOTIS- 6: R/R DLBCL

Carlo-Stella ICML 2021

Bispecific T-cell engager(BiTE)

• BsAbs combine the specificity of two antibodies so that they can simultaneously bind to different antigens.
• Most BsAbs involve specificities that bind to an antigen on a cancer cell (CD 19, CD20) and to T-cell surface glycoprotein CD3e-chain(CD3)on T cells.

Golay et al J Immunol 2014

Emerging therapies: Bi-specific Antibodies

Courtesy Dr Smith ICML 2021

Emerging therapies: Bi-specific Antibodies�Clinical Efficacy and toxicity (R/R aggressive NHL)

Courtesy Dr Smith ICML 2021

Elderly/Unfit Patients With 1L DLBCL Have Poor Survival

• Up to 30% of patients aged ≥75 years do not receive standard CIT as 1L treatment for DLBCL
• Poor outcomes are commonly reported for elderly/unfit patients with 1L DLBCL who receive no treatment, reduced‑dose R‑CHOP or other therapies such as R‑CVP and R‑Benda
• R-mini CHOP used in very elderly patients (age > 80 y) with 1L DLBCL
• 2-year OS rate: 59% (49–67%)
• 2-year PFS rate: 47% (38–56%)

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• Single-Agent Mosunetuzumab for Elderly/Unfit Patients with Previously Untreated DLBCL
• Key Inclusion Criteria
• Treatment naïve DLBCL or HGBL
• Age ≥80 years or 60–79 years with impairment in:
• ≥1 ADL or
• instrumental ADL or
• inability to tolerate full dose CIT

Early durable complete responses observed with mosunetuzumab in elderly/unfit 1L DLBCL

Months on study

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• Median follow-up: 5.4 (range: 0.3–16.2) months
• Preliminary evidence of durable responses has been observed
• The first patient enrolled achieved a CR and has now been off treatment for more than 10 months
• Median DOR not reached
• Of the 10 patients with PD (from both dosing cohorts), nine have received salvage therapy post progression and are still alive
• Of the four efficacy evaluable patients with DH/TH, two are in CR

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30mg

expansion cohort

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30mg

safety cohort

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13.5mg

safety cohort

Duration of response and time on study

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Death

Complete response

Partial response

Progressive disease

Stable disease

Study discontinuation

Still on treatment

0

1

2

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Early clinical data indicate that single-agent mosunetuzumab has a manageable and acceptable safety profile for elderly/unfit patients with 1L DLBCL. No severe cases of CRS observed

ORR 65%, CR 45.5%

Olszewski et al, # 401 ASH 2020

Relapsed/Refractory (R/R) classic Hodgkin Lymphoma (cHL)

Expected outcomes following after conventional therapy and ASCT

Outcomes of cHL patients with the third or >�relapse after conventional therapy: GHSG

5 yr TTF 49%

Josting et al, JCO 2002; Sureda, et al. Ann Onc 2005; Sirohi et al, Ann Onc 2002

5 yr OS 57%

Brocklemann et al Ann Oncol 2019

Approved novel agents for R/R cHL

• Hodgkin Reed Sternberg (HRS) cells express CD 30
• Brentuximab Vedotin (BV) is an anti CD30 antibody drug conjugate (MMAE) which disrupts the microtubule network and triggers an immune response through the induction of endoplasmic reticulum stress
• Approved for R/R disease, advanced stage front line with AVD and maintenance post transplant

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• HRS harbor genetic alterations of 9p24.1 leading to overexpression of PD-L1, PD-L2 and JAK2
• Nivolumab/Pembrolizumab targets the programmed death-1 (PD-1) immune checkpoint pathway and restores antitumor immune responses
• Approved for R/R disease

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Harnessing the immune system to treat classic Hodgkin Lymphoma (cHL)

Advani et al Blood 2021

Optimization of salvage therapy

Phase I/II study BV + Nivolumab as 1^st salvage: 3y results

S1826: A Phase III Randomized Trial of Nivolumab (Opdivo) or Brentuximab Vedotin (Adcetris) Plus AVD in Patients (Age ≥ 12 Years) With Newly Diagnosed Advanced Stage cHL

• Primary endpoint: PFS
• Secondary endpoints: EFS, OS, CR

Post-Tx ISRT allowed for pts declared ISRT-eligible prior to randomization with EOT:

• DS 4-5
• ≥ 30% reduction in max transverse diameter

AND

• Residual LN ≥ 2.5cm

OR

• Residual extranodal lesion > 1cm

Conclusion�New Updates in the Management of Lymphomas

• Better understanding of biology
• Many advances in lymphoma treatment
• Pipeline of active agents under investigation
• Many novel therapies approved for R/R disease are being tested in front line setting
• Future is promising
• Participate in clinical trials

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