CAR-T Therapy in non-Hodgkin lymphomas - PowerPoint Presentation

Slide1

CAR-T Therapy in non-Hodgkin lymphomas

Jonathon B. Cohen, MD

Dept of

Hematology

/Medical Oncology

Co-Director

Lymphoma Program

Slide2

Relapsed aggressive nhl

associated with shortened survival

Scholar-1 (Crump et al, Blood 2017)

Martin et al, Blood 2016

Chimeric Antigen Receptor (CAR) T Therapy has changed outcomes for patients with relapsed disease.

Slide3

CAR-t constructs and studies

“Normal” T-cell Activation

CAR-T

Westin et al, 2021;

Tyagarajan

et al, 2020;

Escors

et al 2014.

;

Slide4

CD19 directed CAR-T Therapy: indications

Relapsed DLBCL/Transformed NHL:

Axi-cel

, Tisa-cel, Liso-celRelapsed MCL:

Brexu-celRelapsed FL: Axi-celPossible future indications: 2nd

line DLBCLCLLMarginal Zone lymphoma

Press

Release

Slide5

CAR-t outcomes in DLBCL

Study (Product)

ORR/CR

Median PFS

Median DOR

Median OS

Zuma-1 (Axi-cel)1,2

74% / 54%

5.9 months

11.1 months

25.8 months

JULIET (Tisa-

Cel

)

3,4

53% / 39%

NR (65% at 1 year)

12 months

TRANSCEND (

Liso-Cel

)573% / 53%6.8 monthsNR (55% at 1 year)21.1 months

Note: Very hard to compare across studies

Key Points regarding efficacy:Long term remission seems to occur in 35-40% of casesNot clear that one product is better than others.Achieving a CR is critical.

PFS for Tisa-

cel based on achievement of CR

Locke et al, NEJM 2019; Jacobson et al, ASH 2020; Schuster et al, NEJM 2019;

Schuster et al, Lancet Oncol 2021; Abramson et al, Lancet 2020

Slide6

Safety outcomes for Cd19-directed CAR-t

ZUMA-1

Commercial

Axi-cel

JULIET

Commercial

Tisa-

cel

Liso-Cel

Patients collected, n

111

163

165

79

344

Patients infused, n

101

149

111

75

294

Median age, yrs (range)

58 (23-76)

58 (18-85)

56 (22-76)

67 (36-88)

63 (18-86)

ECOG 0/1

100%

86%

100%

94%

99%

Prior ASCT

23%

29%

49%

23%

33%

Grade ≥ 3 CRS

13%

13%

22%

1%

2%

Grade ≥ 3 NEs

31%

41%

12%

3%

9%

Tocilizumab

43%

62%

14%

13%

18%

Steroid use

27%

57%

10%

7%

10%

Slide7

Role of CAR-T in second line for

dlbcl

Currently, CAR-T utilized most frequently post-ASCT or in patients who have active disease after 2 therapies.

Three studies have evaluated role of CAR-T vs ASCT in early relapsing DLBCL (< 1 year)

BELINDA: Tisa-

celZUMA-7: Axi-celTRANSFORM:

Liso-celData are pending but press releases available.

June 28, 2021

Axi-cel

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

--

 Landmark ZUMA-7 Study was Initiated in 2017 as the First Randomized Clinical Trial to Test the Earlier Use of a CAR T-cell Therapy Against Standard of Care --

--

Study Met the Primary and Key Secondary Endpoints of Event-Free Survival and Objective Response Rate, Demonstrating a Highly Statistically and Clinically Significant Improvement Compared to Standard of Care --

June 10, 2021

Positive Topline Results from Phase 3 TRANSFORM Trial Evaluating

lisocabtagene

maraleucel

Versus Chemotherapy Followed by Stem Cell Transplant in Second-line Relapsed or Refractory Large B-cell Lymphoma

Study met primary and key secondary endpoints, demonstrating a highly statistically significant improvement in event-free survival, complete response rate and progression-free survival compared to standard of care

Liso-cel

safety results consistent with data from pivotal TRANSCEND NHL 001 trial

Results represent the first time a therapy has demonstrated benefit compared to high-dose chemotherapy and stem cell transplant in relapsed or refractory large B-cell lymphoma, and support the potential of

liso-cel

in earlier lines of therapy in this patient population

Slide8

Role of CAR-T in second line for

dlbcl

Currently, CAR-T utilized most frequently post-ASCT or in patients who have active disease after 2 therapies.

Three studies have evaluated role of CAR-T vs ASCT in early relapsing DLBCL (< 1 year)

BELINDA: Tisa-

celZUMA-7: Axi-celTRANSFORM:

Liso-celData are pending but press releases available.

June 28, 2021

Axi-cel

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

--

 Landmark ZUMA-7 Study was Initiated in 2017 as the First Randomized Clinical Trial to Test the Earlier Use of a CAR T-cell Therapy Against Standard of Care --

--

Study Met the Primary and Key Secondary Endpoints of Event-Free Survival and Objective Response Rate, Demonstrating a Highly Statistically and Clinically Significant Improvement Compared to Standard of Care --

June 10, 2021

Positive Topline Results from Phase 3 TRANSFORM Trial Evaluating

lisocabtagene

maraleucel

Versus Chemotherapy Followed by Stem Cell Transplant in Second-line Relapsed or Refractory Large B-cell Lymphoma

Study met primary and key secondary endpoints, demonstrating a highly statistically significant improvement in event-free survival, complete response rate and progression-free survival compared to standard of care

Liso-cel

safety results consistent with data from pivotal TRANSCEND NHL 001 trial

Results represent the first time a therapy has demonstrated benefit compared to high-dose chemotherapy and stem cell transplant in relapsed or refractory large B-cell lymphoma, and support the potential of

liso-cel

in earlier lines of therapy in this patient population

Aug 24, 2021

Update on BELINDA study investigating

tisa-cel

as second-line treatment in aggressive B-cell non-Hodgkin lymphoma

  

Phase III BELINDA study did not meet primary endpoint of event-free survival for patients with aggressive B-cell non-Hodgkin lymphoma who had primary refractory disease or who relapsed within 12 months of first-line treatment

CAR-T innovation continues to accelerate development of next-generation platform with improved CAR-T cellular characteristics, high speed, lower cost of goods sold (COGS) and advancement of clinical research into new indications and targets; early clinical data anticipated at upcoming medical meeting

In its approved indications,

tisa-cel

is an efficacious treatment offering potential for durable responses and a favorable safety profile based on clinical and real-world experience in more than 5,300 patients to date

Slide9

Mantle cell lymphoma – Brexucabtagene

autoleucel

Wang et al, NEJM 2020

Slide10

Mantle cell lymphoma – Brexucabtagene

autoleucel

Wang et al, NEJM 2020

Slide11

Mantle cell lymphoma – liso-cel

Median on-study follow-up: 5.9 mos (range: 0.4-24.8)

Median time to first CR or PR: 0.95 mos (range: 0.9-2.0)

Median DoR: not yet reached (data maturing)

CRS: 50% (3% were grade ≥ 3)

Neurologic events: 34% (12.5% were grade ≥ 3)

Palomba

et al, Ash 2020

Slide12

Follicular lymphoma – zuma

5

Outcomes for relapsed follicular lymphoma are typically quite good.

Appropriate selection of patients for cellular therapy is important.Early relapsers likely at highest risk.

Slide13

Zuma 5 efficacy in relapsed/refractory indolent

nhl

ORR 93% for patients with POD24

Jacobson et al, ASH 2020

Slide14

Zuma 5 efficacy in relapsed/refractory indolent

nhl

Slide15

ZUMA-5 CRS and Neurologic toxicity

1 Grade 5 CRS

1 Grade 4 CRS

3 Grade 4 Neurologic Events

Slide16

Other Follicular lymphoma studies - ELARA

Tisagenlecleucel

in relapsed/refractory follicular lymphoma

Patients with relapse after 2nd line therapy or post-auto transplant94 evaluable patients – CR Rate 66%, ORR 86%

6 month duration of response: 94%Zero grade 3 CRS events, 1 Grade 4 Neurologic event.

Fowler et al, ICML 2021

Slide17

Chronic lymphocytic leukemia – Transcend

cll

2 Phase 1 cohorts

Liso-cel monotherapy for patients who are pre-treated with a BTK inhibitorLiso-cel

+ ibrutinib for patients previously treated with BTK inhibitor including with inadequate response, high risk mutations.

Combination cohort: Wierda et al, ASH 2020

95% ORR, 47% CR

Monotherapy cohort; Siddiqi et al ASH 2020

Slide18

The future

Despite exciting findings and several current indications, future studies may improve outcomes….

Allogeneic CAR-T

CD19/20 Bispecific CAR-TCAR-T-containing combinationsFront-line therapy for high risk patients

Bottom line – More studies are ongoing. Any patients with relapsed NHL (or high risk untreated NHL) should be referred for evaluation.

Slide19

Case 1 - DLBCL

A 64 year old female presented with relapsed DLBCL in 2013.

She was diagnosed with Stage IIB DLBCL in 2008 and had received 6 cycles of R-CHOP, achieving a CR. She received radiation therapy to the mediastinum and then was treated for 18 months with maintenance rituximab, until January 2011.

She presented to our clinic in 2013 with progressive adenopathy above and below the diaphragm that was biopsied and consistent with relapsed DLBCL.

She received R-ICE x 3 cycles and subsequently completed autologous stem cell transplantation with BEAM in early 2014.She relapsed again in Fall, 2015 and at that time enrolled on a clinical trial of CD19-directed CAR-T. She completed apheresis in November 2015 and then received a cycle of RGDP starting in December, 2015, complicated by sepsis and hypotension. A second attempted cycle was associated with infusion reaction and was terminated.

She was subsequently observed until initiation of lymphodepleting therapy and CAR-T infusion on March 1, 2016. Course was complicated by a grade 1 rash treated with triamcinolone but no evidence of CRS.

She was seen last week, > 5 years out from completing CAR-T. Remains in complete remission.

Slide20

Case 2 - dlbcl

59

yo

male who was initially diagnosed with DLBCL in 2016 when he was found to have a nasal lesion that was biopsied and consistent with DLBCL. He completed 3 cycles of R-CHOP which was “poorly tolerated” and then completed RT to the sino-nasal region.He relapsed in August 2017 with a thigh lesion, confirmed to be relapsed NHL. He completed RICE followed by autologous transplant in November 2017. Relapse occurred ~10 months after diagnosis.

About 8 months later, he presented with a recurrent thigh lesion and a concurrent lesion on the contralateral leg. This was biopsied and was consistent with relapse.In September, 2018, he received gemcitabine-based therapy and ultimately in November, 2018, he completed lymphodepleting therapy and CAR-T infusion (Axi-cel

).Immediate post-CAR-T course was unremarkable……But……6 months later….

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Slide21

Case 2 - dlbcl

21

Hit his head on the car door, resulting in intra-cranial

hemorrhage and prolonged hospitalization.

At time of event:

WBC 2.9

Hgb 8.1Plts 6

Course further complicated by failure to thrive and

progressive renal dysfunction

Platelets ultimately responded to NPLATE

He ultimately died from long-term COVID infection,

still

pancytopenic

in 2020, 2 years post CAR-T.

Slide22

Case 3 - MCL

60 year old male initially diagnosed with mantle cell lymphoma in 2014. He completed induction therapy with RCHOP/RDHAP and subsequently completed autologous stem cell transplant in August 2015.

In October 2016, he was found to have new adenopathy consistent with relapse. As he was asymptomatic he was observed for a few months but ultimately initiated therapy with ibrutinib/

venetoclax on study for 6 months from February to July 2017.He progressed again in early 2018, again with asymptomatic disease initially but then rapid progression. He subsequently completed CAR-T therapy with

brexu-cel in March 2018. Prior to CAR-T his disease progressed very rapidly with numerous extranodal sites of disease prior to CAR-T infusion.

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Slide23

Case 3- MCL

Course complicated by neurologic toxicity, requiring dexamethasone and readmission. Noted by family to be having word finding difficulties, difficulty with arithmetic despite being an engineer. Fully recovered over a few weeks.

He remained in remission for ~ 1 year, then relapsed and initiated

venetoclax, then bendamustine-rituximab.He completed reduced intensity conditioning allogeneic transplant in June, 2019, complicated by septic shock and liver failure, ultimately resulting in death.

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