Is there a role for targeted therapy in the adjuvant or neoadjuvant - - PowerPoint PPT Presentation

▶
is there a role for targeted therapy in the adjuvant or
SMART_READER_LITE
LIVE PREVIEW

Is there a role for targeted therapy in the adjuvant or neoadjuvant - - PowerPoint PPT Presentation

Oct 28, 2022 249 likes •468 views

Is there a role for targeted therapy in the adjuvant or neoadjuvant setting? Nathan Pennell, M.D., Ph.D. February 11, 2017 44 Year Old Woman, Nonsmoker Presented in 2009 with RLL nodule, staging indicated likely stage IA adenocarcinoma

slide-1
SLIDE 1

Is there a role for targeted therapy in the adjuvant or neoadjuvant setting?

Nathan Pennell, M.D., Ph.D.

February 11, 2017

slide-2
SLIDE 2

44 Year Old Woman, Nonsmoker

  • Presented in 2009 with RLL nodule, staging

indicated likely stage IA adenocarcinoma

  • RLL lobectomy: 2.8cm adeno, level 7 node+ (N2;

Stage IIIA), EGFR exon 19 deletion mutation

  • Completed adjuvant cisplatin/pemetrexed and

PORT

  • Enrolled on phase 2 trial of 2 years of adjuvant

erlotinib, required dose reduction to 100mg

  • Completed 2 years of erlotinib in 2011

2

slide-3
SLIDE 3

Case continued

  • Recurrence in right pleural space in 2013
  • Biopsy showed same exon 19 deletion

mutation

  • Restarted erlotinib with partial response
  • Late 2014 had progression (after 14 months)
  • Progressed on chemotherapy and then

nivolumab

  • Rebiopsy in Dec 2015 showed T790M

mutation, started osimertinib, no PD to date

3

slide-4
SLIDE 4

PET/CT 2009

4

slide-5
SLIDE 5

PET/CT 2013

5

slide-6
SLIDE 6

Is there a role for targeted therapy in the adjuvant or neoadjuvant setting?

Nathan Pennell, M.D., Ph.D.

February 11, 2017

slide-7
SLIDE 7

Overview

  • Adjuvant chemotherapy improves survival in

early-stage non-small cell lung cancer (NSCLC)

  • EGFR and ALK-targeted therapies are more

effective than chemotherapy in advanced EGFR/ALK+ NSCLC, but do they improve cure rates in earlier stages?

  • Review data on adjuvant targeted therapies
  • Review ongoing adjuvant trials

7

slide-8
SLIDE 8

LACE Meta-Analysis of Adjuvant Cisplatin-Based Chemo in NSCLC

Pignon et al., JCO 2008;26(21):3552-9. 5-year absolute benefit of 5.4% from chemotherapy

slide-9
SLIDE 9

Phase III Trials of EGFR and ALK TKIs vs. Chemotherapy as First-Line Treatment of Patients with Advanced EGFR/ALK+ NSCLC

Study Response Rate PFS LUX-Lung 3 56% vs. 22% 13.6 vs. 6.9 months (HR 0.47) LUX-Lung 6 67% vs. 28% 11 vs. 5.6 months (HR 0.28) EURTAC 58% vs. 14.9% 9.7 vs. 5.2 months (HR 0.37) OPTIMAL 83% vs. 36% 13.1 vs. 4.6 months (HR 0.16) NEJ 002 74% vs. 31% 10.8 vs. 5.4 months (HR 0.30) WJTOG 3405 62% vs. 31% 9.2 vs. 6.3 months (HR 0.49) Profile 1014 (crizotinib) 74% vs. 45% 10.9 vs. 7 months (HR 0.45)

No differences in overall survival!

slide-10
SLIDE 10

If TKIs are more effective than chemotherapy in stage 4 disease, why not try them in the adjuvant setting?

  • Adjuvant targeted treatment is proven

effective and approved in

– Breast cancer (hormonal1 and HER2-directed2 therapy) – GIST (cKIT directed therapy, i.e. imatinib3) – Melanoma (anti-CTLA4 i.e. ipilimumab4)

1EBCTCG meta-analysis, Lancet Oncol 2012 2Moja et al., Cochrane Database Syst Rev 2012 3Joensuu et al., JAMA 2012 4Eggermont et al., Lancet Oncol 2015

slide-11
SLIDE 11

Evidence in Favor? MSK Retrospective Cohort Study

Janjigian et al. J Thoracic Oncol. 2011;6:569. D’Angelo et al., 2012 JTO 7(12); 1815-22.

A retrospective cohort study demonstrated an 89% vs. 72% 2-year DFS in EGFR mutant patients prescribed adjuvant erlotinib or gefitinib compared with untreated patients

slide-12
SLIDE 12

Evidence Against? BR.19

  • Phase 3 trial of adjuvant gefitinib versus

placebo in UNSELECTED early stage NSCLC

  • Halted early after <50% accrued (509 pts)
  • Possible harm in adjuvant TKI arm (HR 1.24)
  • BUT only 15 patients with EGFR mutations

identified so too few to draw conclusions of benefit or harm

12

slide-13
SLIDE 13

Prospective Data to Date for Adjuvant TKIs

  • For ALK? Nothing to date.
  • For EGFR mutant NSCLC, there have been 2

trials completed: RADIANT and SELECT

13

slide-14
SLIDE 14

(n=350) Placebo

(N=973) Randomization stratified by: histology, stage, prior adjuvant chemo, EGFR FISH status, smoking status, country

(n=623) Erlotinib 150mg/day Up to 4 cycles of platinum-based doublet Tumor samples EGFR IHC+ and/or EGFR FISH+ £90 d £180 d

RADIANT Trial Design

  • Radiology assessment: every 3 months on treatment and yearly during long-term

follow up

  • Primary endpoint: DFS
  • Secondary endpoints: OS; DFS and OS in patients with del19/L858R (EGFR M+)

14 Adopted from Dr. Karen Kelly ASCO 2014

No adjuvant chemotherapy 2:1 Stage IB–IIIA NSCLC Complete surgical resection

2-yr treatment period

slide-15
SLIDE 15

RADIANT Mutation + Subgroup (n=161): Disease Free Survival and Overall Survival

6 12 18 24 30 36 42 48 54 60 66 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Disease-free Survival (Months) Disease-free Survival Probability Placebo Erlotinib Placebo (32 events) Median: 28.5 m Erlotinib (39 events) Median: 46.4 m Log-rank test: p=0.0391 HR: 0.61 (95% CI: 0.384, 0.981)

Number at Risk 43 80 35 76 12 22 49 94 59 102 30 68 23 56 15 35 10 10 5 3 Placebo Erlotinib

6 12 18 24 30 36 42 48 54 60 66 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Overall Survival (Months) Overall Survival Probability Erlotinib Placebo Placebo (13 events) Median: not reached Erlotinib (22 events) Median: not reached Log-rank test: p=0.8153 HR: 1.09 (95% CI: 0.545, 2.161)

Number at Risk 56 94 53 91 30 43 57 100 59 102 51 88 50 86 41 75 24 26 5 7 14 15 Placebo Erlotinib

Kelly et al., ASCO 2014

Median DFS 46.4 mos vs. 28.5 mos with placebo, p=0.0391

slide-16
SLIDE 16

SELECT: Study Design

2 years duration CT surveillance: - Every 6 mo x 3 years

  • Annually years 4 and 5

Observation Erlotinib 150 mg PO daily

Primary Endpoint:

  • Disease Free Survival:

Goal: 2-year >86% Secondary Endpoints:

  • Safety and Tolerability
  • Overall Survival

¨ Single arm Phase II study ¨ Adjuvant erlotinib following surgery and standard adjuvant therapy

  • Stage IA-IIIA NSCLC
  • Surgically resected
  • EGFR mutation

positive

  • Completed routine

adjuvant chemotherapy and/or XRT

slide-17
SLIDE 17

SELECT Results

  • 45% stage 1, 27% stage 2, 28% stage 3
  • 2/3 completed full 2 years of treatment
  • 2-year DFS was 89% compared to expected

76% in historical control (MSK cohort)

  • 29 recurrences, but only 4 on erlotinib
  • Most recurrent pts responded to rechallenge

with TKI, only 1 T790M+ on recurrence

  • DFS consistent with improvements seen in

retrospective cohort and RADIANT subgroup!

17

Pennell et al., ASCO 2014

slide-18
SLIDE 18

Ongoing Adjuvant Trials

  • NCI Cooperative group ALCHEMIST trials
  • Phase 2 trial of 3 yrs vs. 3 months of adjuvant

afatinib (NCCN; NCT01746251)

  • ADAURA Phase 3 trial of 3 yrs of adjuvant
  • simertinib versus placebo in stage IB-IIIA EGFR

mutant NSCLC (NCT02511106)

  • Japanese WJOG 6410L comparing 2 yrs of adjuvant

gefitinib vs. chemo for resected stage II to IIIA EGFR mutant NSCLC

  • Chinese C-TONG 1104 same design

18

slide-19
SLIDE 19

ALCHEMIST Design

19

https://www.allianceforclinicaltrialsinoncology.org/main/cmsfile?cmsPath=/Public/Alliance-Feature/files/ALCHEMIST-Slide-Deck-08182014.pdf

slide-20
SLIDE 20

Conclusions

  • Adjuvant EGFR TKIs in early stage EGFR

mutant NSCLC may improve DFS based on consistent signal in multiple studies

  • However, unclear if this will lead to improved

OS or cure rates and so not routinely recommended at this time

  • Support ALCHEMIST and other trials
  • Longer duration of therapy and more tolerable

drugs may be necessary (ADAURA?)

20

slide-21
SLIDE 21

Is there a role for targeted therapy in the adjuvant or neoadjuvant setting?

Nathan Pennell, M.D., Ph.D.

February 11, 2017