Disclosures I have no relevant exposures. Companies are smart. The - - PDF document

7/31/2014 1 Winship Cancer Institute of Emory University

Off Protocol Adjuvant TKI therapy for driver mutations in early‐stage NSCLC after systemic chemotherapy‐No!

Fadlo Raja Khuri, MD Professor and Chair, Department of Hematology & Medical Oncology Deputy Director, Winship Cancer Institute of Emory University Roberto C. Goizueta Chair in Cancer Research

Debates and Didactics in Hematology and Medical Oncology Sea Island, GA August 9, 2014

Disclosures

• I have no relevant exposures.
• Companies are smart. The prefer Ram’s
• pinions over mine!

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RADIANT Trial Design

ASCO 2014

RADIANT: Historical Context

ASCO 2014

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Disease-free Survival KM Plot

ASCO 2014

Sites of Relapse (>5%)

ASCO 2014

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Overall Survival KM Plot

ASCO 2014

Drug Exposure

ASCO 2014

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Drug Exposure: EGFR M+

ASCO 2014

Safety: EGFR M+

ASCO 2014

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Slide 22

ASCO 2014

Slide 24

ASCO 2014

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Outcomes Secondary Endpoint in EGFR mutated subgroup

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Perspective on adjuvant EGFR TKI Phase III trial of Adjuvant Gefitinib: NCI-C BR19 trial<br />Goss et al, JCO 2013; 31(27):3320-6

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BR-19: Adjuvant gefitinib in unselected population MSKCC experience<br />Janjigian et al, JTO 2011;March 6(3):569-575<br />

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Adjuvant EGFR TKI SELECT phase II study<br />Pennell et al, ASCO 2014, abstract 7514

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SELECT results Perspective on adjuvant targeted agents FDA approved in the U.S.

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Questions to consider CTONG1104: A national, multi center, randomized, open-label, phase III trial of gefitinib versus combination of vinorelbine plus platinum as adjuvant treatment in pathological stage II- IIIA(N1-N2) NSCLC with EGFR activating mutation (ADJUVANT)

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IMPACT: WJOG6410L<br />Iressa for Mutation Positive lung cancer as Adjuvant ChemoTherapy <br />(A randomized phase III trial of adjuvant gefitinib versus cisplatin and vinorelbine in completely resected (stage II-III) NSCLC patients with mutated EGFR)

ALCHEMIST (Adjuvant Lung Cancer Enrichment Marker Identification And Sequencing Trial) Umbrella Protocol Will Screen Patients

Trial Category A151216 ALCHEMIST E5412 A081105

Target Registry/Intervention with biopsy at recurrence ALK+ EGFR mut Prevalence all comers ~5% ~10% Total Sample Size 6000 – 8000 378 (5% inflation) 430 (5% ineligible) Primary Endpoint N/A Overall Survival Overall Survival Power N/A 80% 85% One-sided α N/A 0.05 0.05 Hazard Ratio N/A 0.67 0.67

Doroshow JH. Available at: deainfo.nci.nih/gov/advisory/ncab/164_1213/Doroshow.pdf. Accessed May 14, 2014. 26

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Decision Tree for Adjuvant Therapy for NSCLC: Utilization of Data to positively impact outcomes

• Personalization of care by histology (pemetrexed

and possible bevacizumab) for nonsquamous

• Molecular markers

– ERCC1, etc, not helpful – EGFR and ALK testing critical at the time of surgery

• Support ALCHEMIST by referring and enrolling

patients with EGFR and ALK mutation carrying tumors

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Conclusions

• No evidence yet that adjuvant targeted

therapy even in patients whose tumors have driver mutations adds to cure.

• No reason to over-interpret secondary

analyses when there is no survival benefit!

• Giving drugs earlier is not necessarily better

unless you can impact overall survival (still the Gold Standard).

• Dr. Ramalingam is the PI of ALCHEMIST and

he knows the right answer here. He stated it at ASCO 2014!

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Final Conclusion

• Careful planning and data interpretation

always beats over-rating what data or players you have!