When to Treat Beyond Progression with Systemic Therapies? Manuela Schmidinger Medical University of Vienna, Austria

Is Treatment Beyond Progression a Valid Strategy? 1) NO YES?

Is Treatment Beyond Progression a Valid Strategy? SWITCHING TREATMENT 1) Is what most patients would want: new drug= new hope

Is Treatment Beyond Progression a Valid Strategy? SWITCHING TREATMENT 1) Is what most patients would want: new drug= new hope 2) Will most likely also comfort the treating physician (for the same reasons) 3) May be biologically reasonable and promising when the next drug inhibits targets that have been linked to resistance and progression

1. Paez-Ribes M et al., Cancer Cell 2009 March 3;15(3);220-231 Antiangiogenic Therapy Elicit Increased Local Invasion and Distant Metastasis 1 Pàez-Ribes et al. Page 21 Tumors first respond to VEGF(R)- inhibitors: stasis or regression and loss of vasculatur Induction of a hypoxic microenvironment (occurrence of resistance, epithelial to mesenchymal transition) Figure 8. Adaptive-Evasive Responses by Tumors to Antiangiogenic Therapies Schematic summary of adaptive responses to VEGF/VEGFR inhibitors (and likely other angiogenesis inhibitors) that elicit evasive resistance. Tumors respond to VEGF/VEGFR pathway inhibition with tumor stasis or regression and a loss of blood vessels, but mechanisms of evasive resistance to the antiangiogenic treatment are then induced that can variously enable revascularization via alternative proangiogenic signals, increased local invasiveness, and/or enhanced distant metastasis. Various VEGF-independent mechanisms enable revascularization and progression Switching to an agent that does not primarily target VEGF appears reasonable

Success Demonstrated with Biologically Reasonable Strategies Cabozantinib is an oral small molecule inhibitor of tyrosine kinases including MET, VEGF receptors, and AXL 3 Increased MET and AXL expression has been associated with poor prognosis and resistance to VEGFR inhibitors in RCC 1,2 4 1 Zhou L et al., Oncogene, 2015; 2 Ciamporcero E et al., Mol Cancer Ther, 2014; 3 Yakes FM et al., Mol Cancer Ther, 2011 ; 4. Choueiri TK et al,, N Engl J Med 2015

Is Treatment Beyond Progression a Valid Strategy? SWITCHING TREATMENT 1) Is what most patients would want: new drug= new hope 2) Will most likely also the treating physician (for the same reasons) 3) May be biologically reasonable and promising when the next drug inhibits targets that have been linked to resistance and progression 4) Is tempting if second-line studies are available and open for accrual 5) Is supported by guidelines

Treatment Guidelines for mrcc Treatment group Standard Option First line Good or intermediate risk Sunitinib [I,A] Bevacizumab + IFN-α [I,A] Pazopanib [I,A] High-dose IL-2 [III,C] Sorafenib [II,B] Bevacizumab + low-dose IFN-α [III,A] Poor risk Temsirolimus [II,A] Sunitinib [II,B] Sorafenib [III,B] Second line Post-cytokines Post-TKIs Axitinib [I,A] Sorafenib [I,A] Pazopanib [II,A] Axitinib [I,B] Everolimus [II,A] Sunitinib [III,A] Sorafenib [II,A] Nivolumab Cabozantinib Post-two TKIs Everolimus [II,A] Third line Post-TKI and mtor inhibitor Sorafenib [I,B] Other TKI [IV,B] Rechallenge [IV,B] IFN-α, interferon-α; IL, interleukin; VEGFR, VEGF receptor Escudier et al. Ann Oncol 2014

...But Can We Maintain a Treatment Beyond Progression? SWITCHING TREATMENT MAINTAINING TREATMENT 1) Is what most patients would want: new drug= new hope 2) Will most likely also comfort the treating physician (for the same reasons) 3) May be biologically reasonable and promising when the next drug inhibits targets that have been linked to resistance and progression 4) Is tempting if second-line studies are available and open for accrual 5) Is supported by guidelines

...But Can We Maintain a Treatment Beyond Progression? SWITCHING TREATMENT 1) Is what most patients would want: new drug= new hope 2) Is most likely a strategy to comfort the treating physician (for the same reasons) 3) May be biologically reasonable and promising when the next drug inhibits targets that have been linked to resistance and progression 4) Is tempting if second-line studies are available and open for accrual 5) Is supported by guidelines MAINTAINING TREATMENT 1) Evidence against?

Evidence (and What We Believe in) Depends on What Has Been Investigated

Former second-line studies did not include a treatment arm with the first-line agent given beyond progression Eligibility criteria: Histologically confirmed mrcc with clear cell component Failure of prior first-line regimen containing 1 of: Sunitinib Bevacizumab + IFN-α Temsirolimus Cytokine(s) N=741 R A N D O M I S A T I O N e.g. Sunitinib beyond progression Axitinib 5 mg BID Sorafenib 400 mg BID www.clinicaltrials.gov (NCT00920816)

Analysis of the Growth Rate of RCC while Sunitinib Treatment Sunitinib more effectively reduce the growth rate of RCC when comapred with IFN-alpha this reduction was correlated with better PFS and OS 1 Sunitinib treatment is also associated with prolonged stability of growth rate 2 Growth rate over time for 234 patients who had evidence of tumor growth: Tumor growth rates remained stable in the overwhelming majority 1.SteinWD et al., Clin Cancer Res ; 18(8) April 15, 2012; 2.Burotto M et al., PLOS/one May 2014, Vol 9; Issu 5, e96316.

Using the median estimated growth rate and regression rate constants: theoretical curves depicting tumor quantity over time This allows to estimate the fraction of tumor at any given point in time that is still sensitive to therapy (blue line) A projected PFS of 7.3 months would be a valid treatment option in second-line Burotto M et al., PLOS/one May 2014, Vol 9; Issu 5, e96316

Patient CG Male patient, 28 years at diagnosis, dramatic weight loss since June 2012 December 2012: palpable tumor mass, diagnosis RCC Radical nephrectomy and cavotomy: pt4, Nx, G4, Vimentin positive, clear cell with necrosis and >80 % sarcomatoid percentage Few weeks after surgery: CRP, thrombocytosis; CTs: multiple 7 cm tumor masses at the site of nephrectomy, infiltration M. psoas, displacement of intestines Multiple lesions in M. quadratus lumborum 17 mm lesion between abdominal wall and colon ascendens Subcutaneous mets Liver mets Lung mets

Patient CG 1st-line Sunitinib: 50 mg April 2013 Major improvement in performance status, decrease of CRP and thrombocytosis Reports on tumor-associated symptoms during breaks, therefore 50 mg continuously Best response: RECIST SD (minor remission) Remained on first-line sunitinib for 12 months because withdrawal of treatment associated with pain, night sweats and fever

Rapid disease progression and deterioration of performance status at treatment discontinuation Short before sorafenib discontinuation 1 week after sorafenib discontinuation CT before second stop of sorafenib CT after final sorafenib discontinuation Desar IM et al., 2009 Acta Oncologica, 48:6,927-931

Mixed Responses The underlying biology of this phenomenon is poorly understood Pseudoprogression? Intratumor heterogeneity 1? Differences in site-specific TME, e.g excellent response of pancreatic metastases and poor response to LN-metastases 2?... Gerlinger M et al., New Engl J Med 2012; 2. Grassi P et al., Future Oncol 2014; 10(8), 1361-1372

64 yrs old Patient April 2016 with cc-mrcc Before Sunitinib 3 months after sunitinib

Before Sunitinib 3 months after sunitinib

Clinical Considerations in Patients with Mixed Response We will not be able to identify and target all new drivers of the disease, It might be difficult to optimize/influence the TME Why not maintaining a treatment that controls effectively some areas or the larger amount of metastases? and adding a local treatment for those metastases that do not behave?

Stereotactic Body Radiotherapy for Oligometastatic RCC as a Bridge Therapy to Delay Systemic treatment or to Delay Change of Systemic Treatment? Lesion-based control after SBRT Overall survival for all patients Ranck MC et al., Am J Clin Oncol 36, 6; December 2013

Adding a Local Treatment and Maintaining Systemic Treatment: Particularly useful in the case of stable extracerebral disease and newly diagnosed brain mets Degree of sunitinib penetration through the BAB and BBB is very low (< 5%) 1 Local control of BM by local treatment 1.Sobanska K et al., European review for medical and Pharmacol Sciences 2016; 20: 166-173; 2.Ippen FM and Mahadevan A et al; J Oncol 2015

Maintaining Treatment AND Overcoming Resistance: Alternative Strategy? WAIT Interrupting treatment on which progression and epithelial to mesenchymal transition 1 has occurred may allow the TME to reset Tumor may regain sensitivity to sunitinib 2 ESCALATE 1. Hammers HJ et al., Mol Cancer Ther 2010; 2. Hammers HJ et al., Mol Cancer Ther 2010

Vorher Nachher

Maintaining Treatment AND Overcoming Resistance: Alternative Strategy? WAIT Interrupting treatment on which progression and epithelial to mesenchymal transition has occurred may allow the TME to reset 1 Tumor may regain sensitivity to sunitinib 2 ESCALATE Experiments conducted in xenografts and patients revealed that resistance can be overcome by dose escalation at the time point of disease progression 3 1. Bergers G and Hanahan D: Nat Rec Cancer 2008 ; 2. Hammers HJ et al., Mol Cancer Ther 2010; 3. Pili J Clin Oncol 2013

Patient FR courtesy of Dr. Ponhold April 2013 July 2013

...Can We Maintain a Treatment Beyond Progression? SWITCHING TREATMENT 1) Is what most patients would want: new drug= new hope 2) Is most likely a strategy to comfort the treating physician (for the same reasons) 3) May be biologically reasonable and promising when the next drug inhibits targets that have been linked to resistance and progression 4) Is tempting if second-line studies are available and open for accrual 5) Is supported by guidelines MAINTAINING TREATMENT 1) Evidence against? 2) RECIST: quantifies PD but : clinical evidence that this quantity is a clinically valid EP that should result in change of tx? 3) Clinical reasons 4) Mixed responses 5) Overcoming resistance is possible 6) Pseudoprogression

A New Challenge: PD-1 Inhibitors Do Not Move Progression-free survival Progression-Free Survival (Probability) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Everolimus Median PFS, months (95% CI) Nivolumab 4.6 (3.7 5.4) Everolimus 4.4 (3.7 5.5) HR (95% CI): 0.88 (0.75 1.03) P = 0.1135 Nivolumab 0 3 6 9 12 15 18 21 24 27 30 No. of patients at risk Months Nivolumab 410 230 145 116 81 66 48 29 11 4 0 Everolimus 411 227 129 97 61 47 25 16 3 0 0 In a post-hoc analysis of patients who had not progressed or died at 6 months, median PFS was 15.6 months for nivolumab vs 11.7 months for everolimus (HR (95% CI): 0.64 (0.47 0.88))

But Overall Survival Appears to Improve with Treatment Beyond Progression 1.0 0.9 0.8 0.7 Median OS, months (95% CI) Treated beyond progression (N = 36) Not treated beyond progression (N = 92) 30.5 (18.1 41.1) 15.2 (11.6 23.4) 0.6 Patients treated beyond progression 0.5 0.4 0.3 Censored Patients treated beyond progression Patients no treated beyond progression 0.2 0.1 0.0 Patients not treated beyond progression 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 Months 36 36 36 34 29 26 24 22 21 19 18 16 14 10 3 0 92 83 69 60 53 47 43 38 35 26 23 23 19 7 2 0 38

A challenge in mrcc patients undergoing check-point inhibitor treatment Tumor flaire phenomenon? How to deal with progression Progression of tumor cells that regained sensitivity for VEGF-I? TX beyond PD Pseudoprogression? RCC is a VEGF-driven disease TX beyond PD and adding a VEGF-I? Switching?

Are Second-Line Agents Easily Available Everywhere? E.g. Axitinib approval and launch status

Nivolumab RCC EMA Approval and Availability Challenging reimbursement situation in most CECOG countries Bulgaria Croatia Cyprus Czech Republic Estonia Greece Hungary Latvia Lithuania Poland Portugal Rumania Slovakia Slovenia

Treatment Beyond Progression is a Valid Strategy May be justified if: Acceptable treatment tolerance AND Clinical benefit AND Clinical need (symptoms upon discontinuation) OR Slow progression OR Mixed response (de novo brain mets and stable extracerebral disease or mixed response in extracerebral metastases) OR Room for dose escalation OR If progression occurs after a treatment break OR If pseudoprogression is suspected OR Any of the situations above AND limited drug availability/limited resources OR/AND If no clinical study open for accrual/no new drug available