The advent of neoadjuvant therapy in malignant melanoma might prove to be practice changing. Though still in research yet OPACIN and Neo OPACIN trials have unraveled the potential of neoadjuvant immunotherapy in malignant melanoma

1. Neoadjuvant or Adjuvant
immunotherapy in high risk
melanoma – which is better?
Dr Sameer Rastogi
Associate Prof., Dept of Medical Oncology
Dr BRA IRCH, AIIMS, New Delhi
Email – samdoc_mamc@yahoo.com

2. Questions asked
• Adjuvant therapy and benefit – Single agent anti PD1
• Adjuvant therapy – the combination of anti PD1 and CTLA4 ?
• Neoadjuvant therapy – Rationale, Why, whom, which combination,
how many cycles, adjuvant therapy???

3. Keynote 054 trial – Pembrolizumab vs placebo
RFS = 59.1% vs 41%
Eggermont et al. Lancet 2021

5. Adjuvant Nivolumab vs ipilimumab –
checkmate 238
4 year RFS = 52% vs 41%

6. OS outcomes – checkmate 238
4 year OS – 77% in both
arms

7. Adjuvant therapies in stage III melanoma

8. Combination for adjuvant therapy ipilimumab
and nivolumab
• Checkmate 915
• Phase 3 trial
• Adjuvant nivolumab vs adjuvant nivolumab plus ipilimumab
• 2 year RFS = 64% vs 63 %
• No role of doublet in adjuvant setting
AACR Annual Meeting 2021; April 10-15, 2021; Virtual. Abstract CT004

9. Why/ whom/ which combination and what
dose/ till when/ benefit? /

10. Why neoadjuvant therapy ?
• Presence of full tumor mass at the start of immunotherapy – Induction of
broader and stronger T cell response
• Response to therapy can be established for an individual patient and can
be used for prognosis and further tailoring of adjuvant therapy
• Extensive surgery can be conceivably omitted in patients who achieve pCR
or CR. (more cost effective/ less morbidity)
• In BRAF positive patients – If there is progression on immunotherapy then
adjuvant BRAF therapy can be given
Rozeman et al. Lancet 2019

11. pCR in neoadjuvant melanoma trials
Category of pathologic response Pathologic findings
pCR Absence of viable cells
Near pCR More than 0% but 10% or less viable tumor cells
pPR More than 10% but 50% or less viable tumor cells
pNR More than 50% viable tumor cells

12. OPACIN trial– Neoadjuvant vs adjuvant check
point inhibitor – Macroscopic lymph node
involvement stage 3
• Co Primary objective-
safety and feasibility
• Comparison of immune
activating capacity of
neoadjuvant versus
adjuvant ipi plus
nivolumab.
Blank et al. Nature Medicine 2018

13. Neoadjuvant arm of OPACIN trial (n=10)
• 7/ 9 patients achieved pathological remission (78%) of 9 evaluable
patients
• NONE of THESE patients have relapsed after a median follow up of 32
months
• Toxicity was overwhelming with 9/10 patients developing Gr 3-4
toxicity in each arm. – Another schedule for the combination ??
2 cycles of NAIT might be sufficient
This schedule is too toxic and alternative schedule needs to
be explored. Since stage 3 melanoma have less immune
suppression- it might correspond to more immune toxicity

14. patients achieving pathological response n=7
pCR near pCR pPR
N=3
N=3
N=1

15. OPACIN-Neo study
To figure out
best schedule
Rozeman et al.
Lancet 2019

16. Primary end points
• Proportion of patients with grade 3–4 immune-related toxicity within
the first 12 weeks
• Proportion of patients achieving a radiological objective response
and pathological response at 6 weeks

17. Grade 3-4 events at 12 weeks
40% 20% 50%

18. Pathological response in OPACIN Neo trial
Depth of Response Arm A Arm B Arm C
Pathological Response 80% 77% 65%
Pathological CR 47% 57% 23%
Near complete pCR 23% 7% 23%
Pathologic partial response 10% 13% 19%

19. Patient who had responses outcomes

20. 2 cycles of immuno- Nivo 3mg/ kg and ipi 1mg / kg
Most tolerable with retained efficacy

21. Further therapy design? PRADO trial
Blank et al. Journal of
Clinical Oncology 38,
no. 15_suppl 2020

22. PRADO trial (preliminary results)
• In the entire study path response was seen in 71% (70 patients)
• 60 patients (61%) with MPR and 10 patients with p PR
• pNR was seen in 20%
• Using neoadjuvant immunotherapy TLND was omitted in 59 patients (60%)
• Additionally compared with patients treated with TlND, patients who
received index lymph node surgery alone reported less surgical adverse
events
• Longer follow up and full publication awaited Blank et al. Journal of
Clinical Oncology 38,
no. 15_suppl 2020

23. Summary of Neoadjuvant immunotherapy
• OPACIN trial – 2 cycles neoadjuvant immune therapy
• OPACIN –Neo- The schedule nivo – 3mg/kg and Ipi 1mg/kg
efficacious and tolerable
• PRADO – Further therapies – Extensive surgery can be avoided –
longer follow up for adjuvant treatment needed.
• OPACIN, OPACIN- Neo, PRADO- CR and nCR – Excellent surrogates
while radiological response underestimates pCR

24. The comparison
Adjuvant Neoadjuvant
Mature data available Data is young but exciting
Patients taken were relatively low risk (both with
micro and macroscopic lymph nodes)
Higher risk patients
Modest benefit and longer treatment needed Great benefit in patients with CR and nCR, shorter
treatment
No prognostic biomarkers Path response is excellent prognostic biomarker and
further therapy can be tailored specially in BRAF
mutated patients
10-20% patients progress before immunotherapy is
started in various trials
can start systemic therapy earlier
Less cost effective and longer treatment Shorter treatment in at least 60% of patients