asco poster review pancreatic cancer -...

Oncologia Medica AIOM post ASCO

Roma 16-17 febbraio 2018

ASCO Poster Review

PANCREATIC CANCER

Dr.ssa Michela Squadroni

U.O. Oncologia

Humanitas Gavazzeni – Bergamo



TOPICAL ISSUES

Gemcitabine/Nab-paclitaxel and FOLFIRINOX

comparison

Neoadjuvant and perioperative treatment

New drugs, immunotherapy

Genomics and molecular biology



Gemcitabine-Nabpaclitaxel and

FOLFIRINOX comparison (first line)

Potential first line treatment: FOLFIRINOX or Gemcitabine and Nab-paclitaxel

Which one should we use?

No comparative prospective trial

•861 patients with metastatic pancreatic cancer

•Median OS 8.5 vs 6.7 months (Gem/Nab-paclitaxel vs Gem)

•342 patients with metastatic/locally advanced pancreatic cancer

•Median OS 11.1 vs 6.8 months (FOLFIRINOX vs Gem)



Retrospective cohort study from US oncologist record

PATIENTS selection:

• Metastatic pancreatic cancer

• Treated from april to december 2015 with Gem/Nab-paclitaxel or FOLFIRINOX

• Not enrolled in clinical trial

COMPARISON

• First line therapy: Gem/Nab-paclitaxel vs FOLFIRINOX

• Second line therapy: Gem/Nab-paclitaxel vs FOLFIRINOX treated with second line

654 patients analyzed, median follow-up 10.7 months

• Gem/Nab-paclitaxel: 337 (51.5%) vs FOLFIRINOX: 317 (48.5%)

Kim S. et al



RESULTS Patients treated with gem-abraxane were

•Older (median age 64 vs 59)

•Worst clinical condition(ECOG 2 27.9% vs 9.2%; more comorbidities) than

patients treated with FOLFIRINOX

•Similar percentage of second line chemotherapy (36.1 vs 41% gem abraxane vs

FOLFIRINOX)

Toxicity: incidence of any grade 3-4 toxicity were similar in Gem-Abraxane and

FOLFIRINOX (35% vs 33.6%, p 0.57). Nausea/vomiting, diarrhea, stomatitis and

fatigue more frequent in FOLFIRINOX

Non statistically significant difference in term of OS by first and second line between

Gem-Abraxane and FOLFIRINOX



Gemcitabine-Nabpaclitaxel and

FOLFIRINOX comparison (second line)

30-40% of patients do not receive second line chemotherapy

Many phase II trials and retrospective analysis

Nanoliposomal irinotecan is the only validated drug for second line

chemotherapy (NAPOLI-1 Wang-Gillam et al; Lancet 2016)

•417 patients randomized, 117 5FU+NALIRI, 151 NALIRI, 151 5FU

•Median OS 6.1 vs 4.2 months (5FU/NALIRI vs 5FU)

•No difference between monotherapy (NALIRI and 5FU)



FOLFIRINOX or Nab-Paclitaxel based second line?

Phase II and retrospectitve data supporting potential role of both

FOLFIRINOX and Nab-paclitaxel based chemotherapy in second line

setting



AIM of the study

Comparison of second line mFOLFIRINOX after Gem/Abraxane and Gem/Nab-paclitaxel after

mFOLFIRINOX

Similar patients characteristics (age, ECOG performance Status, metastatic sites, primary tumor

site and biliary stent presence)

GnP

N=25



RESULTS

No statistically significant difference in term of OS and PFS and DCR



Neoadjuvant and perioperative therapy

Phase II trials, retrospective analysis and meta analysis support

neoadjuvant treatment (chemotherapy and chemoradiotherapy)

Phase III trials are ongoing

Adjuvant chemotherapy improves survival in pts treated with preoperative

treatment (Roland et al; Ann Surg Oncol 2015)

Why neoadjuvant?

•Patients selection

•Tumor shrinkage to improve R0 resection rate

•Better delivery of chemotherapy and radiotherapy



Neoadjuvant therapy

Neoadjuvant therapy is not a standard yet, but it should be considered in

locally advanced and border line resectable pancreatic cancer (3rd St. Gallen

Gastrointestinal Cancer Conference; 2017)



Neoadjuvant therapy

UNSOLVED QUESTIONS

Which chemotherapy

Chemotherapy alone or chemoradiotherapy

Treatment duration

Postoperative treatment



Interim analysis About 70% in both arms had borderline resectable disease

After induction chemotherapy 22.6 % of patients discontinued therapy (mainly progressive disease, and

adverse events)

68% of patients completed treatment after randomization

No survival data available

Preliminary results of randomized patients

Arm A

nabPac/Gem

(N=42)

ARMB

FOLFIRINOX

(N=44)

DCR (%) 93 89

PD(%) 7 11

Exploratory laparotomy (%) 55 48

R0/R1 resection (%) 26 29

RO/R1 resection (of surgically

explored pts)

11/23 13/21

CONCLUSIONS

Both FOLFIRINOX and nabPac/Gem are effective and feasible

High disease control rate (90%)

Promising surgical conversion rates

RESULTS



AIM of the study: evaluate the impact of neoadjuvant chemoradiotherapy (NACRT) on

perioperative and long term clinical outcome

Retrospective analysis

290 pts from 2006 to 2016: 160 treated with neoadjuvant CRT and 130 with upfront surgery)

Of 160 NACRT pts

•153 completed treatment (96%)

•139 underwent surgery (87%)



RESULTS

CONCLUSIONS High rate of treatment completion (96%)

Long term better survival in NACRT (with the exception of arterial invasive tumor)

Favourable pathological effect (lower N+ rate and higher R0 resection rate)



Potential novel therapy

New chemotherapy combinations

Biological agents

Moleculer/genomics driven treatment

Immunotherapy



Novel Chemotherapy Combination



Multicentric phase I/II trial investigating the substituion of CPT11 or Oxaliplatin with Nab-paclitaxel in

FOLFIRINOX

Primary Endpoint: To assess the activity of NabFOLFIRI and NabFOLFOX in first line in term of ORR

Secondary Endpoint: Clinical Benefit, PFS, OS, Safety profile

Inclusion Criteria:

Age >18 and < 75 years

Metastatic disease

Non prior chemotherapy o radiotherapy for advanced cancer

Performance Status ECOG 0-1



RESULTS

TUMOR ASSESSMENT

Best Overall

Response

Arm A

(Nab-FOLFIRI) %(N)

ArmB

(Nab-FOLFOX)

CR 0 0

PR 31%(13) 31%(13)

SD 38%(16) 49%(17)

PD 26%(11) 12%(5)

Not assessed 5%(2) 12%(5%)

CBR (CR+PR+SD) 69%(29) 71%(30%)

•No significant difference in term of CBR and ORR

•Grade 3 toxicity was 24% and 50% for NabFOLFIRI

and nabFOLFOX respectively

•Grade 4 toxicity was 17% and 5% for NabFOLFIRI

and nabFOLFOX respectively

Nab-FOLFIRI PFS 6 month, OS 13.6 months

Nab-FOLFOX PFS 5.6 months, OS 10.5 months

CONCLUSION NabFOLFIRI and NabFOLFOX could represent a potential alternative firts line CT

(achieving similar OS and PFS rate of FOLFIRINOX; with lower toxicity rate)

Need for further investigation and validation (phase III trial)



Immunotherapy?



Analyzing the efficacy and safety of immunotherapy in pancreatic ductal

adenocarcinoma (PDA): a systematic review and meta-analysis Babiker HM, et al.

Meta-analysis and review of published and

presented data of immunotherapy in pancreatic

cancer

Many data derive from ongoing trials (16%)

or abstract (44%)

Fifty four trials met criteria for further analysis

(39 metastic, 12 adjuvant and 3 neoadjuvant)

Modest activity and inconclusive data

Need for further investigation !



Pancreatic cancer microenvironment

•Pancreatic stellate cells and fibroblasts: produce ECM

(collagen ,laminin, fibronectin). Reduce therapeutic sensitivity

•Inflammatory fibroblasts (CAF: cancer asociated fibroblasts):

CAFs promote tumor growth and favour immunosuppression

•Myeloid cells: induce dense stromal cell reaction, and

immunosoppressive microenvoronment. Immune infiltrate is

mainly constituted by myeloid suppressor cells. Possible

correlation with fibrosis

•T cells: not clear correlation and presence in pancreatic cancer.

About a quarter present CD4 and CD8, but functional cells are

rare

No benefit from T cell regulatory immunotherapy

Possibility to enhance immunotherapy acitivy in pancreatic cancer

Use of chemotherapy to enhance antigen expression

Repletion of myeloid cells (in order to reduce fibrosis and imunosuppression)

Recruitment and augmentation of T cells expressione



Immunotherapy?



Rational for immunotherapy and chemotherapy in pancreatic cancer

Durvalumab: specific binding PD L-1 Tremelimumab: anti CTLA-4 antibody

Cancer associated fibroblast (CAF)reduce immunotherapy activity and nab paclitaxel induce CAF depletion

Chemotherapy may induce antigens expression

Double immunotherapy (anti PDL1 and CTLA-4) has sinergistic activity in mouse models

Phase II randomized trial of double immunotherapy (Durvalumab and Tremelimumab) + Chemotherapy

(gemcitabine/Nab-paclitaxel) vs Gemcitabine /Nab-paclitaxel

PRIMARY ENDPOINT: Overall Survival

SECONDARY ENDPOINT: PFS, ORR, safety and toxicity



RESULTS

Preliminary data from safety run in (11 patients enrolled)

Median follow-up of 8.3 months

Toxicity:

1 patient had grade 3 colitis

Most common grade 2 toxicity:fatigue, anemia, abnormal WBC and lipase, hyponatremia

Efficacy:

8/11 (73%) had partial response, median duration of 7.4 months

Median PFS 7.9 months

Median OS not reached, 6 Months survival rate 80%

CONCLUSION

Data of safety run in showed interesting acivity and acceptable toxicity profile

Phase II trial is ongoing (planned enrollment of 130 patients)



Genetic profile of pancreatic cancer

•Most common genetic mutation: KRAS, TP53, CDKN2A, SMAD4, RNF43, ARID1A, TGFbR2, GNAS, RREB1,

and PBRM1

•KRAS mutation in > 90% pancreatic cancer

•10% harbor mutation in BRCA1/2, PALB 2 and ATM

•MMR gene mutation could be observed

•BRAF mutation and mTOR pathway activation are frequent in KRAS WT



Pihlak R. et al. Cancers 2018

Potential therapeutic target

-BRCA, PALB2 (platinum sensitivity,

potential PARP inhibitor sensitivity)

-BRAF

-Currently no other potential target

Therapeutical and clinical implication

BAYLEY (Nature 2016):

- Squamous and adenosquamous

- Pancreatic progenitor

- Immunogenic

- ADEX (aberrantly differentiated

endocrine exocrine)

WADDEL (Nature 2015)

- Stable

- Scaterred

- Locall rearranged

- Unstable.

MOFFITT

- Basal like

- Classical

PROPOSED GENOMIC CLASSIFICATION On the basis of mutational status and clinical characteristics



Genomic and molecular biology



BACKGROUND AND AIM OFTHE STUDY

Pancreatic cancer can have BRCA 1/2 mutation and other homologous

recombinant paththway genes.

AIM of the study is to investigate the therapeuthic prognostic significance of

these mutations

3030 patients analyzed comparing carriers and non carrieris of BRCA 1/2,

PALB2 and ATM deletereous mutations (4.6% of patients had germline mutation)

Comparison of clinical outcome with chemotherapy according to mutational

status



RESULTS

Survival benefit slightly better in patients with mutation (14.3 vs 11.3 months, p=0.07)

When analyzed post-FOLFIRINOX era, 40 patients with these mutation had better outcome than 668

non carriers (adjusted HR 0.62, p=0.0062)

Relative distribution of BRAC1/2, PALB and

ATM mutations in 139 (4.6%) patients with

deletereous mutations

CONCLUSIONS

BRCA1/2, PALB2 and ATM mutation is present in about 5% of patients,

In post-FOLFIRINOX era pts with mutation had longer survival

Development of trial incorporating this information could have potential value for PDAC (olaparib?

Other treatment)



MultiOmic: gemonic,proteomic and phspoproteomic analysis

AIM of the study: to define frequency of genetic and proteomic mutation in

primary tumor and metastatic site and identify potential differences between

them

To explore potential moleculal target for treatment

Methods

505 patients, tumor sample analyzed according to Perthera reports

182 primary sites and 323 metastatic site



RESULTS

The 4 most common mutations seen in pancreatic cancer (SMAD4, CDKN2Am

p53 and KRS ) were similar between primary and metastatic site

Proportion of actionable mutations was similar between groups

Within metastatic site specific tissue pattern expression was observed (liver vs

lung higher TUBB3 and lower PTEN mutation)

CONCLUSION

No statistically significant difference in specific gene mutation observed between

primary tumor and metastatic site

Confirm the reason of early metastatization

Potential molecular target even in early disease

Non need for rebiopsy



CONCLUSION

• Gemcitabine-Nabpaclitaxel and FOLFIRINOX comparison

o Comparison in real life shows similar activity both in first and second line

o NB different patients characteristics and toxicity profile

• Neoadjuvant and perioperative treatment

o FOLFIRINOX and Gem-Nabpaclitaxel potentially active in LAPC

o Long term benefit confirmed with preoperative CT-RT

o New treatment/schedules under investigation (Gem/Nabp+RT) and Phase III

clinicl trial

• New drugs, immunotherapy

o Nab FOLFOx/Nab FOLFIRI

o Excaping immunotherapy resistance (immunotherapy and chemotherapy

combination)

o Other moleculer treatment under evaluation (immunotherapy , olaparib)

• Genomics and molecular biology

o Prognostic and predictive role

o Potential molecular target identification

asco poster review pancreatic cancer -...

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