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El tratamiento actual de primera línea en CPNCP. EGFR mutado: balance entre eficacia/perfil de tolerancia
Manuel Dómine
Servicio de Oncología Médica. Hospital Universitario Fundación Jiménez Díaz
Instituto de Investigación Sanitaria- Fundación Jiménez Díaz (IIS-FJD).
• 17,664 patients with
NSCLC
• A genetic alteration
was recorded in about
50% of the analyses
• Presence of a genetic
alteration compared
with absence of a
genetic alteration was
associated with
improved:
first-line progression-
free survival (10·0
months [95% CI 9·2-
10·7] vs 7·1 months
[6·1-7·9]; p<0·0001)
overall survival (16·5
months [15·0-18·3] vs
11·8 months [10·1-
13·5]; p<0·0001)
Estudios Randomizados TKIs Vs Quimioterapia en pacientes con
mutaciones EGFR (TKIs 1ª generación)
Gefitinib
Estudio/ Fase Ramas de tratamiento Nºpacientes
(región) RR ( (%)
p m SLP
(meses) HR p
Supervivencia
SM (meses)
HR p
IPASS 1 2/III Gefitinib vs Carbo-taxol 261 Asia
71.2 vs 47.3 p<0.001
9.5 vs 6.3 0.48
p<0.001
21.6 vs 21.9
1
p= 0.990
First-SIGNAL 3/III Gefitinib vs Cis-gem 96
Corea 84.6 vs 37.5
p= 0.002 8.5 vs 6.7
0.54 p= 0.086
27.2 vs 25.6
1.043
p=0.428
WJTOC 3405 4 5/III Gefitinib vs Cis-docetaxel
177 Japón
62.1 vs 32.2 p< 0.0001
9.2 vs 6.3 0.488
p< 0.0001
36 vs 39
1.19
p= 0.443
NEJ002 6 7 /III Gefitinib vs Carbo-taxol
230 Japón
73.7 vs 30.7 p<0.001
10.4 vs 5.4
0.30 p<0.001
27.7 vs 26.6
0.887 p=0.483
RR: tasa de respuestas, mSLP: mediana de Supervivencia libre de progresión, SM: Supervivencia Mediana NR: no reportado
Estudios Randomizados TKIs Vs Quimioterapia en pacientes con
mutaciones EGFR (TKIs 1ª generación)
Erlotinib
Estudio/ Fase Ramas de tratamiento Nºpacientes
(región) RR ( (%)
p m SLP
(meses) HR p
Supervivencia
SM (meses)
HR p
OPTIMAL 8 9/III Erlotinib vs carbo-gem 154
China
83 vs 36
p< 0.0001
13.1 vs 4.6
0.16 p< 0.0001
22.8 vs 27.2
1.19 p = 0.2663
EURTAC 10/III Erlotinib vs cis-docetaxel 174
Europa 58 vs 15
p< 0.0001 9.7 vs 5.2
0.37 p< 0.0001
19.3 vs 19.5
1.04 p=0.87
ENSURE 11/III Erlotinib vs cis-gem 148 Asia
62.7 vs 33.6 p< 0.0001
11 vs 5.25 0.34
p< 0.0001
26.3 vs 25.5
0.91
p=0.607
RR: tasa de respuestas, mSLP: mediana de Supervivencia libre de progresión, SM: Supervivencia Mediana NR: no reportado
Estudios Randomizados TKIs Vs Quimioterapia en pacientes con
mutaciones EGFR (TKIs 2ª generación)
(Afatinib)
Estudio/ Fase
Ramas de tratamiento
Nºpacientes (región)
RR ( (%) p
m SLP (meses)
HR p
Supervivencia SM
(meses)
HR p
LUX-LUNG 3/III Afatinib vs Cis-pem 345
Global 345
Global 11.1 vs 6.9
0.58 p= 0.001
28.2 vs 28.2
0.88
p=0.39
LUX-LUNG 6 /III Afatinib vs Cis-gem
364 China
67 vs 23 p< 0.0001
11 vs 5.6
0.28 p< 0.001
23.1 vs 23.5
0.93
p=061
RR: tasa de respuestas, mSLP: mediana de Supervivencia libre de progresión, SM: Supervivencia Mediana NR: no reportado
L858R Del19
Del19 and L858R Subgroups
Combined OS analysis of LUX-lung 3 and LUX- lung 6 *
0.2
0.4
0.6
0.8
1.0
Estim
ate
d O
S p
rob
ab
ility
0.0
0 6 9 12 15 18 21 24 27 3 30 33 36 39 42 45 48 51
Time of overall survival (months)
Afatinib Chemotherapy
Del19
Afatinib (n=236)
Chemo (n=119)
Median, months 31.7 20.7
HR (95% CI)
P value
0.59 (0.45-0.77)
P=0.0001
L858R
Afatinib (n=183)
Chemo (n=93)
Median, months 22.1 26.9
HR (95% CI)
P value
1.25 (0.92-1.71)
P=0.1600
0 6 9 12 15 18 21 24 27
Time of overall survival (months)
0.0
3 30 33 36 39 42 45 48 51
0.4
0.6
0.8
1.0
Estim
ate
d O
S p
rob
ab
ility
0.2
Afatinib Chemotherapy
No. of patients:
Afatinib 183 181 167 154 141 128 11 91 80 70 64 51 27 20 11 30 0 0
Chemotherapy 93 86 82 78 75 69 61 55 50 40 32 25 20 14 9 4 1 0
No. of patients:
Afatinib 236 230 223 217 202 192 173 160 145 131 117 90 50 38 22 6 1 0
Chemotherapy 119 113 103 95 87 72 63 55 51 43 38 27 14 9 1 1 0 0
*Yang et al. Lancet Oncology 2015
LUX-LUNG 7 STUDY DESIGN
Co-primary endpoints:
• PFS (independent review)
• TTF • OS
Secondary endpoints:
• ORR • Time to response • Duration of response • Tumour shrinkage • HRQoL
1:1
Patients (N=319)
• Stage IIIB/IV adenocarcinoma of the lung
• EGFR mutation (Del19 and/or L858R) in the tumour tissue*
• No prior treatment for advanced/metastatic disease
• ECOG PS 0/1
Stratified by
• Mutation type (Del19/L858R)
•Brain metastases (present/absent)
Afatinib
40 mg QD†
Gefitinib
250 mg QD
Treatment beyond progression allowed if deemed beneficial by investigator
RECIST assessment performed at Weeks 4, 8 and every 8 weeks thereafter until Week 64, and every 12 weeks thereafter
Primary PFS analysis conducted after ~250 events; primary OS analysis conducted after ~213 events and ≥32-mo follow-up
All statistical testing at two-sided 5% alpha level with no adjustment for multiplicity
PFS by Independent Review
No. at risk:
Afatinib 160 142 112 94 67 47 34 27 21 13 6 3 1 0 0
Gefitinib 159 132 106 83 52 22 14 9 7 5 3 3 1 1 0
1.0
0.8
0.6
0.4
0.2
0
0
Time of progression free survival (months)
Esti
mat
ed P
FS p
rob
abili
ty
Afatinib Gefitinib
Median, mo 11.0 10.9
HR (95% CI) P-value
0.73 (0.57-0.95) 0.0165
27%*
18%†
15% 8%
3 6 9 12 15 18 21 24 27 30 33 36 39 42
Afatinib
Gefitinib
Park K et al. Lancet Oncol. 2016;17(5):577-89; * P=0.0176 †. P=0.0184
PFS by Mutation Type (Independent Review) Del19
No. at risk:
Afatinib 93 83 67 58 43 31 22 18 14 9 4 2 1 0 0
Gefitinib 93 76 64 53 32 17 11 7 6 4 3 3 1 1 0
Time of progression-free survival (months)
Esti
mat
ed P
FS p
rob
abili
ty
1.0
0.8
0.6
0.4
0.2
0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42
L858R
No. at risk:
Afatinib 67 59 45 36 24 16 12 9 7 4 2 1 0 0 0
Gefitinib 66 56 42 30 20 5 3 2 1 1 0 0 0 0 0
Time of progression-free survival (months)
Esti
mat
ed P
FS p
rob
abili
ty
1.0
0.8
0.6
0.4
0.2
0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42
Afatinib (n=67)
Gefitinib (n=66)
Median, mo 10.9 10.8
HR (95% CI), P-value
0.71 (0.47-1.06) 0.0856
Afatinib
Gefitinib
Afatinib
Gefitinib
Afatinib (n=93)
Gefitinib (n=93)
Median, mo 12.7 11.0
HR (95% CI), P-value
0.76 (0.55-1.06) 0.1071
Park K et al. Lancet Oncol. 2016;17(5):577-89
Overall Survival (71% Maturity; April 2016) Es
tim
ated
Ove
rall
Surv
ival
Pro
bab
ility
No. at risk:
Afatinib 160 156 153 148 139 125 111 104 94 81 74 61 50 36 30 12 2 0
Gefitinib 159 153 148 142 133 119 105 90 80 71 62 56 48 44 27 7 0 0
Time to Death (months)
0.8
1.0
0.6
0.4
0.2
0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51
Afatinib Gefitinib
Events 109 117
Median, mo 27.9 24.5
HR (95% CI) P-value
0.86 (0.66-1.12) 0.2580
Afatinib
Gefitinib
61%#
51%
48%$
40%
* #P=0.0756; $P=0.1321. Paz-Ares L et al. Ann Oncol, 2017 epub ahead of print
Os by EGFR mutation subtype. (Update Dec. 2016)
OS trends with afatinib were consistent across mutational (Del19, 30.7 months; L858R, 25.0 months) subgroups
Del19
L858R
Corral J et al., ELCC 2017; #93PD
Drug-Related AEs (≥20, updated)
Low rates of treatment discontinuation due to drug-related AEs were observed in each arm (6,3% each)
Afatinib (n=160) Gefitinib (n=159)
All Gr Grade ≥3* All Gr Grade ≥3*
Any AE, n (%) 156 (97.5) 50 (31.3) 153 (96.2) 31 (19.5)
Diarrhoea 144 (90.0) 21 (13.1)† 97 (61.0) 2 (1.3)
Rash/Acne‡ 142 (88.8) 15 (9.4) 129 (81.1) 5 (3.1)
Stomatitis‡ 103 (64.4) 7 (4.4) 38 (23.9) 0
Paronychia‡ 90 (56.3) 3 (1.9) 28 (17.6) 1 (0.6)
Dry skin 52 (32.5) 0 59 (37.1) 0
Pruritus 37 (23.1) 0 36 (22.6) 0
Fatigue‡ 33 (20.6) 9 (5.6) 23 (14.5) 0
ALT increased 15 (9.4) 0 38 (23.9) 13 (8.2)†
AST increased 10 (6.3) 0 33 (20.8) 4 (2.5)
Paz-Ares L et al Paz-Ares L et al. Ann Oncol, 2017
Median PFS was similar in patients who had dose reductions in the first 6 months and those who remained on afatinib 40 mg once daily
Yang J et al. J Clin Oncol 33, 2015 (suppl; abstr 8073); Schuler M et al., ELCC 2016, #138PD; Hirsh V JCO 34, 2016 (suppl; abstr 9046
<40 mg in first 6 months
≥40 mg in first 6 months
Time (months)
1.0
0.6
0.4
0.2
0
Estim
ate
d P
FS
pro
ba
bility
0 3 6 9 12 15 18 21 24 27
0.8
Estim
ate
d P
FS
Pro
ba
bility
Time (months)
1.0
0.6
0.4
0.2
0
0 3 6 9 12 15 18 21 24 27
0.8
Estim
ate
d P
FS
pro
ba
bility
Time of progression-free survival (months)
1.0
0.8
0.6
0.4
0.2
0
0 3 6 9 12 15 18 21 24 27 30 33 36 39
LUX-Lung 3
LUX-Lung 6
LUX-Lung 7
Phase III trial ARCHER 1050
Dacomitinib vs Gefitinib for the First-Line Treatment of Advanced NSCLC
Mok T, et al. ASCO 2017. Abstract LBA9007.
AE Occurring in ≥ 15% in Either Arm, %
Dacomitinib (n = 227) Gefitinib (n = 224)
Any Gr 1 Gr 2 Gr 3 Any Gr 1 Gr 2 Gr 3
Diarrhea* 87.2 49.8 28.6 8.4 55.8 46.0 8.9 0.9
Paronychia 61.7 20.3 33.9 7.5 20.1 13.4 5.4 1.3
Dermatitis acneiform 48.9 16.3 18.9 13.7 28.6 19.2 9.4 0
Stomatitis 43.6 22.5 17.6 3.5 17.9 14.7 2.7 0.4
Decreased appetite 30.8 17.6 10.1 3.1 24.6 21.4 2.7 0.4
Dry skin 27.8 18.5 7.9 1.3 17.0 15.6 1.3 0
Weight decrease 25.6 13.7 9.7 2.2 16.5 9.8 6.3 0.4
Alopecia 23.3 18.1 4.8 0.4 12.5 11.6 0.9 0
Cough 21.1 17.2 4.0 0 18.8 16.1 2.2 0.4
Pruritis 19.8 11.9 7.5 0.4 13.8 10.7 1.8 1.3
ALT increase 19.4 16.3 2.2 0.9 39.3 20.1 10.7 8.5
Outcome Dacomitinib
(n = 227) Gefitinib (n = 224)
Serious AE, n (%) •Any •Treatment related
• Causing discontinuation • Causing death
62 (27.3) 21 (9.3) 22 (9.7) 2 (0.9)*
50 (22.3) 10 (4.5) 15 (6.7) 1 (0.4)†
Median time to dose reduction, mos (range) 2.8 (0.3-20.3) 3.3 (1.2-25.7)
Median duration of dose reduction, mos (range) 11.3 (0.1-33.6) 5.2 (0.3-17.8)
Reduced dose given, n (%) •30 mg/day •15 mg/day
87 (38.3) 63 (27.8)
NA
Pts requiring dose reduction, n (%) 150 (66.1) 18 (8.0)
ARCHER 1050: Serious AE and Dose Modification
*Gr 5 diarrhea, n = 1. Otherwise, no listed AE with severity above grade 3 in either arm.
JO25567: erlotinib vs erlotinib + bevacizumab PFS by independent review in all patients
(primary endpoint)
75 72 69 64 60 53 49 38 30 20 13 8 4 4 0
77 66 57 44 39 29 24 21 18 12 10 5 2 1 0 T
A+T
Number at risk
0 0
1.0
Time (months)
4 8 12 2 6 10 14 18 22 26 16 20 24 28
0.2
0.4
0.6
0.8
PF
S p
robabili
ty
9.7 16.0
HR=0.54 (0.36–0.79) Log-rank p<0.0015
Avastin + Tarceva
Tarceva
Seto, et al. Lancet Oncol, 2014
JO25567: PFS by EGFR mutation type
Seto, et al. Lancet Oncol, 2014
Seto, et al. Lancet Oncol 2014
JO25567: AEs in >20% of patients
First line EGFR m+ Erlotinib + BVZ BELIEF Phase II trial
• Ph II BELIEF (2015 ECC)
– 1st Line: erlotinib + BVZ
– n=109 EGFRm+ (Del 19, L858R)
– 37 pts T790m+ pretreatment
• SLP 1a: 72.4%
• SLPm 16m
• TRO: 70.3%
– 72 pts T790m- pretreatment
• SLP 1a: 49.4%
• SLPm: 10.5m
• TRO: 79.2%
Rosell R, et al. Lancet Respir Med. 2017;5:435-444
FLAURA: Phase III TRIAL Osimertinib vs SoC EGFD-TKI as first-line treatment in patients with EGFRm
advanced NSCLC
Soria et al. NEJM 2017; November 18, 2017DOI: 10.1056/NEJMoa1713137
FLAURA: Phase III TRIAL Osimertinib vs SoC EGFD-TKI as first-line treatment in patients with EGFRm advanced
NSCLC
Soria et al. NEJM 2017; November 18, 2017DOI: 10.1056/NEJMoa1713137
FLAURA: Phase III TRIAL Osimertinib vs SoC EGFD-TKI as first-line treatment in patients with EGFRm
advanced NSCLC
Soria et al. NEJM 2017; November 18, 2017DOI: 10.1056/NEJMoa1713137
FLAURA: Phase III TRIAL Osimertinib vs SoC EGFD-TKI as first-line treatment in patients with EGFRm
advanced NSCLC
Soria et al. NEJM 2017; November 18, 2017DOI: 10.1056/NEJMoa1713137
Median PFS, months (95% CI)
18.9 (15.2, 21.4)
10.2 (9.6, 11.1)
1.0
Pro
bab
ility
of
pro
gre
ssio
n-f
ree
surv
ival
0.2
0.4
0.6
0.8
0.0
0 3 6 9 12 15 18 21 24 27
Time from randomisation (months)
279
277
262
239
233
197
210
152
178
107
139
78
71
37
26
10
4
2
0
0
No. at risk
Osimertinib
SoC
Osimertinib
SoC
HR 0.46
(95% CI 0.37, 0.57)
p<0.0001
# Pre-existing T-790M IN
34-35% of patients.
Rosell Lancet Respiratory
2017, Rosell CCR11
Osimertinib in first line increase PFS because target clones with T790M from the beginning OR RELAPSE THE APARITION OF T790M AS THE FIRST
RESISTANCE MECHANISM ?
All causality AE in
≥15% of patients, %
Osimertinib (n=279) SoC (n=277)
Any grade Grade 3 Grade 4 Any grade Grade 3 Grade 4
Diarrhoea 161 (58) 6 (2) 0 159 (57) 6 (2) 0
Dry skin 88 (32) 1 (<1) 0 90 (32) 3 (1) 0
Paronychia 81 (29) 1 (<1) 0 80 (29) 2 (1) 0
Stomatitis 80 (29) 1 (<1) 1 (<1) 56 (20) 1 (<1) 0
Dermatitis acneiform 71 (25) 0 0 134 (48) 13 (5) 0
Decreased appetite 56 (20) 7 (3) 0 51 (18) 5 (2) 0
Pruritus 48 (17) 1 (<1) 0 43 (16) 0 0
Cough 46 (16) 0 0 42 (15) 1 (<1) 0
Constipation 42 (15) 0 0 35 (13) 0 0
AST increased 26 (9) 2 (1) 0 68 (25) 12 (4) 0
ALT increased 18 (6) 1 (<1) 0 75 (27) 21 (8) 4 (1)
FLAURA: Phase III TRIAL Adverse Events
Soria et al. NEJM 2017; November 18, 2017DOI: 10.1056/NEJMoa1713137
AEs
Gefitinib
ARCHER
Erlotinib
JO25567
Afatinib
LL7
Dacomitinib
ARCHER
Osimertinib
FLAURA
Erlo + BVZ
JO25567
Any/Grade ≥ 3 Any/Grade ≥ 3 Any/Grade ≥ 3 Any/Grade ≥ 3 Any/Grade ≥ 3 Any/Grade ≥ 3
Diarrhoea 55.8/0.9 78/1 90/13.1 87.2/8.4 58/2 81/1
Dry skin 17/0 75/3 52/0 27.8/1.3 32/<1 76/3
Paronychia 20.1/1.3 65/4 56.3/13.1 61.7/7.5 29/<1 75/3
Stomatitis 17.9/0.4 60/3 64.4/4.4 43.6/3.5 29/<2 63/1
Dermatitis acneiform 28.6/0 99/19 88.8/9.4 48.9/13.7 25/0 99/25
Decreased appetite 24.6/0.4 32/1 17/0 30.8/3.1 20/3 35/1
Pruritus 13.8/1.3 42/0 23.1/0 19.8/0.4 17/<1 45/1
AST/ALT increased 39.3/8.5 51/18 16/0 19.4/0.9 18/1 44/8
Hypertension - 13/10 - - - 76/60
Haemorrhagic Event
- 29/0 - - - 72/3
Proteinuria - 4/0 - - - 52/8
AEs causing
discontinuation %
8
18
6.3
9.7
13
16
Randomized Trials EGFR TKIs Trials Adverse Events
First Line Trials with TKIs EGFR + Progression Free survival (months)
0
2
4
6
8
10
12
14
16
18
20
Gefitinib Erlotinib Afatinib Dacomitinib Erlo + Bvz Osimertinib
IPA
SS
Fir
st
Sig
nal
WJT
OG
NE
J002
OP
TIM
AL
EU
RT
AC
EN
SU
RE
LU
X -
LU
NG
3
LU
X -
LU
NG
6
LU
X -
LU
NG
7 AR
CH
ER
1050
J025567
BE
LIE
F
FL
AU
RA
PFS comparison second vs third gen TKIs
35.8%
LL7 ARCHER FLAURA
Efficacy of Afatinib in Uncommon mutations
Preliminary results: poziotinib induces partial response in 73% of patients with EGFR Exon 20 mutations
-11 EGFR exon 20 patients with baseline and follow
up scans at 2 m (longest on treatment=6 months).
-Activity: 8/11 PR observed; 2 patients have had
additional follow up scans confirming PR.
-duration of response not yet evaluable; only one
patient with PD thus far.
-Evidence of CNS activity in patient with CNS
metastasis and another with LMD
-additional patient treated on compassionate use IND
(CIND) also had PR
-Toxicities: significant EGFR-related toxicities
include rash, diarrhea, paronychia, mucositis
consistent with those previously described.
-55% underwent dose reduction to 12mg thus far
-6 0
-4 5
-3 0
-1 5
0
1 5
3 0
4 5
Ma
xim
um
Re
sp
on
se
fro
m
Ba
se
lin
e
V7
69
ins
GS
V
H7
73
ins
AH
H7
73
du
pP
R
N7
71
ins
HH
D7
70
ins
G
P7
72
ins
DN
P
A7
67
du
pA
SV
S7
68
I
S7
68
du
pS
VD
D7
70
de
l in
sG
Y
D7
70
ins
Y H
77
3Y
S E,AA,P
PoziotinibPrior Therapy:
P = AP32788
S= ASP 8273
E = Erlotiniib
A = Afatinib
Abstract ID 10369, Elamin et al. Elamin et al. IASLC 2017 Ab 10369
Poziotinib in exon 20 inertions EGFR Exon 20 insertions have a sterically hindered binding pocket
Robichaux et al WCLC 2016
EGFR D770insSVD EGFR T790M
PD: rebiopsy Initial biopsy PD: rebiopsy
Thress et al, NEJM 2015, Ortiz-Cuaran et al, CCR 2016,
Fassunke et al, in prep.
Erlotinib, Gefitinib,
Afatinib (10m) T790M Osimertinib (10m) EGFRde
l 19
L858R
also: liquid biopsy
Osimertinib (20m)
EGFR
C797S
EGFR
G724S
hl MET
amp.
HER2
amp.
KRAS
mut
clinical
trials
Chemotherapy
Targeted treatments are evaluated in resistance to 3rd gen inhibitor
also: liquid biopsy also: liquid biopsy
OS in patients treated with a subsequent 3rd-generation EGFR TKI
20% / 17% who discontinued afatinib / gefitinib received 3rd gen TKIs (osimertinib, olmutinib and rociletinib)
Corral J et al., ELCC 2017; #93PD
35
¿Cuál es la secuencia óptima para EGFR mutados?
1ª generación TKI
(10 meses)
Osimertinib en T790M
(10 meses) OS 27
meses
OS 22
meses
2ª generación TKI
(14-16 meses)
Osimertinib en T790M
(10 meses)
QT
(5 meses)
Osimertinib
(19 meses)
OS ?
OS 27
meses
QT
(5 meses)
QT
(5 meses) OS ?
Erlotinib + BVZ
(16 meses)
Osimertinib en T790M
(10 meses)
QT
(5 meses)
OS ?
OS ?
CONCLUSIONES
• Osimertinib es el fármaco más eficaz en términos de SLP
• Osimertinib es el que presenta mejor perfil de tolerancia
• ¿Debe ser nuestra primera opcíón de tratamiento en todos los pacientes?
• Si en pacientes con metastasis cerebrales
• Si en pacientes con mutaciones de T790M de novo
• En pacientes con mutaciones no comunes (18-21 (L861Q, G719S, G719A, G719C,
S768I, y otras), afatinib ha mostrado una eficacia alta y podría ser la primera opción.
• En el resto de pacientes los tratamientos secuenciales con TKIs de 1ª y 2ª generación
seguido de orsimetinib en T790M + pueden obtener SLP comparables a osimetinib en
1ª línea. Inserciones 20: Pociotinib
• La secuencia óptima todavia es incierta y todavía está pendiente de los resultados de
supervivencia de los estudios AURA y FLAURA
• Pendientes de resultados de estudios de combinaciones con antiangiogénicos e
inmmunoterapia