ESMO 2014 ABS TRA CT 4958

Adaptation of theimmune-related response
criteria: irRECISTOliver Bohnsack, Calyx
Katarina Ludajic, Calyx
Axel Hoos, GSK

AIMRECIST 1.1 has its shortcomings
for targeted immunotherapy inoncology. Using RECIST 1.1
in immunotherapy trials would
lead to declaration of progressive
disease (PD) too early, when thetreatment effect is not yet fully
evident. RECIST also neglects
the importance of the ‘flare
effect’ - pseudo-progression
effect within the so-called flaretime window. Immune relatedResponse Criteria (irRC) basedon WHO criteria were publishedwith an aim to provide better
assessment of the effect of
immunotherapeutic agents.
With this poster we introduce
irRECIST based on RECIST
1.1, irRC and Nishino et al.,2013 findings. Our aim is
to define criteria that better
capture antitumor activity andreduce irRC criteria ambiguity.
Consistent implementation ofirRECIST by both investigatorsand blinded independent readers
will help reduce site: central
discordance.

©2021 Calyx

IRRECIST
MODIFICATIONS AND
CLARIFICATIONSORIGINAL IRRC, INCLUDING
WHO CRITERIA REFERENCES

At the baseline tumor assessment, thesum of the products of the two largest
perpendicular diameters (SPD) of allindex lesions (five lesions per organ, up
to 10 visceral lesions and five cutaneousindex lesions) is calculated.

WHO 5.1.2
Unmeasurable Disease
There are many forms of unmeasurable
disease, and only a few are mentioned
as examples:

1. 0 Baseline: Measurable Lesion
Definitions and Target Lesion
Selection Follow the definitions fromRECIST 1.1.
Measurable lesions must be accurately
measured in at least one dimension
with a minimum size of:–

10 mm in the longest diameterby CT or MRI scan (or no lessthan double the slice thickness)for nonnodal lesions and ≥15mm in short axis for nodal
lesions–

10 mm caliper measurement
byclinical exam–

20 mm by chest X-ray

1.1. Baseline: Non-measurable
Lesion Definitions
Non-target lesions will include:–

Measurable lesions not selected
as target lesions–

All sites of non-measurable
disease, such as neoplastic
masses that are too small tomeasure because their longest
uninterrupted diameter is < 10mm (or < two times the axialslice thickness), ie. the longest
per-pendicular diameter is ≥10and < 15 mm.

–

Other types of lesions that are
confidently felt to represent
neoplastic tissue, but are difficult
to measure in a reproduciblemanner. These include bonemetastases, leptomeningeal
metastases, malignant ascites,
pleural or pericardial effusions,ascites, inflammatory breastdisease, lymphangitis cutis/pulmonis, cystic lesions, illdefined abdominal masses, skinlesions, etc.

Lymphangitic pulmonary metastases.
Skin involvement in breast cancer.
Abdominal masses that can be palpatedbut not measured

RATIONALE FOR MODIFICATION

Up to 5 target lesions may be selectedat baseline. Lesions will be measured
unidimensionally. The minimum target
lesion size at baseline in irRECIST isaligned with RECIST 1.1, as outlinedin Nishino et al., 2013.

Although irRC does not specificallydefine non-target lesions, irRC isderived from WHO criteria andindicates accordance with the samefor the purposes of definitions of nontarget lesions. Further clarifications
in alignment with RECIST 1.1 areprovided.

Not specified.

1.2 Baseline: Target and Non-TargetLymph Node Lesion Definitions
Follow the definitions from RECIST
1.1

No change in definition of target andnon-target lymph nodes from RECIST
1.1.

Not specified.

1.3 Baseline: Non-Target Lesion
SelectionAll lesions or sites of disease notrecorded as target lesions should
be recorded as non-target lesions
at baseline. There is no limit to thenumber of non-target lesions that canbe recorded at baseline.

In alignment with RECIST 1.1, allmalignant lesions have to be selectedat baseline. The excess of measurable
lesions and all true non-measurable
lesions will be selected as non-target
lesions at baseline and followed atsubsequent timepoints.

Not specified.

1.4 Baseline: Bone Lesions
Follow the definitions from RECIST
1.1. Regardless of the imaging modality
blastic bone lesions will not be selected
as target lesions. Lytic or mixed lyticblastic lesions with a measurable soft
tissue component ≥10 mm can beselected as target lesions.

Bone lesions are to be handled thesame as in RECIST 1.1.

Not specified.

1.5 Baseline: Brain Lesions detectedon brain scans can be considered asboth target or non-target lesions.

Brain lesions can be selected as target
or non-target lesions at baseline,
depending on the protocol definition,indication, and study design.

2Methods
The adaptations from irRC andWHO criteria, as applicablein immunotherapy clinicalstudies, are documented in
the “irRECIST Modifications
and Clarifications” column
in a comparative table format
within our Blinded Independent
Central Review (BICR)
Charter. The modifications we
introduce represent adaptationsof published criteria based onradiology practice and clinical
trial experience, and they provide
more objective and reproducibleresponse assessments forinvestigators and for the central
independent image review.

©2021 Calyx

IRRECIST
MODIFICATIONS AND
CLARIFICATIONSORIGINAL IRRC, INCLUDING
WHO CRITERIA REFERENCES

At the baseline tumor assessment, thesum of the products of the two largest
perpendicular diameters (SPD) of allindex lesions (five lesions per organ, up
to 10 visceral lesions and five cutaneousindex lesions) is calculated.

WHO 5.1.2
Unmeasurable Disease
There are many forms of unmeasurable
disease, and only a few are mentioned
as examples:

1. 0 Baseline: Measurable LesionDefinitions and Target Lesion
Selection Follow the definitions fromRECIST 1.1.
Measurable lesions must be accurately
measured in at least one dimension
with a minimum size of:–

10 mm in the longest diameterby CT or MRI scan (or no lessthan double the slice thickness)for nonnodal lesions and ≥15mm in short axis for nodallesions–

10 mm caliper measurement
byclinical exam–

20 mm by chest X-ray

1.1. Baseline: Non-measurable
Lesion Definitions
Non-target lesions will include:–

Measurable lesions not selectedas target lesions–All sites of non-measurabledisease, such as neoplastic
masses that are too small tomeasure because their longest
uninterrupted diameter is < 10mm (or < two times the axial
slice thickness), ie. the longest
per-pendicular diameter is ≥10and < 15 mm.

–

Other types of lesions that are
confidently felt to represent
neoplastic tissue, but are difficult
to measure in a reproduciblemanner. These include bonemetastases, leptomeningeal
metastases, malignant ascites,
pleural or pericardial effusions,
ascites, inflammatory breastdisease, lymphangitis cutis/pulmonis, cystic lesions, illdefined abdominal masses, skinlesions, etc.

Lymphangitic pulmonary metastases.
Skin involvement in breast cancer.
Abdominal masses that can be palpatedbut not measured

RATIONALE FOR MODIFICATION

Up to 5 target lesions may be selectedat baseline. Lesions will be measured
unidimensionally. The minimum target
lesion size at baseline in irRECIST isaligned with RECIST 1.1, as outlinedin Nishino et al., 2013.

Although irRC does not specificallydefine non-target lesions, irRC isderived from WHO criteria andindicates accordance with the samefor the purposes of definitions of nontarget lesions. Further clarifications
in alignment with RECIST 1.1 areprovided.

Not specified.

1.2 Baseline: Target and Non-Target
Lymph Node Lesion Definitions
Follow the definitions from RECIST
1.1

No change in definition of target andnon-target lymph nodes from RECIST
1.1.

Not specified.

1.3 Baseline: Non-Target Lesion
Selection
All lesions or sites of disease notrecorded as target lesions should
be recorded as non-target lesions
at baseline. There is no limit to thenumber of non-target lesions that canbe recorded at baseline.

In alignment with RECIST 1.1, allmalignant lesions have to be selectedat baseline. The excess of measurable
lesions and all true non-measurable
lesions will be selected as non-target
lesions at baseline and followed atsubsequent timepoints.

Not specified.

1.4 Baseline: Bone Lesions
Follow the definitions from RECIST
1.1. Regardless of the imaging modality
blastic bone lesions will not be selected
as target lesions. Lytic or mixed lyticblastic lesions with a measurable soft
tissue component ≥10 mm can beselected as target lesions.

Bone lesions are to be handled thesame as in RECIST 1.1.

Not specified.

1.5 Baseline: Brain Lesions detectedon brain scans can be considered asboth target or non-target lesions.

Brain lesions can be selected as target
or non-target lesions at baseline,
depending on the protocol definition,indication, and study design.

3

Results
irRECIST criteria are basedon irRC criteria adapted for
unidimensional measurements,
as outlined in Nishino et al.,2013. To further align the criteriawith RECIST 1.1 we outline
the approach for the assessmentof baselineselected non-target
lesions and new non-measurablelesions, and discuss the impact of
those lesions on the overall tumor
response assessment.
Guidelines for the evaluation ofpatients with non-target disease
only and patients in adjuvant
setting is provided.

ORIGINAL IRRC, INCLUDING
WHO CRITERIA REFERENCES

Non-index lesions at follow-up
timepoints contribute to defining irCR
(complete disappearance required).

IRRECIST
MODIFICATIONS AND
CLARIFICATIONS

2.2 Follow-up: Non-Target Lesion
Assessment
The RECIST 1.1 definitions forthe
assessment of non-target lesions apply.
The response of non-target lesions
primarily contributes to the overall
response assessments of irCR andirNon-CR/Non-PD (irNN). Nontarget lesions do not affect irPR andirSD assessments. Only a massive andunequivocal worsening of non-target
lesions alone, even without progress in
the TMTB is indicative of irPD.

RATIONALE FOR MODIFICATION

Non-target lesions have a subordinate
function. In the event that non-target
lesions massively progress one cannot
ignore such worsening and in these rarecases irPD based only on non-target
lesions will be a valid assessment
option.

New, non-measurable lesions atfollow-up timepoints do not define
progression, they only preclude irCR.

2.3 Follow-up: New Non-Measurable
Lesions Definition and Assessment
All new lesions not selected as newmeasurable lesions are considered
new non-measurable lesions andare followed qualitatively. Only amassive and unequivocal progressionof new non-measurable lesions leads
to an overall assessment of irPD
for the timepoint. Persisting newnonmeasurable lesions prevent irCR.:

When new non-measurable lesions
substantially worsen in these rarecases irPD based only on new
non-measurable lesions will be anassessment option.

irRC Overall Tumor Assessments

2.4 irRC Overall Tumor Assessments

irCR, complete disappearance of alllesions (whether measurable or not,and no new lesions)

irCR, complete disappearance of
all measurable and non-measurable
lesions. Lymph nodes must decrease to< 10 mm in short axis. Confirmationof response is not mandatory.

The irRECIST overall tumor
assessment is based on TMTB ofmeasured target and new lesions,non-target lesion assessment and new
non-measurable lesions.

–Confirmation by a repeat,
consecutive assessment no lessthan 4 weeks from the date first
documented

irPR, decrease in tumor burden ≥50%
relative to baseline–

Confirmed by a consecutive
assessment at least 4 weeks
after first documentation

irSD, not meeting criteria for irCR or
irPR, in absence of irPD
irPD, increase in tumor burden ≥25%
relative to nadir (minimum recordedtumor burden)–

Confirmation by a repeat,
consecutive assessment no lessthan 4 weeks from the date first
documented

irPR, decrease of ≥ 30% in TMTB
relative to baseline, non-target
lesions are irNN, and no unequivocal
progression of new non-measurable
lesions.
irSD, failure to meet criteria for irCRor irPR in the absence of irPD.
irNN, no target disease was identified
at baseline and at follow-up the patient
fails to meet criteria for irCR or irPD.

The thresholds for irPR and irPD
assessment are aligned with RECIST
1.1, and confirmation of response isnot required.
An irPD confirmation scan may berecommended for patients with aminimal TMTB %-increase over
20% and especially during the flaretime-window of the first 12 weeks
of treatment, depending on thecompound efficacy expectations, toaccount for expected delayed response.

irPD, minimum 20% increase andminimum 5 mm absolute increase in
TMTB compared to nadir, or irPD
for non-target or new non-measurablelesions. Confirmation of progression isrecommended minimum 4 weeks after
the first irPD assessment.
irNE, used in exceptional cases whereinsufficient data exists.
irND, in adjuvant setting when nodisease is detected.

©2021 Calyx4Conclusions
irRECIST criteria as outlined here introduce the needed clarifications and adjustments to irRC criteria andNishino et al., 2013 publication to allow for treatment evaluations that better meet both investigators’ andpatients’ needs and with that better reflect sponsors’ demands for more reliable and reproducible study data intargeted immunotherapy in oncology studies. The main adaptation of the existing immune-response criteiralies in the assessment of all detected lesions. Unequivocal and substantial increase of non-target and new nonmeasurable lesions prevents irCR and may also lead to irPD. Reduction of the tumor burden in patients in anadjuvant setting may lead to irPR and such patients may therefore be enrolled in studies with response endpoints.
Clinical relevance of these adaptations needs to be confirmed.

©2021 Calyx

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Summary and AdditionalGuidance
1. TMTB: Baseline-selected target lesions and newmeasurable lesions should NOT be assessed
separately. Measurements of those lesions should becombined into the Total Measured Tumor Burden(TMTB), and one combined assessment provided.
2. New Measurable Lesions: According to irRC ameasurable new lesion has to be at least 5 mm
x 5 mm to be selected as an index lesion. For
bidimensional measurements this threshold
was acceptable. In irRECIST, criteria for
unidimensional lesion measurment apply to bothtarget and new measurable lesions: a minimum 10
mm in the longest diameter for non-nodal lesions,and a minimum 15 mm in short axis for lymph
nodes. Smaller lesions contribute to the non-target
or new nonmeasurable tumor burden, but do not
get measured.
3. irPR if no Target Lesions: If new measurable lesions
appear in patients with no target lesions at baseline,
irPD will be assessed. That irPD timepoint will
be considered a new baseline, and all subsequent
timepoints will be compared to it for response
assessment. irPR is possible if the TMTB of new
measurable lesions decreases by ≥ 30% compared to
the first irPD documentation.
4. irPR in Adjuvant Studies: irRECIST can beused in the adjuvant setting, in patients with novisible disease on CT/MRI scans. The appearanceof new measurable lesion(s) automatically leads
to an increase in TMTB by 100% and leads toirPD. These patients can achieve a response if theTMTB decreases at follow-up, as a sign of delayedresponse.
Considering 3 and 4, sponsors may consider enrolling
patients with no measurable disease and/or patientswith no visible disease at all in studies with response
related endpoints.

©2021 Calyx

5. Non-Target Lesions: In alignment with RECIST
1.1, baseline selected non-target lesions can neverconvert to measurable lesions, not even if they
increase in size at subsequent timepoints andbecome measurable. Only true new lesions can bemeasured and contribute to the TMTB.
6. Example: A patient has multiple lung metastases,
all smaller than 10 mm and selected as non-target
lesions at baseline. If, at a subsequent timepoint
some of these non-target lesions increase andbecome > 10 mm, and one new lesion >10 mm
appears, only the new measurable lesion willcontribute to the TMTB, and not the baseline
selected non-target lesion that increased in size.
Otherwise such an increase would make persisting
non-target lesions switch into the new measurable
lesion category which would be inaccurate, as thelesion existed at baseline.
7. irPD Based on Non-Target Lesions: Unlike irRC
that neglect non-target lesions for the assessment ofirPD, in irRECIST a substantial and unequivocal
increase of non-target lesions is indicative ofprogression.
8. irPD Based on New Non-Measurable Lesions:
According to irRC, a patient with multiple newlesions of 9 mm would be considered non-PD,
whereas a patient with just one new lesion of 10mm may be assessed as irPD if the TMTB of sucha patient increases ≥ 20% compared to nadir.
According to irRECIST, the reviewer may assign
irPD for the patient with multiple new lesionsof 9 mm if they are considered to be a sign ofunequivocal, massive worsening (see 2.3)
9. irPD Confirmation: Progression confirmation noless than 4 weeks after the initial irPD assessment isrecommended especially in case of marginal disease
growth and if the first irPD assessment is within thecompound-specific tumor flare window.

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References
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2. Nishino M et al. Developing a common language for tumor response to immunotherapy: immune-related
response criteria using unidimensional measurements. Clin Cancer Res. 2013 Jul 15;19(14):3936-43
3. Therasse P, Arbuck SG, et al.: New Guidelines to Evaluate the Response to Treatment in Solid Tumors. Journalof the National Cancer Institute 2000 92(3):205-216]
4. Eisenhauer EA, Therasse P, Bogaerts J, et al.: New response evaluation criteria in solid tumours: revised
RECIST guideline (version 1.1). In: Eur. J. Cancer. 45, Nr. 2, Januar 2009, S. 228–47.
5. Therasse P, Eisenhauer EA, Verweij J: RECIST revisited: a review of validation studies on tumour assessment.
In: Eur. J. Cancer. 42, Nr. 8, Mai 2006, S. 1031–9.
6. WHO handbook for reporting results of cancer treatment. Geneva (Switzerland): World Health Organization
Offset Publication No. 48; 1979.

©2021 Calyx

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Reliably solving the complex.
Oliver.Bohnsack@calyx.ai

calyx.aicontact us at: hello@calyx.ai©2021 Calyx