Analysis of the Association Between Adverse Events and ...€¦ · and overall survival (OS) as well as the effect of cortico-steroid use on the duration of response. ... with autoimmune

originalreport

Analysis of the Association Between AdverseEvents and Outcome in Patients Receivinga Programmed Death Protein 1 or ProgrammedDeath Ligand 1 AntibodyV. Ellen Maher, MD1; Laura L. Fernandes, PhD1; Chana Weinstock, MD1; Shenghui Tang, PhD1; Sundeep Agarwal, MD1;

Michael Brave, MD1; Yang-min Ning, MD, PhD1; Harpreet Singh, MD1; Daniel Suzman, MD1; James Xu, MD1; Kirsten B. Goldberg, MA1;

Rajeshwari Sridhara, PhD1; Amna Ibrahim, MD1; Marc Theoret, MD1; Julia A. Beaver, MD1; and Richard Pazdur, MD1

abstract

PURPOSE To assess the relationship among tumor response rate, overall survival, and the development of relatedadverse events of special interest (AESIs) or related immune-mediated adverse events (imAEs) in patients withurothelial cancer treated with anti–programmed death protein 1 or ligand 1 (anti–PD-1/L1) antibodies.

PATIENTS AND METHODS We examined seven trials in 1,747 patients with metastatic or locally advancedurothelial cancer that led to approval of an anti–PD-1/L1 antibody. Five trials enrolled patients who had receivedprior platinum-based therapy, and two enrolled patients who were cisplatin ineligible. The data sets weresearched for AESIs, related AESIs, imAEs, and related imAEs. The relationship to study drug was determined bythe investigator. ImAEs were defined as AESIs treated with topical or systemic corticosteroids.

RESULTS In these exploratory analyses, a related AESI was reported in 64% of responding patients and in 34% ofpatients who did not respond to the anti–PD-1/L1 antibody, whereas a related imAE occurred in 28% and 12% ofpatients who did and did not respond to study drug, respectively. In a responder analysis, an increase in overallsurvival was seen in patients with related AESIs compared with those with no related AESIs (hazard ratio, 0.45;95% CI, 0.39 to 0.52). Fifty-seven percent of responding patients with a related AESI reported the AESI beforedocumentation of response.

CONCLUSION Patients who responded to treatment with an anti–PD-1/L1 antibody were more likely to reporta related AESI or related imAE. This relationship did not seem to be due to the increased duration of exposure inresponding patients. Systemic corticosteroid use did not appear to affect the duration of response.

J Clin Oncol 37. Published by American Society of Clinical Oncology

INTRODUCTION

Five monoclonal antibodies directed against pro-grammed death protein 1 (PD-1) or programmed deathprotein ligand 1 (PD-L1) have been approved in theUnited States for the treatment of advanced or meta-static urothelial cancer. All have been approved for thetreatment of patients who received prior platinum-based therapy, and two were also approved for thetreatment of patients who are cisplatin ineligible.

A relationship between patient outcome and the de-velopment of characteristic adverse events (AEs) hasbeen seen with nonimmunotherapy agents. For ex-ample, the development of rash after treatment withepidermal growth factor receptor inhibitors was initiallyassociated with patient outcome.1,2 Given the immunemechanism of action of anti–PD-1/L1 antibodies, it isreasonable to associate the development of autoimmuneevents with improved outcome because activation of the

immune system could lead to both tumor response andautoimmunity. It is unclear whether the development ofautoimmune AEs in patients with melanoma who receiveipilimumab affects outcome, although the development ofautoimmune AEs has been associated with improvedoutcome with nivolumab.3-5

Data from the trials that have led to the approvals of fiveanti–PD-1/L1 antibodies in the treatment of urothelialcancer provide an opportunity to study the interplaybetween patient outcome and the development of AEsof special interest (AESIs) and immune-mediated AEs(imAEs) that are related to the use of study drug.Because of concerns about the effect of corticosteroiduse on patient outcome, imAEs were examined sep-arately. To investigate the relationship between patientoutcome and related AESIs/imAEs, we performeda pooled analysis of these trials that permitted anexamination of the association between related AESIs/imAEs and tumor response, the timing of response,

ASSOCIATEDCONTENT

Appendix

Author affiliationsand supportinformation (ifapplicable) appearat the end of thisarticle.

Accepted on April 2,2019 and published atjco.org on May 22,2019: DOI https://doi.org/10.1200/JCO.19.00318

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and overall survival (OS) as well as the effect of cortico-steroid use on the duration of response.

PATIENTS AND METHODS

Selection Criteria

Trials were eligible for this pooled analysis if they weresubmitted to the US Food and Drug Administration tosupport amarketing application that was ultimately approvedfor the treatment of patients with advanced or metastaticurothelial cancer. Individual patient data were pooled.

Trial Design

The study designs of the included trials were similar, andthe results have been published elsewhere (Table 1).6-12 Alltrials enrolled patients with locally advanced or metastaticurothelial cancer. Five trials enrolled patients who hadreceived prior platinum-based therapy (cisplatin or car-boplatin), and two enrolled patients who were cisplatinineligible. Cisplatin ineligible was defined as one of thefollowing: creatinine clearance of approximately 30 to59mL/min, performance status (PS) of 2, grade 2 or greaterperipheral neuropathy, or grade 2 or greater hearing loss.One trial also included class 3 heart failure in the definitionof cisplatin ineligible. Note that cisplatin-ineligible patientsmay have received prior cisplatin but were cisplatin in-eligible at the time of enrollment. All trials excluded patientswith autoimmune disease, although most permitted theentry of patients with vitiligo, psoriasis, thyroid disease,adrenal disease, or controlled diabetes. Patients who re-quired a corticosteroid dose greater than physiologic re-placement and those who required other immunosuppressivemedications were excluded from entry. Patients received studydrug every 2 to 3 weeks, and tumor assessments occurredevery 6 to 9 weeks. In general, treatment continued until ra-diographic (often requiring confirmation) or clinical progres-sion. In six single-arm trials, the primary end point wasresponse rate. In the seventh randomized trial, response rate

was a secondary end point. In all trials, response rate wasdetermined by independent review using Response EvaluationCriteria in Solid Tumors (RECIST) version 1.1. The protocols foreach study included a list of AESIs. These lists not only focusedon autoimmune events but also included broad terms, such asdiarrhea or rash, that could occur as a result of other causes.

Statistical Methods

All analyses should be considered exploratory. The AESIsidentified in each protocol were grouped and used toidentify AEs in each trial. Because all the studies includedat least 30 days of follow-up after the last dose of study drug,the cutoff of 30 days was chosen for AESIs in these ana-lyses. ImAEs were defined as any AESI treated with a topicalor systemic corticosteroid. The relationship between AESIs,imAEs, and the study drug was determined by the in-vestigator. Concomitant medication data sets were exam-ined for the use of corticosteroids, immunosuppressivemedications, or thyroid medications. Many patients re-ceived corticosteroids for indications that did not seem tobe immune related (eg, fatigue, nausea) and were notincluded in the list of AESIs.

Analyses included a descriptive exploratory evaluation of theassociation between the development of an AESI/imAE orrelated AESI/imAE and tumor response (complete or partialresponse). The associations between the development ofa related AESI and response or a related imAE and responsein patients who used topical corticosteroids or thyroidmedications also were examined in thosewho did not receivesystemic corticosteroids during the treatment period.

The relationship between the development of a relatedAESI/imAE and time in the study was examined by ana-lyzing the time to first related AESI or imAE in patients whodid and did not respond to study drug using the stratifiedCox regression model, stratified by study. The responderstatus (responded yes/no) and the exposure duration wereincluded in the model as covariates. Exposure duration was

TABLE 1. Clinical Trials Included in the Pooled AnalysisVariable Atezolizumab Avelumab Durvalumab Nivolumab Pembrolizumab Atezolizumab Pembrolizumab

ClinicalTrials.govidentifier*

NCT02951767 NCT01772004 NCT01693562 NCT02387996 NCT02256436† NCT02108652 NCT02335424

No. of patients 310 226 182 270 270 119 370

Antibody target Anti–PD-L1 Anti–PD-L1 Anti–PD-L1 Anti–PD-1 Anti–PD-1 Anti–PD-L1 Anti–PD-1

Trial design Single arm Single arm Single arm Single arm Randomized Single arm Single arm

Population Prior platinum Prior platinum Prior platinum Prior platinum Prior platinum Cisplatin ineligible Cisplatin ineligible

Primary end point* RR RR RR RR and DoR OS and PFS RR RR

Secondary end points* DoRPFSOS

PFSOSDoR

DoRPFSOS

PFSOS

RR DoRPFSOS

DoRPFSOS

Abbreviations: DoR, duration of response; OS, overall survival; PD-1, programmed death protein 1; PD-L1, programmed death protein ligand 1; PFS,progression-free survival; RR, response rate.*For detailed information about the primary and secondary end points, refer to the trial publications.3-9

†Only the pembrolizumab arm (n = 270) of the randomized trial is included in these analyses.

2 Published by American Society of Clinical Oncology

Maher et al


http://ClinicalTrials.gov

the difference in days between the treatment stop and startdates. An interaction term was included to determinewhether there were differences by response and treatmentexposure and retained in the model if found to be statis-tically significant. The association between responderstatus and development of a related AESI/imAE also wasexplored using a binary outcome multivariable-stratifiedlogistic regression model, stratified by study. To examinethe effect of the duration of exposure on the development ofa related AESI/imAE, the responder status, the duration ofexposure, and a multiplicative interaction term were in-cluded as covariates in the model.

Analyses of the association between related AESIs/imAEsand OS were adjusted for age, sex, PS, and the presence orabsence of liver metastases at baseline as covariates in theCox proportional hazards regression model, with the indi-vidual studies as stratification factors to account for theheterogeneity within the studies. Among responders, theduration of response in patients who did or did not receivecorticosteroids was examined. These analyses usedKaplan-Meier curves and the Cox proportional hazardsregression model, with the individual studies as stratificationfactors. All analyses were performed using R statisticalsoftware (www.r-project.org).

TABLE 2. Demographics and Baseline Disease CharacteristicsCharacteristic Prior Platinum (% ) Cisplatin Ineligible (%) Total* (%)

No. of patients 1,258 489 1,747

Median age, years (range) 67 (29-91) 73 (34-94) 68 (29-94)

Sex

Male 75 78 76

Female 25 22 24

Race

White 79 89 82

Asian 12 6 10

Other 8 5 7

Performance status

0 42 26 37

1 58 37 52

2 0.2 37 10

Prior cisplatin 73 10 55

Prior carboplatin 43 2 32

Neoadjuvant/adjuvant only 17 11 15

Reason cisplatin ineligible

Creatinine clearance . 60 mL/min 45 62 50

Performance status 2 0.2 37 10

Grade $ 2 hearing loss Unknown 12 3

Grade $ 2 neuropathy Unknown 4 1

Class 3 heart failure Unknown 0.6 0.2

Bellmunt score

0 34 21 31

1 39 54 43

2 21 20 21

3 6 5 5

Bajorin score

0 36 24 32

1 64 62 59

2 0.2 29 8

*Missing data are not included as a separate category. Patients may have received both cisplatin and carboplatin or hadmore than one reasonthey were cisplatin ineligible.

Journal of Clinical Oncology 3

Adverse Events and Anti–PD-1/L1 Antibodies


http://www.r-project.org

Most of the trials analyzed patient subgroups on thebasis of either the Bellmunt or Bajorin risk scores, whichwere calculated in patients who received prior platinum-based therapy and first-line treatment, respectively.13,14

In these analyses, both risk scores were calculated foreach trial (using the sites of disease determined byindependent review) so that these results could becompared easily.

RESULTS

Seven multicenter clinical trials in 1,747 patients werepooled for this analysis (Table 1). Patient demographicsand baseline characteristics, those who had received priorplatinum-based therapy, and those who were cisplatinineligible are listed in Table 2. Compared with the five trialsthat enrolled patients who had received prior platinum-based therapy, the patients who were cisplatin ineligiblewere slightly older, more likely to have a PS of 2, and morelikely to have a reduced creatinine clearance.

A relationship was seen between confirmed response byRECIST version 1.1 and the development of a related AESI/imAE in the pooled data (Table 3). Each individual trialdemonstrated a substantial association between the de-velopment of a related AESI/imAE and response, with re-lated AESIs occurring in 52% to 73% of respondingpatients. This association was evaluated through a logisticregression model adjusted for the duration of exposurewherein the odds ratio (OR) of having a related AESI was5.38 (95% CI, 3.06 to 9.46) for responders compared withnonresponders (Appendix Table A6, online only); for re-lated imAEs, the OR was 3.77 (95% CI, 2.02 to 7.03;Appendix Table A5, online only). The interaction was sig-nificant in both models, which indicates that the re-sponders and nonresponders had a differential proclivity fordeveloping a related AESI/imAE given the same duration ofexposure. Results from the Cox proportional hazards re-gression models of the time to first related AESI adjusted forexposure found an HR of 1.30 (95% CI, 1.06 to 1.59;Appendix Fig A1, online only). A similar analysis of related

imAEs found an HR of 1.67 (95% CI, 1.24 to 2.27, Ap-pendix Fig A2, online only).

It was believed that the relationship between related AESIs/imAEs and response may be stronger in patients who hadnot received a systemic corticosteroid. This was furtherexamined in patients who received a topical corticosteroidor thyroid medication to treat a related AESI but who did notreceive a systemic corticosteroid during the treatmentperiod. The relationship between response and the de-velopment of a related AESI, topical corticosteroid use, orthe use of thyroid medication seemed to be similar, re-gardless of the use of a systemic corticosteroid (Table 3).

Given the differences in patient populations, additionalexaminations included the association of response andrelated AESIs/imAEs by sex, age (less than 80 years or80 years and older), prior platinum-based therapy, orcisplatin ineligibility (Appendix Tables A1 and A2, onlineonly). These examinations did not show a substantialchange in the association between response and reports ofrelated AESIs/imAEs. This relationship also was examinedin patients who received a PD-1 or a PD-L1 inhibitor; inthose who received zero, one, or two prior systemic regi-mens; and in those who had a PS of 0, 1, or 2. Theseanalyses were limited to patients who received atezolizu-mab or pembrolizumab because both were administered topatients who had received prior platinum-based therapyand to patients who were cisplatin ineligible (AppendixTables A3 and A4, online only). All patients who had notreceived a prior systemic regimen and most of those witha PS of 2 were enrolled in the studies of patients who werecisplatin ineligible. Again, these examinations did not showa substantial change in the association between the de-velopment of a related AESI or related imAE and tumorresponse.

A responder analysis of the relationship between the de-velopment of a related AESI or imAE and OS when adjustedfor baseline covariates found an improvement in OS amongpatients who developed a related AESI (HR, 0.45; 95% CI,0.39 to 0.53) or a related imAE (HR, 0.53; 95% CI, 0.43 to

TABLE 3. Association Between Response and Development of Related AESIs or Related imAEsVariable Response, No. (%) No Response, No. (%)

No. of patients 351 1,396

Related AESI 226 (64) 470 (34)

95% CI 59 to 69 31 to 36

Related AESI* (no systemic corticosteroids) 147 (42) 291 (22)

Related imAE* 100 (28) 167 (12)

Topical corticosteroids* (no systemic corticosteroids) 40 (11) 31 (2)

Thyroid medication* 46 (13) 44 (3)

Thyroid medication* (no systemic corticosteroids) 29 (8) 29 (2)

NOTE. Related refers to the AESIs or imAEs that the investigator believed was related to study drug.Abbreviations: AESI, adverse event of special interest; imAE, immune-mediated adverse event.*The incidence is presented for patients who received topical or systemic corticosteroids and patients who received no systemic corticosteroids.


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0.66). The relationship between OS and the development ofa related AESI is shown in Figure 1, whereas the re-lationship between OS and the development of a relatedimAE is shown in Appendix Figure A3 (online only).

After the relationship between patient outcome and thedevelopment of a related AESI/imAE was seen, the timing ofresponse relative to the development of these events wasexamined (Table 4). Patients with a related AESI/imAE bothbefore and after the date of response were counted morethan once in this table. Among the 226 responding patientswho reported a related AESI, 57% reported an event beforedocumentation of a response. The most common relatedAESIs before response were pruritus, rash, and thyroiddisease. Most were grade 1 to 2 events, but seven patients(5%) had a grade 3 to 4 related AESI. Among the 100responding patients who had related imAEs, 27 wereprescribed a corticosteroid before response. This includedsix patients who began a systemic corticosteroid at a me-dian of 44 days before response (range, 61 to 11 daysbefore the day of response).

The use of systemic corticosteroids did not seem to neg-atively affect the chances of developing a response and didnot seem to affect the duration of response (Fig 2).Responding patients who did and did not receive systemiccorticosteroids (administered for any reason, including animAE) seemed to have a similar duration of response (HR,1.09; 95% CI, 0.70 to 1.69).

DISCUSSION

These exploratory analyses focused on the associationbetween efficacy and the development of related AESIs/imAEs among 1,747 patients with urothelial cancer whoreceived a PD-1/L1 inhibitor in seven clinical trials that ledto product approval in the United States. We observeda substantial relationship between the development ofa related AESI/imAE and patient outcome in terms of

response and OS. This relationship did not seem to beaffected by systemic corticosteroids. Likewise, systemiccorticosteroids did not seem to affect the duration of re-sponse. Our analyses also examined the relationship be-tween the timing of the onset of related AESIs or the timingof the initiation of corticosteroids with related imAEs and thedocumentation of response. We note that in many cases,the responding patients developed a related AESI or a re-lated imAE before documentation of tumor response.

A key limitation is that the incidence of related AESIs/imAEsamong responders was confounded by the duration oftreatment. To adjust for duration of exposure, multivariableanalyses were conducted, including an assessment of theOR, corrected for the duration of exposure, for the devel-opment of related AESIs/imAEs in responding and non-responding patients and the time to first related AESI/imAE.The ORs, corrected for the duration of exposure, continuedto show an association between response and the devel-opment of related AESIs/imAEs. The significant interactionterm between response and duration of exposure in thelogistic regression model suggests that the OR for re-sponders compared with nonresponders is different forpatients with different exposure times. The analyses of timeto first related AESI/imAE found that when adjusted forexposure, responding patients were 30% more likely tohave a related AESI and 67% more likely to havea related imAE.

These analyses also are limited by their exploratory andretrospective nature and do not account for the fact thatrelated AESI/imAEs are treatment-mediated events thatoccur after the initiation of therapy. The duration of ob-servation for AESIs/imAEs, given that these are biologictherapies with a prolonged half-life, also may have limitedaccurate collection of these events. In addition, theseanalyses are limited by the definitions of AESIs and imAEsand the determination of their relationship to study drug (ie,that AESIs are events of interest that may not be immune

0 5 10 15 20 25

0.25

0.50

0.75

1.00

Duration (months)

Over

all S

urvi

val (

prob

abili

ty) Not treatment related

Treatment related

Not treatment relatedNo. at risk (No. censored)

1,051 (0)

696 (0)

503 (97)

506 (63)

269 (186)

331 (151)

63 (341)

81 (358)

5 (392)

6 (429)

1 (396)

0 (435)Treatment related

FIG 1. Overall survival, adjusted fortrial, age, sex, performance status,and liver metastases (yes/no), inpatients who did and did not reporttreatment-related adverse events ofspecial interest. Includes data fromall seven trials.




mediated). AESIs and imAEs that were believed by theinvestigator to be related to the use of an anti–PD-1/L1antibody were used in these analyses to increase thelikelihood that these events are, in fact, immune mediated.Another limitation is that although imAEs are defined by theuse of corticosteroids, the decision to use corticosteroidsmay vary among practitioners and among the anti–PD-1/L1antibodies. The fact that a large database and five differentanti–PD-1/L1 antibodies were examined may lessen thisconcern. Furthermore, these analyses did not distinguishamong the dose, duration, or route of the corticosteroid todetermine whether these variables may have had an ad-ditional effect on patient outcomes. Finally, although eachtrial showed a substantial relationship between the devel-opment of a related AESI/imAE and response, there wasa difference in the percentage of responding patients witha related AESI/imAE among the seven trials. Additional workis needed on the related AESIs that occurred before re-sponse and other factors, such as AESI grade, that may bepredictive of patient outcome.

The interplay between imAEs and markers of efficacy, suchas response rate and OS, remains a research question withimportant clinical implications. First, there is the question ofwhether the same activation of the immune system thatleads to the development of antitumor responses could alsosimultaneously lead to the development of related AESIs/imAEs. This would have implications for counseling patients

who may develop such AEs if these events are confirmed tobe correlative biomarkers of efficacy outcome. An additionalquestion with clinical implications is whether the use ofsystemic corticosteroids to abrogate immune activation alsomight dampen the desired immune-mediated responses.Our analyses provide reassuring data on the effect of sys-temic corticosteroids on the duration of response. However,this analysis should be viewed with caution because of thelimited, nonuniform follow-up between studies.

Much of what was previously known about the relationshipbetween the development of AESIs/imAEs and efficacy wasderived from retrospective analyses of patients with mel-anoma, for whom ipilimumab has been Food and DrugAdministration approved since 2011. Some analyses ofipilimumab-treated patients who developed imAEs seem toindicate that these patients may indeed have an increasedresponse rate compared with those who do not developimAEs and that the use of corticosteroids does not seem tohave a negative effect on response rates or durations.3 Alandmark analysis, however, found no relationship betweenimAEs and time to treatment failure.4 Analysis of the use ofnivolumab in patients with melanoma, when adjusted forthe number of doses of nivolumab, also seemed to showa trend toward improved response rates in patients withimAEs versus those without imAEs. The use of cortico-steroids in patients who received nivolumab similarly didnot seem to have a detrimental effect on efficacy outcomes.5

TABLE 4. Timing of Related AESIs and Related imAEs Relative to Documentation of ResponseVariable Before Response,* No. (%) After Response, No. (%)

Response and related AESI (n = 226) 128 (57) 165 (73)

Response and related imAE (n = 100) 27 (27) 81 (81)

NOTE. Related refers to AESIs or imAEs that the investigator believed were related to study drug.Abbreviations: AESI, adverse events of special interest; imAE, immune-mediated adverse event.*Adverse events that began or corticosteroids that were initiated on the day of response were considered before.

No. at risk (No. censored)

No systemic corticosteroids

Systemic corticosteroids

267 (0)

84 (0)

232 (23)

76 (3)

160 (64)

55 (13)

72 (121)

28 (33)

20 (146)

8 (46)

1 (160)

0 (53)

4 (158)

1 (53)

0 100 200 300 400 500 600

0.25

0.50

0.75

1.00

Duration of Response (days)

Over

all S

urvi

val (

prob

abili

ty)

No systemic corticosteroids

Systemic corticosteroids

FIG 2. Duration of response for pa-tients who did and did not receivesystemic corticosteroids. This analy-sis is limited to patients with a con-firmed response and includes theadministration of systemic cortico-steroids, regardless of indication.


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Discipline-specific literature also describes the observedinterplay between imAEs and tumor responses. One case-control study in the dermatology literature of 20 patientsobserved that patients with immune-mediated dermatitison PD-1 inhibitors tended to have higher overall responserates than matched patients who did not develop der-matitis (65% v 17%), and that patients with dermatitishad a longer 1-year OS rate (90% v 57%).15 A similareffect was seen in an analysis of patients with melanomatreated with a PD-1 inhibitor where patients who de-veloped vitiligo seemed more likely to have an objectiveresponse to treatment than those who did not developvitiligo (71% v 28%). This difference was not statisticallysignificant when corrected for lead-time bias.16 Therheumatology literature describes a single-institution ex-perience in which 35 of 524 consecutive checkpoint inhib-itor–treated patients were referred to rheumatology for

management of rheumatic imAEs. Among patients withrheumatic imAEs, response rates were significantlyhigher than in patients without imAEs (85.7% v 35.3%).The proportion of responders was also higher in patientswho presented with other imAEs compared with thosewithout imAEs (75.1% v 35.3%).17

To our knowledge, this study of seven trials using five anti–PD-1/L1 antibodies in the treatment of a single canceranalyzes the largest patient population to date (n = 1,747)in which the development of related AESIs/imAEs could beexamined. We observed a substantial association betweenthe development of related AESIs/imAEs and patient out-come. This relationship was seen both before and afterdocumented response. Equally important is our observa-tion that the use of systemic corticosteroids did not seem toaffect the duration of response.

AFFILIATION1US Food and Drug Administration, Silver Spring, MD

CORRESPONDING AUTHORV. Ellen Maher, MD, 9419 Seven Locks Rd, Bethesda, MD 20817;e-mail: [email protected]

EQUAL CONTRIBUTIONJ.A.B. and R.P. contributed equally to this work and are co-seniorauthors.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTERESTAND DATA AVAILABILITY STATEMENTDisclosures provided by the authors and data availability statement (ifapplicable) are available with this article at DOI https://doi.org/10.1200/JCO.19.00318.

AUTHOR CONTRIBUTIONSConception and design: V. Ellen Maher, Laura Fernandes, ChanaWeinstock, Shenghui Tang, Marc Theoret, Julia A. Beaver, RichardPazdur

Administrative support: Kirsten B. GoldbergCollection and assembly of data: V. Ellen Maher, Laura L. Fernandes,Chana Weinstock, Sundeep Agrawal, Michael Brave, Yang-min Ning,Harpreet Singh, Daniel Suzman, James XuData analysis and interpretation: V. Ellen Maher, Laura L. Fernandes,Chana Weinstock, Shenghui Tang, Rajeshwari Sridhara, Amna Ibrahim,Marc Theoret, Julia A. Beaver, Richard Pazdur

Manuscript writing: All authorsFinal approval of manuscript: All authorsAccountable for all aspects of the work: All authors

ACKNOWLEDGMENT

We thank the patients, staff, and investigators who participated in theseseven trials in addition to the pharmaceutical companies who sponsoredthe trials: AstraZeneca, Bristol-Myers Squibb, EMD Serono, Genentech,and Merck.

REFERENCES1. Perez-Soler R, Saltz L: Cutaneous adverse effects with HER1/EGFR-targeted agents: Is there a silver lining? J Clin Oncol 23:5235-5246, 2005

2. Abdel-Rahman O, Fouad M: Correlation of cetuximab-induced skin rash and outcomes of solid tumor patients treated with cetuximab: A systematic review andmeta-analysis. Crit Rev Oncol Hematol 93:127-135, 2015

3. Beck KE, Blansfield JA, Tran KQ, et al: Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4. J Clin Oncol24:2283-2289, 2006

4. Horvat TZ, Adel NG, Dang TO, et al: Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatmentfailure in patients with melanoma treated with ipilimumab at Memorial Sloan Kettering Cancer Center. J Clin Oncol 33:3193-3198, 2015

5. Weber JS, Hodi FS, Wolchok JD, et al: Safety profile of nivolumab monotherapy: A pooled analysis of patients with advanced melanoma. J Clin Oncol 35:785-792, 2017

6. Rosenberg JE, Hoffman-Censits J, Powles T, et al: Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressedfollowing treatment with platinum-based chemotherapy: A single-arm, multicentre, phase 2 trial. Lancet 387:1909-1920, 2016

7. Balar AV, Galsky MD, Rosenberg JE, et al: Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelialcarcinoma: A single-arm, multicentre, phase 2 trial. Lancet 389:67-76, 2017

8. Patel MR, Ellerton J, Infante JR, et al: Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): Pooled results from twoexpansion cohorts of an open-label, phase 1 trial. Lancet Oncol 19:51-64, 2018

9. Powles T, O’Donnell PH, Massard C, et al: Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: Updated results froma phase 1/2 open-label study. JAMA Oncol 3:e172411, 2017

10. Sharma P, Retz M, Siefker-Radtke A, et al: Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): A multicentre, single-arm,phase 2 trial. Lancet Oncol 18:312-322, 2017




mailto:[email protected]



11. Bellmunt J, de Wit R, Vaughn DJ, et al: Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med 376:1015-1026, 2017

12. Balar AV, Castellano D, O’Donnell PH, et al: First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastaticurothelial cancer (KEYNOTE-052): A multicentre, single-arm, phase 2 study. Lancet Oncol 18:1483-1492, 2017

13. Bellmunt J, Choueiri TK, Fougeray R, et al: Prognostic factors in patients with advanced transitional cell carcinoma of the urothelial tract experiencing treatmentfailure with platinum-containing regimens. J Clin Oncol 28:1850-1855, 2010

14. Bajorin DF, Dodd PM, Mazumdar M, et al: Long-term survival in metastatic transitional-cell carcinoma and prognostic factors predicting outcome of therapy.J Clin Oncol 17:3173-3181, 1999

15. Min Lee CK, Li S, Tran DC, et al: Characterization of dermatitis after PD-1/PD-L1 inhibitor therapy and association with multiple oncologic outcomes: Aretrospective case-control study. J Am Acad Dermatol 79:1047-1052, 2018

16. Hua C, Boussemart L, Mateus C, et al: Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab. JAMADermatol 152:45-51, 2016

17. Kostine M, Rouxel L, Barnetche T, et al: Rheumatic disorders associated with immune checkpoint inhibitors in patients with cancer-clinical aspects andrelationship with tumour response: A single-centre prospective cohort study. Ann Rheum Dis 77:393-398, 2018

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AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Analysis of the Association Between Adverse Events and Outcome in Patients Receiving a Programmed Death Protein 1 or Programmed Death Ligand 1 Antibody

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-heldunless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information aboutASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.

Daniel Suzman

Other Relationship: Grand Rounds

No other potential conflicts of interest were reported.

Journal of Clinical Oncology



http://www.asco.org/rwc

http://ascopubs.org/jco/site/ifc

APPENDIX

0.25

0.50

0.75

1.00

Time to First Related imAE (days)

Over

all S

urvi

val (

prob

abili

ty)

Nonresponder

Responder

0 200 400 600 800

1,392 (0) 146 (1082) 13 (1211) 2 (1222) 0 (1224)

351 (0) 184 (79) 51 (201) 7 (245) 0 (251)Responder

Nonresponder


FIG A2. Time to first related immune-mediated adverse event (imAE) in patients with a confirmed response and inthose who did not respond to study drug. The hazard ratio for this analysis was 1.67 (95% CI, 1.24 to 2.27). Includedare data from all seven trials, but four patients in the randomized trial who were not treated were omitted.

0 200 400 600 800

0.25

0.50

0.75

1.00

Time to First Related AESI (days)

Over

all S

urvi

val (

prob

abili

ty)

Nonresponder

Responder

1,392 (0) 84 (850) 7 (915) 2 (920) 0 (922)

351 (0) 107 (43) 28 (101) 5 (121) 0 (125)Responder

Nonresponder


FIG A1. Time to first related adverse event of special interest (AESI) in patients with a confirmed response and inthose who did not respond to study drug. The hazard ratio for this analysis was 1.30 (95%CI, 1.06 to 1.59). Includedare data from all seven trials, but four patients in the randomized trial who were not treated were omitted.

Published by American Society of Clinical Oncology

Maher et al


0.25

0.50

0.75

1.00

Time (months)

Over

all S

urvi

val (

prob

abili

ty) No imAEs

imAEs

0 5 10 15 20 25

1,479 (0) 814 (136) 461 (287) 111 (560) 8 (653) 1 (660)

268 (0) 195 (24) 139 (50) 33 (139) 3 (168) 0 (171)imAEs

No imAEs


FIG A3. Overall survival, adjusted for trial, age, sex, performance status, and liver metastases (yes/no), amongpatients with and without a related immune-mediated adverse event (imAE). The hazard ratio for this analysis was0.53 (95% CI, 0.43 to 0.66). Included are data from all seven trials.




TABLE A1. Response and the Development of Related AESIs or Related imAEsAmong Patients Who Received Prior Platinum-Based Therapy or Were CisplatinIneligible

Prior Platinum, No. (%) Cisplatin Ineligible, No. (%)

Variable Response No Response Response No Response

No. of patients 217 1,041 134 355

Related AESI 139 (64) 346 (33) 87 (65) 124 (35)

Related imAE 61 (28) 118 (11) 39 (29) 49 (14)

Thyroid medication 26 (12) 36 (3) 20 (15) 8 (2)

NOTE. Related refers to AESIs or imAEs that the investigator believed wererelated to study drug.Abbreviations: AESI, adverse event of special interest; imAE, immune-mediated

adverse event.

TABLE A2. Development of Related AESIs or Related imAEs and Response by Age,Sex, and the Use of a PD-1 or PD-L1 Inhibitor

Related AESI, No. (%) Related imAE, No. (%)

Variable Response No Response Response No Response

Age, years

No. of patients 298 1,229 53 167

, 80 191 (64) 410 (33) 35 (66) 60 (36)

$ 80 83 (28) 146 (12) 17 (32) 21 (13)

Sex

No. of patients 277 1,050 74 346

Male 177 (64) 347 (33) 49 (66) 123 (36)

Female 79 (29) 126 (12) 21 (28) 41 (12)

PD-1/L1 inhibitors

No. of patients 216 694 135 702

PD-1 143 (66) 233 (34) 83 (61) 237 (34)

PD-L1 68 (31) 89 (13) 32 (24) 78 (11)

NOTE. Related refers to AESIs or imAEs that the investigator believed wererelated to study drug.Abbreviations: AESI, adverse event of special interest; imAE, immune-mediated

adverse event; PD-1, programmed death protein 1; PD-L1, programmed deathprotein ligand 1.


Maher et al


TABLE A3. Association Between Related AESIs or Related imAEs and Response Among Patients Who Received Zero to Two Prior Therapies:Atezolizumab and Pembrolizumab Only

Prior Systemic Therapies, No. (%)

None One Two

Variable Response No Response Response No Response Response No Response

No. of patients 116 308 96 390 25 123

Related AESI 77 (66) 109 (35) 61 (64) 124 (32) 15 (60) 32 (26)

Related imAE 37 (32) 45 (15) 24 (25) 34 (9) 6 (24) 10 (8)

NOTE. Related refers to AESIs or imAEs that the investigator believed were related to study drug.Abbreviations: AESI, adverse event of special interest; imAE, immune-mediated adverse event.

TABLE A4. Association Between Related AESIs/imAEs and Response Among Patients With a Performance Status of 0 to 2: Atezolizumab andPembrolizumab Only

Performance Status, No. (%)

0 1 2

Variable Response No Response Response No Response Response No Response

No. of patients 70 269 92 426 47 136

Related AESI 61 (86) 99 (37) 64 (70) 131 (31) 27 (57) 36 (26)

Related imAE 35 (50) 28 (10) 20 (22) 46 (11) 11 (23) 17 (13)

NOTE. Related refers to AESIs or imAEs that the investigator believed were related to study drug. Two patients (one with missing performancestatus and one with a performance status of 3) were not included.

Abbreviations: AESI, adverse event of special interest; imAE, immune-mediated adverse event.




TABLE A5. Coefficients From the Stratified Logistic Regression Model for the Related imAEsVariable Coefficient SE (coefficient) P OR Exp (coefficient) 95% CI

Response (yes/no) 1.33 0.319 , .001 3.77 2.02 to 7.03

Exposure, months 0.09 0.023 , .001 1.09 1.04 to 1.14

Response 3 exposure 20.08 0.035 .016 0.92 0.86 to 0.98

NOTE. Responder status (no is the reference category) and exposure (in months) with an interaction term are included in the model.Abbreviations: Exp, experimental; imAE, immune-mediated adverse event; OR, odds ratio.

TABLE A6. Coefficients From the Stratified Logistic Regression Model for Related AESIsVariable Coefficient SE (coefficient) P OR Exp (coefficient) 95% CI

Response (yes/no) 1.68 0.288 , .001 5.38 3.06 to 9.46

Exposure, months 0.19 0.019 , .001 1.20 1.16 to 1.25

Response 3 exposure 20.17 0.033 , .001 0.85 0.79 to 0.90

NOTE. Responder status (no is the reference category) and exposure (in months) with an interaction term are included in the model.Abbreviations: AESI, adverse event of special interest; Exp, experimental; OR, odds ratio.


Maher et al


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