After a grade 2 or higher immune-related adverse event, is an anti–PD-1 or anti–PD-L1 inhibitor rechallenge safe?
In this cohort study of 93 French adults who experienced a grade 2 or higher immune-related adverse event and had an anti–PD-1 or anti–PD-L1 rechallenge, 55% experienced a second adverse event. Earlier initial toxic effect was associated with more frequent recurrence, and the second event was not as severe as the first.
The risk-reward ratio for anti–PD-1 or anti–PD-L1 rechallenge appears to be acceptable, although these patients require close monitoring; rechallenge conditions warrant further investigation in a prospective clinical trial.
Although immune checkpoint inhibitors (ICIs), such as anti–PD-1 (programmed cell death 1) or anti–PD-L1 (programmed cell death 1 ligand 1), have proved effective in treating many cancers, patients receiving ICIs may experience immune-related adverse events (irAEs). Little evidence exists on the safety of resuming these treatments after an irAE.
To investigate the safety of a rechallenge with anti–PD-1 or anti–PD-L1 immunotherapies after an irAE.
Design, Setting, and Participants
This cohort study of the safety of an ICI rechallenge involved consecutive adult patients (n = 93) who were referred to the ImmunoTOX assessment board at the Gustave Roussy cancer center in Villejuif, France, between August 1, 2015, and December 31, 2017. Data were analyzed from May 28 to November 25, 2018.
Main Outcomes and Measures
Incidence of a second irAE in patients who had a readministration of an anti–PD-1 or anti–PD-L1 inhibitor after an initial grade 2 or higher irAE. Characteristics of the patients and the irAEs were reviewed, and the primary end point was the rate of occurrence of second irAEs.
A total of 93 patients were included, among whom 48 (52%) were female, and the median (range) age was 62.5 (33-85) years. The main cancer types or tumor sites were melanoma (31 [33%]), lung (15 [16%]), colorectal (8 [9%]), and lymphoma (8 [9%]). For the initial irAE, 43 grade 2 events (46%), 36 grade 3 events (39%), and 14 grade 4 events (15%) were found, presenting primarily as hepatitis (17 [18%]), skin toxic effect (14 [15%]), pneumonitis (13 [14%]), colitis (11 [12%]), or arthralgia (7 [7.5%]). Forty patients (43%) were rechallenged with the same anti–PD-1 or anti–PD-L1 agent. The rechallenged and non-rechallenged groups did not differ in terms of median (range) age (61 [34-84] years vs 63 [33-85] years; P = .37), time to initial irAE (5 [1-40] treatment cycles vs 3 [1-22] treatment cycles; P = .32), irAE severity (grade 2: 18 [47.5%] vs 27 [51%]; grades 3-4: 22 [52.5%] vs 26 [49%]; P = .70), or steroid use (17 [42.5%] vs 32 [60%]; P = .09). With a median follow-up period of 14 months, the same irAE or a different irAE occurred in 22 patients (55%). Shorter time to the initial irAE was linked to the occurrence of a second irAE (9 vs 15 weeks; P = .04). The second irAEs were not found to be more severe than the first.
Conclusions and Relevance
The risk-reward ratio for an anti–PD-1 or anti–PD-L1 rechallenge appears to be acceptable, although these patients require close monitoring; further investigation into rechallenge conditions through a prospective clinical trial is needed.
Marketing authorizations granted by the European Medicines Agency and the US Food and Drug Administration have made immunotherapy a standard of care in cancer treatment. Along with the initially validated indications (metastatic melanoma,1-3 adjuvant treatment,4,5 and metastatic non–small cell lung cancer6-8) for the immune checkpoint inhibitors (ICIs) of anti–cytotoxic T-lymphocyte antigen-4 (CTLA-4), anti–PD-1 (programmed cell death 1), and anti–PD-L1 (programmed death 1 ligand 1), favorable response rates and survival rates have been observed for many other types of cancer, such as advanced renal cell carcinoma,9,10 metastatic urothelial cancer,11 relapsed or refractory Hodgkin lymphoma,12 and mismatch repair–deficient colorectal cancer.13
The number of patients exposed to ICIs has increased over the past few years. Although ICIs are generally well tolerated, they have the ability to unbalance the immune system, which can generate immune-related adverse events (irAEs).14 Most irAEs are mild or moderately severe, and the most severe events (grades 3 and 4) occur in approximately 8% of patients undergoing anti–PD-1 or anti–PD-L1 monotherapy, 25% of patients undergoing anti–CTLA-4 monotherapy, and 50% receiving combination treatment with nivolumab-ipilimumab.15-17 These irAEs must be detected rapidly and, when indicated, treated with steroids.18,19
Most irAEs resolve after discontinuation of the ICI and treatment with steroids; only a few affected patients will require additional immunosuppressive therapy. According to the European Society for Medical Oncology Clinical Practice Guidelines on diagnosis, treatment, and follow-up and the American Society of Clinical Oncology Clinical Practice Guideline,20 most grade 2 irAEs (other than skin and endocrine toxic effects) will require systemic oral or intravenous steroid therapy and the temporary discontinuation of the ICI until the adverse event grade falls below 2. Grade 3 irAEs require high-dose intravenous steroids and the temporary or permanent discontinuation of the ICI. After Grade 4 irAEs, ICIs are generally discontinued permanently. The resumption of ICI treatment (ie, ICI rechallenge) will depend on the physician’s estimation of the risk-reward ratio and the availability of other treatment options.
Few data are available on the safety of rechallenge after an initial grade 2 or higher irAE has prompted the discontinuation of the anti–PD-1 or anti–PD-L1 agent.
Study Design and Participants
We performed a retrospective cohort study of anti–PD-1 or anti–PD-L1 rechallenge after the occurrence of an initial grade 2 or higher irAE. This study involved consecutive adult patients referred to ImmunoTOX, a multidisciplinary immunotoxicity assessment board at the Gustave Roussy cancer center in Villejuif, France, between August 1, 2015, and December 31, 2017. Data were analyzed from May 28 to November 25, 2018. This study and the creation of the ImmunoTOX board were approved by the institutional review board of the Gustave Roussy cancer center. Patients provided oral informed consent for their participation in the study. The study was registered in the Gustave Roussy REISAMIC (Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie) registry.
The ImmunoTOX board is part of a nationwide network of oncologists, pharmacovigilance physicians, immunologists, and other specialists who manage irAEs in patients with cancer. For inclusion in the present study, the irAE had to have a certain or probable causal association with the anti–PD-1 or anti–PD-L1 inhibitor as assessed on the World Health Organization Uppsala Monitoring Centre scale. All irAEs were reported using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03. The following data were reviewed: characteristics of the ICIs and any concomitant treatments received, clinical and laboratory characteristics of the patients, characteristics of the irAEs, medications administered to treat the irAEs, and the outcome of the irAEs. Rechallenge was defined as the readministration of the same drug class in the same patient.21 The first-ever irAE during anti–PD-1 or anti–PD-L1 treatment was defined as the initial irAE, and the irAE that occurred after the rechallenge was defined as the second irAE.
The study investigated the characteristics of (1) the initial irAEs; (2) the rechallenged group, or the patients who had a readministration of an anti–PD-1 or anti–PD-L1 agent after the grade 2 or higher irAE; and (3) the non-rechallenged group, or the patients who did not undergo readministration.
Patients with a second irAE were monitored from the start of the event until the final follow-up or death.
Data were extracted from the patients’ medical records. Qualitative variables were reported as the frequency (percentage), and quantitative variables were reported as the median (range). The rechallenged and non-rechallenged groups were compared by using a χ2 test or Fisher exact test for qualitative variables and an unpaired, 2-tailed t test or Kruskal-Wallis test for quantitative variables. The threshold for statistical significance was set to 2-sided P < .05.
Progression-free survival (PFS) was defined as the time interval between first administration of the anti–PD-1 or anti–PD-L1 agent and disease progression or death. Overall survival (OS) was defined as the time interval between the first administration of the anti–PD-1 or anti–PD-L1 agent and death from any cause. Patients who were alive at the time of the final analysis were censored at the final follow-up. Progression-free survival and OS were evaluated with the Kaplan-Meier method and reported with their 95% CIs. Survival outcomes were compared using the log-rank test. To assess the potential association of anti–PD-1 or anti–PD-L1 rechallenge with survival, we analyzed OS and PFS in nonprogressing patients only.
Characteristics of the Study Population
Of the 159 patients referred to the ImmunoTOX board over the study period, 123 were treated in the Gustave Roussy cancer center and 36 were treated in other clinics in France. Sixty-six patients were excluded from the present study: 27 experienced an adverse event related to disease progression or an intercurrent disease, 3 had an irAE below grade 2, 11 were referred to the ImmunoTOX board before anti–PD-1 or anti–PD-L1 initiation (for guidance on treatment of at-risk patients), and 25 had missing follow-up data. In these 25 patients, 1 (4%) had grade 1, 6 (24%) had grade 2, 7 (28%) had grade 3, 3 (12%) had grade 4, and 8 (32%) had an unknown grade of irAE.
Ultimately, 93 patients with a grade 2 or higher irAE after anti–PD-1 or anti–PD-L1 therapy were included in the study (eFigure 1 in the Supplement).
The patient characteristics are summarized in Table 1. In total, 48 (52%) of the patients were female, the median (range) age was 62.5 (33-85) years, and the median (range) duration of follow-up after anti–PD-1 or anti–PD-L1 initiation was 14 (4.3-48) months. The main tumor types were melanoma (n = 31 [33%]), lung (15 [16%]), colorectal (8 [9%]), lymphoma (8 [9%]), and others (31 [33%]). Patients were treated with an anti–PD-1 agent (46 [50%]), an anti–PD-L1 agent (9 [10%]), an anti–CTLA-4 and anti–PD-1 combination (8 [9%]), or an anti–PD-1 or anti–PD-L1 combined with another ICI (25 [27%]).
The irAEs experienced by the study population were distributed as follows: hepatitis, defined as an elevation of the liver enzymes alanine or aspartate transaminase greater than or equal to 3 times the upper limit of normal after exclusion of other causes, especially viral hepatitis (17 [18%]), skin toxic effect (14 [15%]), pneumonitis (13 [14%]), colitis (11 [12%]), arthralgia (7 [7.5%]), lipase elevation (6 [6.5%]), hematologic events (6 [6.5%]), endocrine events (6 [6.5%]), muscle-related events (4 [4%]), neurologic events (4 [4%]), ocular events (2 [2%]), nephrologic events (2 [2%]), and cardiac events (1 [1%]). There were 43 grade 2 events (46%), 36 grade 3 events (39%), and 14 grade 4 events (15%). During follow-up, 1 patient with a grade 4 hematologic event (immune-related aplastic anemia) died during the course of the irAE (Table 2).
More than half of the irAEs (49 [53%]) had been treated with steroids, and 7 patients (7.5%) required disease-modifying antirheumatic drugs or immunosuppressive drugs for the management of their irAEs: hydrochloroquine in 2 cases of skin toxic effect, mycophenolate mofetil in 2 cases of hepatitis, infliximab in 2 cases of colitis, and oral low-dose methotrexate in a case of arthralgia. The other patients were treated with topical drugs (6 [5%]), hormone replacement therapy (5 [4%]), and intravenous immunoglobulins (5 [4%]).
Forty (43%) of the 93 patients were rechallenged. The anti–PD-1 or anti–PD-L1 agent was temporarily discontinued for a median (range) of 3.8 (1-169) weeks in these patients. The anti–PD-1 or anti–PD-L1 inhibitor was permanently discontinued in the other 53 patients because of disease progression (16 [30%]), the severity of the initial irAE (16 [30%]), or the treating physician’s decision (21 [40%]).
No statistically significant differences were found between the rechallenged and non-rechallenged groups in terms of median (range) age (61 [34-84] years vs 63 [33-85] years; P = .37), the male to female ratio (18 to 22 vs 27 to 26; P = .68), the median (range) number of cycles of treatment before the occurrence of the irAE (5 [1-40] treatment cycles vs 3 [1-22] treatment cycles; P = .32), the median (range) duration of treatment before the irAE (12 [0.4-99] weeks vs 9.6 [0.6-76] weeks; P = .66), the toxic effect grade of the initial irAE (grade 2: 18 [47.5%] vs 27 [51%]; grades 3-4: 22 [52.5%] vs 26 [49%]; P = .70), or treatment of the initial irAE with systemic steroids (17 [42.5%] vs 32 [60%]; P = .09) (Table 1).
Safety of Rechallenge After an irAE
Of the 40 patients in the rechallenged group, 18 (45%) did not experience further irAEs. However, 17 patients (42.5%) experienced a recurrence of the same type of irAE, and 5 patients (12.5%) experienced a different type of irAE (eFigure 2 in the Supplement). Four of these 22 patients had both a different type of irAE and a recurrence of the first irAE.
The recurrences of the same irAE are described in Table 3. The recurrences affected all of the organs involved in the initial irAE, although the frequency of recurrence differed: 5 of 6 patients for arthralgia, 2 of 3 for grade 4 neutropenia, 3 of 5 for colitis, 3 of 5 for hepatitis, 3 of 7 for skin toxic effect, 1 of 5 for pneumonitis, and 0 of 3 for lipase elevation (Figure).
The severity distribution for the second irAE was 38% for grade 2, 48% for grade 3, and 14% for grade 4 (eFigure 3 in the Supplement). The second irAEs were not more severe than the initial event. No grade 5 irAEs occurred after an ICI rechallenge.
Factors Associated With irAE Recurrence and Effectiveness of Retreatment
The characteristics of patients in the rechallenged group in whom a second irAE occurred are summarized in Table 4. The median time interval between anti–PD-1 or anti–PD-L1 initiation and the initial irAE was shorter in the group with recurrence compared with the group with no recurrence (9 vs 15 weeks; P = .04). These 2 groups did not differ substantially with regard to other characteristics. The intergroup difference in the severity of the initial irAE was not statistically significant at P = .10 despite a higher frequency of grades 3 to 4 events in the group with recurrence. Accordingly, the proportion of patients treated with systemic steroids was higher in the group with recurrence compared with the group with no recurrence, although this difference was not statistically significant (12 of 22 [55%] vs 4 of 18 [22%]; P = .055).
The rechallenged and non-rechallenged groups did not differ statistically significantly with regard to median PFS time (19.1 months; 95% CI, 17-not reached vs 23.6 months; 95% CI, 10.2-not reached). The median OS time was not reached in either group (eFigure 4 in the Supplement). The main characteristics of patients and tumor type distribution were otherwise similar in the 2 groups.
In the rechallenged group (n = 40), the best overall responses at the time of temporary withdrawal from anti–PD-1 or anti–PD-L1 inhibitors were as follows: 9 patients with partial response, 17 with stable disease, 4 with progressive disease, and 10 with an early irAE with no previous radiologic assessment of the response. At the time of rechallenge, 13 patients had a partial response, 15 had stable disease, 9 had progressive disease, and 3 had not been radiologically assessed. The median PFS was 21.5 months among those with partial response, 15.8 months among those with stable disease, and 15.8 months among those with progressive disease.
This study addressed the topic of readministration of anti–PD-1 or anti–PD-L1 agent in patients with previous irAEs but no other treatment options. Despite its retrospective design, the study had a number of strengths, including the broad spectrum of cancers in the study patients and the ImmunoTOX board’s multidisciplinary assessment of the irAEs as to whether to rechallenge or not. The involvement of organ specialists was useful in identifying the irAE’s putative causal relationship with an anti–PD-1 or anti–PD-L1 agent and for helping the oncologists to decide whether to rechallenge with an anti–PD-1 or anti–PD-L1 agent. The results suggest that anti–PD-1 or anti–PD-L1 rechallenge can be performed in patients with various cancers but is associated with the recurrence of a grade 2 or higher irAE (or the occurrence of a different irAE) in 55% of cases. Although no deaths occurred in the present study, we recommend close monitoring.
Data in the literature are few, and the available information is focused on lung cancer. We have reviewed and summarized the findings of studies published on this topic (eTable in the Supplement). Spain et al22 published the first case report on 3 patients who received nivolumab-ipilimumab combination therapy for metastatic melanoma and were rechallenged with the same ICI after a severe irAE. The recurrent irAE was severe in 2 patients. Both patients required high-dose systemic steroids and immunosuppressive drugs. Rechallenge with nivolumab-ipilimumab combination therapy should only be considered in extremely well selected patients.
Pollack et al23 demonstrated that an anti–PD-1 rechallenge after an irAE during combination treatment with anti–CTLA-4 and anti–PD-1 agents for metastatic melanoma was associated with recurrence of the initial irAE (in 18% of patients) or the occurrence of a different irAE (in 21%). This low recurrence rate (compared with the value of 55% observed in the present study) might be associated with the switch from a combination therapy to (potentially safer) monotherapy.
Santini et al24 focused on rechallenge in 69 patients with lung cancer who were treated with an anti–PD-1 or anti–PD-L1 agent. The main irAEs were grade 2 (54%) or grade 3 (42%), and they included pneumonitis (21%), colitis (17%), erythematous rash and pruritus (14%), and hepatitis (13%). Given the lung cancer setting, a high incidence of pneumonitis was not unexpected. Thirty-eight patients (55%) were rechallenged with an anti–PD-1 or anti–PD-L1 inhibitor; half of these patients experienced a recurrent or new irAE, and 2 of them died. This incidence was the same as that observed in the present study, with a broad spectrum of cancers.
In the present study, 1 patient died as a consequence of the initial irAE. However, no deaths occurred after the anti–PD-1 or anti–PD-L1 rechallenge. The initial irAE had occurred earlier in the patients with recurrence of an irAE after anti–PD-1 or anti–PD-L1 rechallenge. As mentioned, we did not observe any statistically significant differences between the group with recurrence and the recurrence-free group with regard to the irAE severity or the need for corticosteroid treatment. However, we did observe a trend toward a higher recurrence rate after a more severe initial irAE and a trend toward more frequent recurrence in patients treated with corticosteroids after the initial irAE. Well-powered, prospective studies with a larger number of patients would be required to generate information on putative risk factors for the recurrence of irAEs. Our results highlighted the value of a review board, like ImmunoTOX, with intention to build a large irAE database and then establish evidence-based guidelines on the safety of a rechallenge.
Unusually, 5 patients in the present study had been rechallenged after a grade 4 irAE. However, all 5 irAEs corresponded to transient (albeit marked) changes in laboratory variables. One of them had isolated grade 4 creatine phosphokinase elevation without any argument for myocarditis, 3 had grade 4 neutropenia requiring granulocyte-colony stimulating factor, and 1 had grade 4 cytolysis. As suggested by Thanarajasingam et al,25 the toxic effect grade may not be the sole marker of relevance when assessing the safety of modern treatments. An irAE recurred in 3 of these 5 patients, and a new irAE occurred in 1, leading to the permanent discontinuation of the immunotherapy only in 1 patient (febrile neutropenia). An anti–PD-1 or anti–PD-L1 rechallenge after a grade 4 irAE should always be considered with caution. Note that 3 of the 5 patients were being treated for lymphoma; anti–PD-1 or anti–PD-L1 rechallenge was notably attempted because of the drug’s anticipated effectiveness in this pathological disease.
The question of whether to rechallenge is crucial. Practical guidelines of irAE management are based on clinical observations and expert consensus, and the possibility of rechallenge is not discussed.18,20,26 Because of the lack of specific recommendation, decision to rechallenge was based on the potential risk-reward ratio for each individual situation. We took the following into account. First, we considered the usefulness of the rechallenge. The readministration could be delayed if the patient was in complete or excellent partial response. The existence of other therapeutic alternatives was also important. Second, we considered the clinical and biological state of the patient. Rechallenge was considered possible only after the grade of the irAE got back to 0 or 1. Third, we considered the potential severity of the irAE recurrence. Because of life-threatening risk, we did not support rechallenge for cardiac (myocarditis) and neurologic irAEs as Guillain-Barré syndrome, encephalitis, and severe myositis. Fourth, we considered the possibility to estimate the recurrence of the irAEs. For some irAEs, imagery (computed tomography scan for lung irAE) or biological monitoring could be useful to estimating the future recurrence of the irAE or to diagnosing it as an early step. The lack of such tools for neurologic irAEs explained our caution about these irAEs.
Hence, anti–PD-1 or anti–PD-L1 rechallenge appears to be feasible and (with close monitoring) safe. However, the rechallenge should first be assessed in a multidisciplinary team meeting with regard to each patient’s individual risk-reward ratio. Further investigations are needed to define the detailed criteria for anti–PD-1 or anti–PD-L1 rechallenge. Identifying the factors associated with ICI toxic effects in general and irAEs in particular is needed so that patients can be appropriately monitored as a function of the risk.27
This study has several limitations. First, it is a retrospective study. Second, the results cannot be generalized to all patients receiving ICIs because only a few patients treated with an anti–CTLA-4 and anti–PD-1 combination were included; none of the patients had a history of autoimmune disease prior to the immunotherapy, which would have increased the risk of the rechallenge; and none of the patients received adjuvant therapy.
After a mild or severe irAE, anti–PD-1 or anti–PD-L1 readministration was associated with the occurrence of a second irAE in 55% of cases. When a second irAE occurred, it was not more severe than the first. Recurrence of an irAE was associated with a shorter time interval between the initiation of anti–PD-1 or anti–PD-L1 treatment and the initial irAE. As long as patients are closely monitored, anti–PD-1 or anti–PD-L1 rechallenge appears to have an acceptable toxic effect profile. Myocarditis and neurologic toxic effect should remain a contraindication. Rechallenge conditions require further investigation in a prospective clinical trial.
Accepted for Publication: March 4, 2019.
Corresponding Author: Olivier Lambotte, MD, PhD, Department of Internal Medicine and Clinical Immunology, CHU Bicêtre, APHP, 78 Rue du Général Leclerc, F-94275 Le Kremlin-Bicêtre, France (firstname.lastname@example.org).
Published Online: June 6, 2019. doi:10.1001/jamaoncol.2019.1022
Author Contributions: Drs Simonaggio and Lambotte had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Simonaggio, Michot, Le Pavec, Laparra, Champiat, Lambotte.
Acquisition, analysis, or interpretation of data: Simonaggio, Michot, Voisin, Le Pavec, Collins, Lallart, Cengizalp, Vozy, Varga, Champiat, Hollebecque, Marabelle, Massard, Lambotte.
Drafting of the manuscript: Michot, Voisin, Le Pavec, Lallart, Cengizalp.
Critical revision of the manuscript for important intellectual content: Simonaggio, Michot, Le Pavec, Collins, Vozy, Laparra, Varga, Champiat, Hollebecque, Marabelle, Massard, Lambotte.
Administrative, technical, or material support: Michot, Champiat, Marabelle, Massard.
Supervision: Simonaggio, Michot, Varga, Hollebecque, Marabelle, Lambotte.
Conflict of Interest Disclosures: Dr Michot reported advisory board membership for Bristol-Myers Squibb, Pfizer, Roche, Novartis, Janssen, AstraZeneca, Celgene, and Gilead. Dr Collins reported lecture fees from MSD, AbbVie, Takeda, and Celgene; advisory board membership for AbbVie; and grant 20170839109 from FRM FDM. Dr Varga reported advisory board membership for Bristol-Myers Squibb, Pfizer, Roche, AstraZeneca, and Celgene. Dr Hollebecque reported advisory board membership for Bristol-Myers Squibb, Pfizer, Roche, AstraZeneca, and Celgene. Dr Champiat reported honoraria from AstraZeneca, Bristol-Myers Squibb, Janssen, MSD, Novartis, and Roche. Dr Marabelle reported scientific advisory board membership for Merck Serono, eTheRNA, Lytix, Kyowa Kirin, Bayer, Novartis, BMS, Symphogen, Genmab, Amgen, Biothera, Nektar, GlaxoSmithKline, Oncovir, Pfizer, Seattle Genetics, Flexus Bio, Roche/Genentech, OSE, Transgene, and Gritstone. Dr Massard reported advisory board membership for Amgen, Astellas, AstraZeneca, Bayer, Celgene, Genentech, Ipsen, Janssen, Lilly, Novartis, Pfizer, Roche, Sanofi, and Orion. Dr Lambotte reported expert testimony and consultancy fees from Bristol-Myers Squibb France, MSD, and AstraZeneca; consultancy fees from Genzyme; and expert testimony fees from Janssen. No other disclosures were reported.
Funding/Support: This research was supported by the Gustave Roussy cancer center and Gustave Roussy Immunotherapy Program.
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: We thank David Fraser, DPhil, Biotech Communication SARL, for editing the manuscript. He received compensation for his contribution.
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