Atypical patterns of responses in the era of immune checkpoint inhibitors in head and neck cancer

Atypical patterns of responses in the era of immune checkpoint inhibitors in head and neck cancer

Oral Oncology 100 (2020) 104477 Contents lists available at ScienceDirect Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology Revi...

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Oral Oncology 100 (2020) 104477

Contents lists available at ScienceDirect

Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology

Review

Atypical patterns of responses in the era of immune checkpoint inhibitors in head and neck cancer

T

Stergios Doumasa, Periklis G. Foukasb, Panagiota Economopoulouc, Ioannis Kotsantisc, ⁎ Amanda Psyrric, a

Maxillofacial Unit, Brighton & Sussex University Hospitals NHS Trust, United Kingdom 2nd Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, Attikon University Hospital, 1st Rimini St, 12462 Haidari, Athens, Greece c Section of Medical Oncology, Second Department of Internal Medicine, Attikon University Hospital National and Kapodistrian University of Athens, 1st Rimini St, 12462 Haidari, Athens, Greece b

A R T I C LE I N FO

A B S T R A C T

Keywords: Immune checkpoint inhibitors Pseudoprogression Hyperprogression Asymptomatic progression Treatment beyond progression Biomarkers

The discovery and implementation into everyday clinical practice of immune checkpoint inhibitors (ICIs) has marked a therapeutic renaissance in the treatment of advanced solid tumors. In head and neck cancer, nivolumab and pembrolizumab have both been approved for recurrent/metastatic disease based on robust clinical activity observed in landmark phase III clinical trials. Despite tremendous improvements in overall survival, patterns of response and progression to ICIs may be distinct from those traditionally described with classical chemotherapy or molecularly targeted therapies. In this context, pseudoprogression is observed in patients treated with ICIs that show response after a transient increase in tumor burden and hyperprogression is described as rapid radiological or clinical progression after immunotherapy. Most importantly, the assessment of radiological response in patients receiving ICIs needs to be differentiated. In this review, we aim to describe radiologic criteria for immune response evaluation and illustrate the newly reported concepts of atypical patterns of response to ICIs.

Introduction The advent of immune checkpoint inhibitors (ICIs) therapy has revolutionized the systemic therapy for solid and some haematological tumours, with unprecedented long-term survival for subsets of patients with advanced cancer and with a step-change increase in the cure rate for cancer types once considered recalcitrant to conventional therapies, such as non–small cell lung cancer and melanoma [1–3]. Since 2011, ICIs have been either approved by the US Food and Drug Administration (FDA) and/or the European Medicines Agency (EMA) for 15 types of cancers including the so-called tissue-agnostic types (tumors with microsatellite instability regardless of histology), both in adjuvant and

recurrent/metastatic (R/M) setting [4–7]. In 2016, two seminal trials, CheckMate141 (NCT02105636) and KEYNOTE-012 (NCT01848834), led to accelerated FDA/EMA approval for the Ig-G4 anti-programmed cell death protein (PD-1) antibodies nivolumab (Opdivo, Bristol-Myers Squibb) and pembrolizumab (Keytruda, Merck) for platinum refractory recurrent/metastatic (R/M) head and neck cancer (HNSCC), respectively [8,9]. This year KEYNOTE-048 (NCT02358031) paved the way for the approval of pembrolizumab as 1st line treatment in the R/M setting [10]. All aforementioned studies provided category 1 evidence for improved overall survival compared to standard of care (SOC). Moreover, phase 3 CheckMate141 showed that nivolumab confers 1-year and 2-

Abbreviations: CTLA-4, Cytotoxic T lymphocyte protein 4; EGFR, Epidermal Growth Factor Receptor; EMA, European Medicine’s Agency; FDA, Food and Drug Administration; HNSCC, Head and Neck Squamous Cell Carcinoma; HPD, Hyperprogressive Disease; ICI, Immune Checkpoint Inhibitors; iCPD, Immune confirmed Progressive Disease; iCR, Immune Complete Response; IGF1, Insulin Growth Factor 1; ILC2, Innate Lymphoid Cells; iPR, Immune Partial Response; irAEs, Immune Related Adverse Events; irRC, Immune Related Response Criteria; iSD, Immune Stable Disease; iUPD, Immune Unconfirmed Progressive Disease; OS, Overall survival; PD-1, Programmed Cell Death Protein; PDL-1, Programmed Cell Death Ligand 1; RECIST, Response Evaluation Criteria in Solid Tumors; R/M, Recurrent/Metastatic; SOC, Standard of Care; TBP, Treatment Beyond Progression; TGF, Transforming Growth Factor; TGR, Tumour Growth Rate; TILs, Tumour Infiltrating Lymphocytes; Tregs, T regulatory cells; TTF, Time to Treatment Failure; VEGF, Vascular Endothelial Growth Factor ⁎ Corresponding author at: Section of Medical Oncology, Department of Internal Medicine, Faculty of Medicine, National and Kapodistrian University of Athens, Attikon University Hospital, 1st Rimini St, 12462 Haidari, Athens, Greece. E-mail address: [email protected] (A. Psyrri). https://doi.org/10.1016/j.oraloncology.2019.104477 Received 22 October 2019; Received in revised form 3 November 2019; Accepted 11 November 2019 1368-8375/ © 2019 Published by Elsevier Ltd.

Disappearance of all lesions ≥30% decrease from baseline Neither CR nor PD is met ≥20% increase in the nadir of the sum of target lesions with a minimum of 5 mm Yes, at least 4 weeks after, and up to 8 weeks [22] Confirmation of PD Ref.

Disappearance of all lesions ≥30% decrease from baseline Neither CR nor PD is met ≥20% increase in the nadir of the sum of target lesions with a minimum of 5 mm – [19] CR PR SD PD

Table 1 Radiological Criteria in assessment of Immune Responses. 2

RECIST v1.1

Radiological criteria for the assessment of immune responses As ICIs differ pharmacodynamically from both cytotoxic and targeted chemotherapy, it was realised that the traditional WHO or RECIST criteria would not suffice for the timely assessment of patients treated with ICIs. The presence of pseudoprogression, albeit rare, necessitated the establishment of the immune-related criteria (immunerelated response criteria, immune-related RECIST and immune-RECIST) in order to spare the premature discontinuation of immunotherapy in patients with late response or need for treatment beyond progression (Table 1) [17,18]. In 2009, Wolchok et al issued the immune-related response criteria (ir-RC) in melanoma patients treated with ipilimumab [20]. The new criteria incorporated several key features that allowed patients with atypical responses to continue therapy and without the false label of disease progression; these features included the need for confirmation of progression at 4 weeks, after it was first documented and the allowance of new metastases (shown in Table 1). Recently, Hodi et al. evaluated the irRC vs. RECIST v1.1 in 655 melanoma patients treated with pembrolizumab. They reported that based on RECIST criteria pembrolizumab was underestimated in 15% of patients. The 2-year OS rates were 77.6% in patients with non-progressive disease per both

Disappearance of all lesions ≥30% decrease from baseline Neither CR nor PD is met ≥20% increase in the nadir of the sum of target lesions with a minimum of 5 mm Yes, at least 4 weeks after, and up to 12 weeks [21]

Unidimensional ≥10 mm 5 lesions in total; 2 per organ iUPD; becomes iCPD if PD is eventually confirmed Unidimensional ≥10 mm 5 lesions in total; 2 per organ Incorporated in the sum of the measurements

Bidimensional 5 × 5 mm 10 in total; 5 per organ Incorporated in the sum of the measurements Disappearance of all lesions ≥50% decrease from baseline Neither CR nor PD is met ≥25% increase in the nadir of the sum of target lesions Yes [20] Unidimensional ≥10 mm 10 in total; 5 per organ PD Measurement Modality Baseline lesion size Min. no lesions to assess Appearance of new lesions

irRC

irRECIST

iRECIST

year overall survival (OS) benefit compared to SOC (36% vs. 16.6% at 1-year, and 16.9% vs. 6.0% at 2 years) in platinum refractory patients, respectively [8,11]. Similarly, phase 1b KEYNOTE-012 demonstrated overall response 18% for pembrolizumab in previously heavily treated HNSCC patients (14% HPV- vs. 25% HPV+) based on central imaging review using Response Evaluation Criteria in Solid Tumors (RESIST) v1.1 [9]. Overall, these studies showed that ICIs have good tolerability and safety profile, improve the quality of life of treated patients, but characteristically produce durable responses in less than 20% of patients [7,12]. Tumour cells generate an immunosuppressive milieu utilising a plethora of mechanisms to evade immune destruction, including disruption of effective antigen presentation, reduction of effector T-cell function, and upregulation of pathways that promote tolerance and Tcell anergy/exhaustion. ICIs elicit robust immune responses by abrogating the co-inhibitory receptors in the immunological synapse [13,14]. To date, cytotoxic T-lymphocyte associated protein 4 (CTLA4), PD-1 and its corresponding ligand PD-L1, are the mainstream ICI targets with various co-inhibitory or co-stimulatory or other molecules alone or in combinations with radiotherapy or chemotherapy being under investigation in both adjuvant and neoadjuvant trials [15]. It seems that ICIs can activate exhausted Tumor Infiltrating Lymphocytes (TILs) or even attract new T cells that were not previously existent in the tumor microenvironment [13,16]. Novel patterns of response, not previously seen with chemotherapy and targeted therapy, are observed with ICIs. In this context, as mentioned earlier, durable responses that may persist even after treatment interruption, challenging the broadly accepted concept of treatment until disease progression, is witnessed in a minority of patients with heavily pre-treated cancers. Also, the so-called pseudoprogression, which is generally evidenced in about 10% of patients with advanced melanoma and rarely with HNSCC, alludes to an objective response following initial disease progression on cross sectional imaging. Recently, the concept of hyperprogression was introduced to account for the accelerated clinical deterioration in a fraction of patients treated with ICIs. In contrary, treatment beyond progression seems to confer survival benefit in selected patients with asymptomatic progression of disease. Finally, dissociated responses were reported in some patients with some lesions shrinking while others continued to grow. This latter pattern of response raises the question of local treatments of growing lesions [17]. Aim of this review is to discuss the current knowledge in these atypical patterns of response and briefly describe the evolution in imaging criteria.

CR: complete response, PR: partial response, SD: stable disease, PD: progressive disease, iUPD: immune unconfirmed progressive disease, iCPD: immune confirmed progressive disease.

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according to RECIST criteria. It was first reported in melanoma cases treated with ipilimumab, but it seems to characterize several cancer types in patients treated with nivolumab or pembrolizumab [20,25,27]. Generally, the incidence does not exceed 10% as shown in several trials in melanomas, NSCLC, RCC, urothelial, colorectal, pancreatic cancers and HNSCC [28–45]. A systematic review of atypical response rates with anti-PD-1 therapy included 19 trials and 2400 patients across a range of malignancies. The overall rate of pseudoprogression was 6%. Rates were 4–10% in melanoma, 3–7% in NSCLC and 9–15% in renal cell carcinoma [46]. In particular for HNSCC, CheckMate141 and KEYNOTE012 quoted 1.3% and 0.96% rates, respectively [7,25]. Consistently, pseudoprogression is associated with improved OS. There is plausible evidence that this spurious increase of tumour burden is due to inflammatory changes secondary to ingress of activated T cells into the tumour site as confirmed in biopsies taken from melanoma patients treated with ipilimumab [18,47]. As mentioned above, the RECIST criteria underestimate the efficacy of ICIs. There are trials in melanomas, NSCLC and HNSCC that demonstrated benefit in some patients treated beyond progression (TBP). Gandara et al retrospectively studied 850 patients with advanced NSCLC randomised into atezolizumab vs. docetaxel arms. The median post-PD OS was 12.7 months (95% confidence interval [CI]: 9.3–14.9) in 168 atezolizumab-arm patients continuing TBP, 8.8 months (95% CI: 6.0–12.1) in 94 patients switching to non-protocol therapy, and 2.2 months (95% CI: 1.9–3.4) in 70 patients receiving no further therapy. Of the atezolizumab TBP patients, 7% achieved a post-progression response in target lesions and 49% had stable target lesions [34]. Beaver et al. conducted a pooled analysis from 2624 patients receiving anti-PD-1 for unresectable or metastatic melanoma. At followup, 1361 (52%) had PD, of whom 692 (51%) received TBP and 669 (49%) did not. Ninety-five (19%) of 500 patients in the TBP cohort with evaluable assessments had a 30% or more decrease in tumour burden, when considering burden at RECIST-defined progression as the reference point, representing 14% of the 692 patients treated beyond progression and 4% of all 2624 patients treated with immunotherapy. Median overall survival in patients with RECIST-defined PD was longer in the TBP cohort (24·4 months, 95% CI 21·2–26·3) than in the cohort of patients who did not receive TBP (11·2 months, 10·1–12·9). Notably, 362 (54%) of 669 patients in the no treatment cohort had a serious adverse event up to 90 days after treatment discontinuation compared with 295 (43%) of 692 patients in the TBP cohort. Recently, post hoc analysis of CheckMate141 attested to the benefit in OS in some patients TBP [25]. In this study 146/240 (61%) of patients treated with nivolumab experienced RECIST-defined PD and among them, 62/146 (42%) patients had nivolumab TBP and 84 (58%) discontinued (NTBP). Among the remaining 94 of 240 patients (39%), 4 did not receive nivolumab, 11 were continuing treatment as of the data cut-off, and the rest discontinued treatment primarily because of either a lack of confirmation of disease progression or adverse events. Tumour burden reduction was noted in 15 of 60 patients (25%) who underwent TBP with nivolumab; 3 patients (5%) experienced a reduction > 30%. The median OS was 12.7 months for patients receiving TBP with nivolumab and 7.7 months in the overall intent‐to‐treat population [25]. SITC subcommittee recommends:

criteria, 37.5% in patients with progressive disease per RECIST v1.1 but non-progressive disease per irRC (n = 84), and 17.3% in patients with progressive disease per both criteria [23]. Nishimo et al. introduced the ir-RECIST in an effort to further improve irRC. Hence, the tumour measurement is unidimensional and measurable disease is defined as non-nodal metastases of 10 mm or more in the long axis and nodal lesions of 15 mm or more in the short axis. The total tumour burden is the sum of the target non-nodal lesions in the long axis and the target nodal lesions in the short axis dimensions. Similar measurements are used for new lesions (Table 1) [21]. In 2017, a consensus guideline iRECIST was published based on RECIST v1.1 in an effort to validate the latter for its use in immunotherapy trials [22]. The nomenclature included the terms: immune complete response (iCR), immune stable disease (iSD), immune partial response (iPR), and immune unconfirmed progressive disease (iUPD) or immune confirmed PD (iCPD) (Table 1). The main difference between iUPD and iCPD is that iUPD uses the same definition as RECIST1.1 for progressive disease, but iUPD must be confirmed to be considered true progression (iCPD) only if a repeat scan attested to this. The scan should be performed at 4–8 weeks after iUPD. The response is considered iCPD when there is an increase of at least 5 mm total of measurements of target lesions from iUPD. A disease can be characterized as iUPD multiple times in a patient on one therapy until there is an iCPD. Unlike RECIST1.1, the response can be categorized as iCR, iPR, or iSD during the follow-up assessment after iUPD, but not after iCPD is reached. For non– target lesions, the same criteria are followed, and iUPD can be assigned several times; however, a new label—noniCPD/ noniUPD—is used when neither iCR nor progressive disease have been reached. The concept of new lesion assessment is noteworthy in iRECIST. Any new lesion should be identified as measurable or nonmeasurable akin to RECIST1.1. Most importantly, if a new lesion is identified (qualifying for iUPD) and the patient is considered asymptomatic or stable, then the treatment should not be withheld [22,24,25]. Overall, the immune related criteria offer advantages over RECIST v1.1 in terms of guiding whether ICIs should be continued in cases of pseudoprogression or even asymptomatic progression in fit patients who do not experience severe irAE [25]. Nonetheless, current imaging criteria inherently lack predictability of tumor growth kinetics as all trials typically include baseline imaging but do not capture data from previous imaging. Thus, albeit pseudoprogression is rare, this hampers our ability to elucidate the phenomenon of hyperprogression [26]. Pertained to head and neck cancer, the SITC subcommittee recommended that: 1. Both RECIST (56% of the subcommittee) and iRECIST (44% of the subcommittee) could be used for assessment of immune responses in head and neck cancer. 2. For initial assessment, the subcommittee recommends using either a CT (53%) or PET-CT (41%) scan following a baseline clinical exam of the patient. To best capture the dynamics of changing tumour size, the subcommittee recommends imaging, particularly utilizing a CT scan (44%). 3. Vigilant monitoring is crucial to identify non-responders, progressors or patients developing adverse effect. Fifty-three percent of the subcommittee opted for a 1-month timeframe for initial clinical follow-up. Signs of response should be evaluated via cross sectional imaging quarterly with SOC imaging to be adapted based on disease status, response, and tolerability of treatment (65%). 4. Monthly monitoring is required in patients with active irAEs (71%) [7].

1. Against use of the term “pseudoprogression” when there is progression of disease. 2. Against TBP if a patient has symptomatic progression/clinical deterioration (88%). In the event of radiographic progression observed early in treatment and the patient is clinically stable, the majority of the subcommittee (76%) recommends continuing immunotherapy treatment until progression is confirmed on a second scan. 3. Patients with PD on or after treatment with a PD-1 inhibitor, enrolment in a clinical trial (81%) or switch to palliative radiotherapy and/or chemotherapy (78%) [3].

Pseudoprogression and treatment beyond progression This term denoted the initial flare up with radiological deterioration of lesions and even the appearance of new lesions followed by response 3

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To date, there are no bona fide predictors for pseudoprogression. However, Long et al. reported an LDH < upper limit of normal at the time the pseudoprogression was seen in all 20 patients that had < 30% decrease in tumour burden after receiving nivolumab TBP for melanoma [30]. Lee et al. found that circulating DNA holds promise as a biomarker for discerning pseudoprogression from true progression. They examined ctDNA for BRAF and NRAS mutation in 125 patients treated with anti-PD-1 alone or in combination with ipilimumab for melanomas using the RECIST criteria [48]. Plasma samples of ctDNA at baseline and while receiving treatment were taken for analysis prospectively over the first 12 weeks of treatment. Favourable ctDNA profile (undetectable ctDNA at baseline or detectable ctDNA at baseline followed by > 10-fold decrease) and unfavourable ctDNA profile (detectable ctDNA at baseline that remained stable or increased) were correlated with response and prognosis. Sensitivity of ctDNA for predicting pseudoprogression was 90% and specificity was 100%. The 1year survival for patients with RECIST-defined PD and favourable ctDNA was 82% vs 39% for unfavourable ctDNA. Haddad et al. recently reported that nivolumab TBP responders had diminished PD1+ regulatory T cells on day 43 (in comparison to baseline) compared to nonresponders [25].

monotherapies to standard-of-care chemotherapies [58]. It is still unclear whether this abnormal tumour growth kinetics is related to immunotherapy or simply represent the natural history of a biologically aggressive disease. It is interesting that this question, posed during the recent American Association for Cancer Research Annual Meeting 2019 in Atlanta, GA, drew mixed responses: 58% said HPD exists, 12% opined otherwise, and 30% were undecided [59]. There are caveats supporting either opinion as there is lack of pre-baseline captured data and no prospective randomised trials [60]. Previous surgery, radiotherapy or chemotherapy may alter the tumour microenvironment, promote neo-angiogenesis and accelerate cancer cell repopulation as seen in HNSCC, cervical and bladder carcinomas [61–66]. Notably, tumour flare up upon discontinuation of tyrosine kinase inhibitors or anti-VEGF is another paradigm. This phenomenon has been evidenced after cessation of erlotinib or gefitinib in EGFR-mutated NSCLC. Similarly, this was observed in patients with ALK-rearranged NSCLC treated with crizotinib [60]. Taken together, heavily pretreated patients may be at risk of tumour acceleration per se, irrelevant to the administration of ICIs. On the contrary, Ferrara et al conducted a multicentre, retrospective, comparative study on HPD following PD1/PD-L1 ICIs (monotherapy in second line or more) versus single-agent chemotherapy. RECIST v1.1 criteria were applied. TGR before and during treatment and variation per month (ΔTGR) were calculated. HPD was defined as disease progression at the first evaluation with ΔTGR exceeding 50%. Fourteen percent (56/406) of ICIS versus 5% (3/59) of chemotherapy cohort experienced HPD. This study, despite its limitations showed that HPD can occur both in chemotherapy, but more commonly in the ICI setting [55]. Of note, HPD is exclusively related to PD1/PD-L1 inhibitors [60]. Notably, there is lack of biomarkers in predicting HPD. SaadaBouzid et al observed HPD rate in 29% (10/34) of HNSCC patients treated with PD-1/PD-L1 inhibitors and correlated with shorter PFS, but not OS. Nine patients presented with at least a locoregional recurrence, and only 1 patient with exclusively distant metastases. HPD was significantly correlated with a regional recurrence and almost invariably involved a previously irradiated field [50]. Ferrara et al. retrospectively studied the tumour kinetics in 406 eligible patients treated with PD1/ PDL-1 inhibitors for NSCLC. They found that the presence of 2 or more metastatic sites before ICI administration was significantly associated with HPD (62.5% (35/56) HPD cohort vs 42.6% (149 of 350) non-HPD)

Hyperprogression Hyperprogressive disease (HPD) refers to the rapid increase in tumour growth rate (TGR) following the initiation of ICIs and is associated with dismal prognosis. In 2016, Champiat et al. reported an abnormally high TGR in 9% of patients treated for various types of cancer with PD-1 ICIs in phase I trials [49]. More retrospective studies followed with rates ranging from 4 to 29% depending on their definition in tumor growth kinetics and timeframes [50–55] (Table 2). This variability in the criteria for the definition of HPD (2D versus 3D-based tumor kinetics, sample size, different assessment approach) may explain the discrepancies noted in the reported rates. Of note, SaadaBouzid E et al. reported the highest HPD rates (29%) for HNSCC patients pre-treated with radiotherapy [50]. This phenomenon was initially hinted by the early crossing over of progression-free and overall survival curves, in the first 3–6 months, in some randomized phase III trials such as CheckMate 057 in NSCLC [32], CheckMate 141 in HNSCC [8] or Keynote 045 [56] and IMvigor211 [57] (urothelial carcinoma) comparing anti-PD(L)1 Table 2 Criteria for definition of HPD among various studies. Study (Ref)

Definition for HPD

Reported rate

Tumours studied

Champiat et al. [49]

TGR ratio ≥ 2 (post vs pre-treatment) on RECIST

9% (12/131)

Saâda-Bouzid et al. [50] Kato et al. [52]

TGR ratio ≥ 2 (post vs pre-treatment) on RECIST Time-to-treatment failure < 2 months > 50% increase in tumour burden compared with pre- immunotherapy (on imaging) > 2-fold increase in progression pace time to treatment failure < 2 months minimum increase in measurable lesions of 10 mm (RECIST) plus: 1. increase of ≥ 40% (upper decile of our cohort) in target tumor burden compared to baseline or 2. increase of ≥20% plus the appearance of multiple new lesions RECIST-defined disease progression at first evaluation ΔTGR increase > 1.5 (on-treatment versus before treatment) > 40% tumor burden increase OR > 20% tumor burden increase plus multiple new lesions

29% (10/34) 6% (6/102)

14% (56/406)

Cholangiocarcinoma 50% (1/2) Uveal Melanoma 50% (1/2(Ovarian 40% (2/5) Urothelial 25% (2/8) Lymphoma 14% (1/7) Colorectal 12% (1/8) Melanoma (9%) (4/45) HNSCC NSCLC 8% (3/38) Urothelial N/D (1/N/A) Breast triple negative N/D (1/N/A) Endometrial N/D (1/N/A) melanoma N/D lung N/D breast N/D colorectal N/D others N/D NSCLC

23.3% (14/60)

Gynecological tumors

Matos et al. [53]

Ferrara et al. [55] Freixinos VR et al [54]

• • • • • • • • •

15% (33/214)

HNSCC, head and neck squamous cell carcinoma; ND, not defined; NSCLC, non-small-cell lung carcinoma; TGK, tumour growth kinetics; TGR, tumour growth rate. a TGR (assumption of 3D exponential tumour growth) and TGK (assumption of 2D linear tumour growth) are similar concepts but different methods are used to evaluate them according to investigator’s preference. 4

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immune related side effects and atypical patterns of immunotherapy. Patients should be evaluated constantly, and treatment should be stopped in the case of clinical deterioration.

[55]. Champiat et al. found that older age > 65y, whereas Kanjanapan et al. considered female gender as an independent risk factor for HPD, respectively, in various cancer types [49,51]. Furthermore, several genetic aberrations have been also linked with HPD. Kato et al. reported a TTF < 2 months under immunotherapy for patients with EGFR and MDM2/4 alterations [52]. Recently, Xiong et al. performed whole exome sequencing and RNA sequencing in paraffin embedded tissues in 2 patients (esophageal, RCC) that developed HPD post PD-1 treatment [67]. They reported somatic mutations in 11 genes including tumour suppressor genes TSC2 and VHL, with upregulation of oncogenic pathways such as Insulin Growth Factor 1 (IGF1), Transforming Growth Factor β (TGFβ), ERK/MAPK, PI3K/AKT. Interestingly, they highlighted the establishment of immunosuppressive milieu with the presence of innate lymphoid cells (ILC3), neutrophils, neutrophil-like MDSC, activated B-cells, and reduction in dendritic cells, monocytes, central memory T cells, γδ T cells, NK cells. In line with Shayan et al, work has been done on TIM-3 upregulation of TIL in HNSCC following PD-1 blockage. This T cell population was rendered more exhausted for activation of PI3K/AKT downstream of TCR supporting the notion of counter-suppression as compensatory mechanism to PD-1 blockage [68]. Recently, a subset of regulatory T cells, the so-called effector Tregs (FoxP3highCD45RA−CD4+), was implicated in HPD of gastric cancer patients following PD-1 blockage. These suspected mechanisms are now added to other reports that support the role of therapeutic antibody activation of M2-like CD163þ CD33þ PD-L1þ macrophages through the Fcc receptor and that of senescent CD4 T cells with a highly differentiated (CD28- CD27) profile [69-71]. Kim et al. attested to the presence of highly exhausted T cells among hyperprogessors in NSCLC. Moreover, their exploratory biomarker analysis with peripheral blood CD8+ T lymphocytes unveiled a lower frequency of effector/memory subsets (CCR7-CD45RA-T cells among the total CD8+ T cells) and a higher frequency of severely exhausted populations (TIGIT+ T cells among PD-1+CD8+ T cells) were associated with HPD and inferior survival rate [72]. HPD seems to affect particular cancer types especially HNSCC. Early recognition of this condition and switch to salvage chemotherapy may improve OS survival [60].

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Conclusion The advent of ICI-based therapies in oncology has resulted in unprecedented improvements in the outcomes of patients with a number of tumour types; however, an increasing body of evidence indicates that a subset of those patients do have a paradoxical acceleration of their disease while receiving anti-PD-1/ PD-L1-antibody therapy. The concept that a given anti- tumour treatment can promote tumour progression is not new, and has always been controversial. Although the current radiological criteria used to evaluate response to therapy present improved sensitivity in tracing pseudoprogression and hence extend the treatment benefit, they appear to be suboptimal for the management of patients with HPD. This entails risks to the patient survival but also increase the financial burden. The integration of pretreatment tumour kinetics is crucial to objectively determining whether HPD is a consequence of treatment independent of the natural course of tumour progression. In addition, disease assessments should be performed at earlier time points (4–6 weeks) than currently used in order to avoid the risk of maintaining a patient on an ineffective treatment [60]. Moreover, a better understanding of the molecular and immunological bases of HPD is essential to designing the next generation of therapeutic interventions in the era of personalised medicine. Most clinical trials do not currently mandate the collection of biological samples (such as blood or tumour tissue) upon disease progression, but such an approach should be considered (OR would be valuable). Finally, patients should always be consented for the potential 5

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