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Metachronous malignancies after response to checkpoint inhibition

Published:August 17, 2022DOI:https://doi.org/10.1016/j.ejca.2022.07.003
      To the Editor,
      Immune checkpoint inhibitors (ICIs) targeting the CTLA-4 and/or PD(L)1 receptors on immune and cancer cells have drastically changed the outcomes for some patients with cancer [
      • Wolchok J.D.
      • Chiarion-Sileni V.
      • Gonzalez R.
      • et al.
      Long-term outcomes with nivolumab plus ipilimumab or nivolumab alone versus ipilimumab in patients with advanced melanoma.
      ,
      • Migden M.R.
      • Rischin D.
      • Schmults C.D.
      • et al.
      PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma.
      ]. Patients achieving an objective response to ICI treatment have a high chance for benefitting form a durable remission of their disease, even after the discontinuation of ICI treatment [
      • Jansen Y.J.L.
      • Rozeman E.A.
      • Mason R.
      • et al.
      Discontinuation of anti-PD-1 antibody therapy in the absence of disease progression or treatment limiting toxicity: clinical outcomes in advanced melanoma.
      ]. As such, unprecedented numbers of patients with advanced melanoma are becoming long-term survivors with little risk for recurrence when more than 5 years have passed since they initiated successful ICI [
      • Loo K.
      • Goldman D.A.
      • Panageas K.
      • et al.
      Characteristics and probability of survival for patients with advanced melanoma who live five or more years after initial treatment with immune checkpoint blockade (ICB).
      ,
      • Hodi F.S.
      • Vanna Chiarion -Sileni V.
      • Lewis K.D.
      • et al.
      Long-term survival in advanced melanoma for patients treated with nivolumab plus ipilimumab in CheckMate 067.
      ].
      This long-lasting immunologically driven response in patients with poor prognosis advanced disease is unprecedented by prior anticancer therapies and therefore necessitates a shift in clinical reasoning with respect to the specific needs of these cancer survivors. For instance, new symptoms or abnormalities on imaging should not be promptly attributed to disease progression and require thorough investigation. Here, we report 15 patients treated in two academic hospitals in whom new symptoms or abnormalities after response to ICI were found to be attributable to a metachronous new primary malignancy.
      Patient characteristics, ICI treatment, second primary malignancy and diagnostic indicators that led to the diagnosis of the metachronous malignancy are summarised in Table 1.
      Table 1Patient characteristics, ICI treatment, second primary malignancy and diagnostic indicators revealing the second primary malignancy.
      Gender (age at diagnosis)ICIResponse at time of SPMSecond malignancyTime after start ICIDiagnostic indicator
      1F (75 Y)PembrolizumabPROesophageal carcinoma36 monthsIncreasing FDG activity oesophagus, peritoneal carcinomatosis, pleural fluid at PET-CT
      2F (54 Y)Pembrolizumab, followed by ipilimumabPRNon-small cell lung cancer47 monthsMultiple new pulmonary nodules at CT
      3M (79 Y)IpilimumabPRColorectal carcinoma (MSS)5 monthsCircumferential wall thickening of the colon at CT
      4M (80 Y)CemiplimabCRColorectal carcinoma (MSS)7 monthsNew liver lesion at CT
      5F (42 Y)PembrolizumabCRTenosynovial giant cell tumour40 monthsFDG-active nodule behind the patella at PET-CT
      6M (75 Y)NivolumabPRColorectal carcinoma (MSS)5 monthsIron deficiency anaemia in routine lab + colon mass at MRI
      7M (51 Y)IpilimumabCRDermatofibrosarcoma protuberans30 monthsSuspicious skin lesion at dermatological follow-up
      8F (56 Y)PembrolizumabCRNon-small cell lung cancer85 monthsSolitary lung nodule at CT
      9F (53 Y)PembrolizumabCRTriple negative breast carcinoma62 monthsSelf-detected breast mass
      10F (66 Y)Ipilimumab, followed by pembrolizumabCRTriple negative breast carcinoma48 monthsFDG-active breast nodule at PET-CT
      11M (59 Y)IpilimumabCRProstate carcinoma110 monthsIncreasing PSA at screening
      12M (74 Y)Ipilimumab, followed by pembrolizumabCRUrothelial cell carcinoma65 monthsIncreasing FDG activity bladder wall at PET-CT
      13M (72 Y)PembrolizumabCRUrothelial cell carcinoma68 monthsHaematuria
      14M (68 Y)Pembrolizumab, followed by nivolumab + ipilimumabCRUrothelial cell carcinoma88 monthsIncreasing FDG activity bladder at PET-CT + haematuria
      15M (61 Y)Ipilimumab, followed by pembrolizumabCRUrothelial cell carcinoma59 monthsHaematuria
      Definitions: F, female; M, male; Y, year; PR, partial response; CR, complete response; SPM, second primary malignancy; MSS, microsatellite stable; PSA, prostate-specific antigen.
      All patients were treated for metastatic or unresectable melanoma, except for patient 5, who was treated for stage IV squamous cell carcinoma. Patients received monotherapy with either a PD-1 (12/15) or anti-CTLA4 (7/15)-blocking monoclonal antibody. Patient 14 was treated with dual ICI therapy after failing PD-1 inhibition monotherapy. The median time from start of checkpoint inhibition to the diagnosis of the metachronous primary malignancy was 48 months (range 5–110 months). At time of diagnosis of the metachronous primary tumour, four patients had a partial response to treatment, whereas 11 patients had reached a complete response. Two patients (patients 4 and 6) were still on treatment at time of the diagnosis; in all other patients, ICI had been discontinued. In five patients, further diagnostics were initiated due to the onset of new clinical symptoms (haematuria, self-palpated breast mass, new suspected skin lesion). In two patients, laboratory abnormalities were the diagnostic indicators that resulted in the discovery a second malignancy. Most patients however showed growing or new lesions on follow-up imaging, while their known disease remained in ongoing response. For this reason, histology was obtained from these new lesions that revealed the presence of a metachronous new malignancy.
      We report the characteristics of 15 patients in which a metachronous malignancy was diagnosed during the treatment or surveillance period following ICI treatment, 11 of whom had a complete response of their primary metastatic disease. Eleven patients developed new lesions more than 3 years after starting ICI. Follow-up studies of ICI-treated advanced melanoma patients consistently show a plateau in overall survival at approximately 2–3 years; thereafter, the risk of death or progression of disease becomes low [
      • Wolchok J.D.
      • Chiarion-Sileni V.
      • Gonzalez R.
      • et al.
      Long-term outcomes with nivolumab plus ipilimumab or nivolumab alone versus ipilimumab in patients with advanced melanoma.
      ,
      • Schadendorf D.
      • Hodi F.S.
      • Robert C.
      • et al.
      Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma.
      ] and new lesions or symptoms after this time period should therefore also trigger a critical reflection on the possibility of a metachronous new malignancy. However, there were also patients who presented with new lesions relatively soon after initial response to ICI. These lesions might therefore have been more easily interpreted as progression of the primary malignancy yet proved to be metachronous primary malignancies.
      The patients presented here were all treated for advanced melanoma or cutaneous squamous cell carcinoma. However, as data suggest that other malignancies may be approaching similar survival plateaus with ICI treatment [
      • O'Malley D.M.
      • Bariani G.M.
      • Cassier P.A.
      • et al.
      Pembrolizumab in patients with microsatellite instability-high advanced endometrial cancer: results from the KEYNOTE-158 study.
      ], awareness for second malignancies will likely be relevant for other ICI-treated patients as well. Little is known at present about the incidence of metachronous primary malignancies during or after ICI [
      • Suijkerbuijk K.P.M.
      • May A.M.
      • van Eijs M.J.M.
      Checkpoint inhibition: protecting against or predisposing for second primary tumors?.
      ]. A recent study suggested that ICI might have a protective effect against the development of a second primary cancer [
      • Heudel P.
      • Chabaud S.
      • Perol D.
      • et al.
      Immune checkpoint inhibitor treatment of a first cancer is associated with a decreased incidence of second primary cancer.
      ]. However, there are also concerns that ICI-treatment might increase this risk [
      • Deng W.
      • Wang Y.
      • Liu X.
      • et al.
      Assessment of trends in second primary cancers in patients with metastatic melanoma from 2005 to 2016.
      ], either directly as a long-term effect of the treatment on healthy tissue or indirectly by increasing the life expectancy of cancer survivors. Nonetheless, this case series stresses the importance of obtaining histological proof of suspected progression in patients that develop new lesions after an initial response to ICI.

      Funding

      None declared.

      Conflict of interest statement

      The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: KS: Consulting/advisory relationship: Bristol-Myers Squibb, Merck Sharp and Dome, Abbvie, Pierre Fabre, Novartis. Honoraria received: Novartis, Roche, Merck Sharp and Dome. Research funding: TigaTx, Bristol Myers Squibb, Philips. All paid to institution and outside the submitted work. BN: Financial compensation for consulting/advisory board participation: Bristol-Myers Squibb, Merck Sharp and Dome, Amgen, Pierre Fabre, Novartis, Roche. Research funding paid to my institution: Pfizer, Novartis, Roche, Merck-Serono. LD: Consulting/advisory relationship: Bristol-Myers Squibb, Merck Sharp and Dome. All paid to institution. All other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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