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Increased Hepatotoxicity Associated with Sequential Immune Checkpoint Inhibitor and Crizotinib Therapy in Patients with Non–Small Cell Lung Cancer

Open ArchivePublished:September 08, 2018DOI:https://doi.org/10.1016/j.jtho.2018.09.001

      Abstract

      Introduction

      Immune checkpoint inhibitors (ICIs) are standard therapies in advanced NSCLC. Although genotype-directed tyrosine kinase inhibitors represent the standard of care for subsets of oncogene-driven NSCLC, patients may receive ICIs during their disease course. The impact of sequential ICI and tyrosine kinase inhibitor therapy on the risk of hepatotoxicity has not been described.

      Methods

      Patients with advanced ALK receptor tyrosine kinase (ALK)-driven, ROS1-driven, or MET proto-oncogene, receptor tyrosine kinase (MET)-driven NSCLC treated with crizotinib, with or without preceding ICI therapy, were identified. The cumulative incidences of crizotinib-associated grade 3 or higher increases in transaminase level (per the Common Terminology Criteria for Adverse Events, version 4.0) were compared.

      Results

      We identified 453 patients who had NSCLC with an oncogenic alteration in ALK receptor tyrosine kinase gene (ALK), ROS1, or MET proto-oncogene, receptor tyrosine kinase gene (MET) and were treated with crizotinib (11 with and 442 without prior ICI therapy). Among the 11 patients treated with an ICI followed by crizotinib, five (cumulative incidence 45.5% [95% confidence interval (CI): 14.9–72.2]) experienced development of a grade 3 or 4 increase in alanine transaminase level and four (cumulative incidence 36.4% [95% CI: 10.0–64.2]) experienced development of a grade 3 or 4 increase in aspartate transaminase level. In comparison, among the 442 patients who received crizotinib only, a grade 3 or 4 increase in alanine transaminase level occurred in 34 patients (cumulative incidence 8.1% [95% CI: 5.7–11.0, p < 0.0001]) and a grade 3 or 4 increase in aspartate transaminase level occurred in 14 (cumulative incidence 3.4% [95% CI: 1.9–5.5, p < 0.0001]). There were no grade 5 transaminitis events. All cases of hepatotoxicity after sequential ICI and crizotinib use were reversible and nonfatal, and no case met the Hy’s law criteria.

      Conclusions

      Sequential ICI and crizotinib treatment is associated with a significantly increased risk of hepatotoxicity. Careful consideration and monitoring for hepatotoxicity may be warranted in patients treated with crizotinib after ICI therapy.

      Keywords

      Introduction

      Immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 and its ligand programmed death ligand 1 (PD-L1) have entered the clinic across multiple solid tumors, including NSCLC.
      • Melosky B.
      • Chu Q.
      • Juergens R.
      • Leighl N.
      • McLeod D.
      • Hirsh V.
      Pointed progress in second-line advanced non-small-cell lung cancer: the rapidly evolving field of checkpoint inhibition.
      On the basis of KEYNOTE-189, pembrolizumab plus platinum-doublet chemotherapy is the standard first-line treatment for nonsquamous NSCLC lacking EGFR mutation or ALK receptor tyrosine kinase gene (ALK) rearrangement regardless of PD-L1 status,
      • Gandhi L.
      • Rodriguez-Abreu D.
      • Gadgeel S.
      • et al.
      Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer.
      and pembrolizumab alone represents an additional first-line option for NSCLC with a high level of PD-L1.
      • Reck M.
      • Rodriguez-Abreu D.
      • Robinson A.G.
      • et al.
      Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer.
      In the clinic, PD-L1 results may return faster than other genetic testing results (e.g., EGFR, ALK, ROS1, and BRAF alterations), or tissue may be insufficient for genotyping, prompting the initiation of an ICI before genotype-directed tyrosine kinase inhibitors (TKIs).
      Thus far, insights into the potential toxicities of sequential ICI and TKI therapy have been limited. In one observational study, the risk of EGFR TKI–associated pneumonitis was substantially higher with sequential or concurrent ICI and TKI therapy, although other toxicities were not investigated.
      • Oshima Y.
      • Tanimoto T.
      • Yuji K.
      • Tojo A.
      EGFR-TKI-associated interstitial pneumonitis in nivolumab-treated patients with non-small cell lung cancer.
      In a separate phase II study of pembrolizumab in TKI-naive EGFR-mutant NSCLC, two of seven patients subsequently treated with an EGFR TKI experienced grade 3 transaminitis and grade 5 pneumonitis, respectively, similarly raising concerns of increased risks with sequential administration of ICIs and TKIs.
      • Lisberg A.
      • Cummings A.
      • Goldman J.W.
      • et al.
      A phase II study of pembrolizumab in EGFR-mutant, PD-L1+, tyrosine kinase inhibitor naïve patients with advanced NSCLC.
      Notably, a high incidence of hepatotoxicity has been reported with certain strategies of concurrent ICI and TKI administration in NSCLC.
      • Spigel D.R.
      • Reynolds C.
      • Waterhouse D.
      • et al.
      Phase 1/2 study of the safety and tolerability of nivolumab plus crizotinib for the first-line treatment of anaplastic lymphoma kinase translocation-positive advanced non-small cell lung cancer (CheckMate 370).
      • Gibbons D.L.
      • Chow L.Q.
      • Kim D.W.
      • et al.
      57O. Efficacy, safety and tolerability of MEDI4736 (durvalumab [D]), a human IgG1 anti-programmed cell death-ligand-1 (PD-L1) antibody, combined with gefitinib (G): a phase I expansion in TKI-naïve patients (pts) with EGFR mutant NSCLC.
      • Felip E.
      • Braud F.G.D.
      • Maur M.
      • et al.
      Ceritinib plus nivolumab (NIVO) in patients (pts) with anaplastic lymphoma kinase positive (ALK+) advanced non-small cell lung cancer (NSCLC) [abstract].
      For example, a phase 1/2 study of nivolumab plus crizotinib in ALK-rearranged NSCLC was terminated early because of severe hepatotoxicity in five of 13 patients (38%).
      • Spigel D.R.
      • Reynolds C.
      • Waterhouse D.
      • et al.
      Phase 1/2 study of the safety and tolerability of nivolumab plus crizotinib for the first-line treatment of anaplastic lymphoma kinase translocation-positive advanced non-small cell lung cancer (CheckMate 370).
      Two patients died, highlighting the importance of diagnosing and intervening on potentially fatal hepatotoxicity. To our knowledge, no study has evaluated whether the use of an ICI followed by TKI is associated with an increased risk of hepatotoxicity. ICIs and TKIs individually can cause hepatotoxicity, and ICIs have long half-lives that could affect the development of subsequent TKI-associated hepatotoxicity.
      Crizotinib is a multitargeted ALK receptor tyrosine kinase/ROS1/MET proto-oncogene, receptor tyrosine kinase (MET) inhibitor, which remains the only approved, standard first-line therapy for ROS1-rearranged NSCLC.
      • Shaw A.T.
      • Ou S.H.
      • Bang Y.J.
      • et al.
      Crizotinib in ROS1-rearranged non-small-cell lung cancer.
      It also represents a clinically meaningful treatment option for NSCLC harboring MET alterations, and recently received U.S. Food and Drug Administration breakthrough therapy designation for NSCLC with MET exon 14 skipping.
      • Drilon A.
      • Ou S.-H.
      • Clark J.
      • et al.
      MA16.09. Antitumor activity and safety of crizotinib in patients with MET exon 14-altered advanced non-small cell lung cancer.
      Here, we report on a retrospective study of 453 patients with ALK/ROS1/MET-altered advanced NSCLC who received crizotinib with or without prior ICI therapy, designed to address whether sequential ICI and crizotinib use increases the risk of hepatotoxicity.

      Methods

      We identified patients with advanced NSCLC who harbored an ALK fusion, ROS1 fusion, or MET exon 14 skipping or amplification who were treated at Massachusetts General Hospital between January 2008 and April 2018. Sequential treatment with an ICI followed by crizotinib was required. For the comparator, we identified patients treated with crizotinib only. Hepatotoxicity occurring during crizotinib treatment was annotated and graded per the Common Terminology Criteria for Adverse Events, version 4.0. All data were updated as of April 1, 2018. Records were reviewed under an institutional review board–approved protocol.
      Categorical and continuous variables between groups were compared by using the Fisher exact test and Wilcoxon rank-sum test, respectively. The cumulative incidence of hepatotoxicity was estimated from the start of crizotinib therapy to the onset of grade 3 or 4 transaminitis and compared between groups by using the Gray test. Among patients treated with crizotinib who did not experience hepatotoxicity, the date of discontinuation of crizotinib therapy was analyzed as a competing risk or censored on the last follow-up date if continuing on crizotinib at the time of data analysis. Statistical analysis was performed with Stata software (version 14, Stata Corp LP, College Station, TX) and SAS software (version 9.4, SAS Institute Inc., Cary, NC), with p values based on a two-sided hypothesis.

      Results

      We identified 453 patients with ALK-driven (n = 345), ROS1-driven (n = 83), or MET-driven (n = 25) NSCLC. Eleven patients received an ICI before receiving crizotinib, and 442 received crizotinib only (Supplementary Table 1). Baseline patient characteristics between the sequential ICI-crizotinib cohort and the crizotinib-only cohort were comparable overall; however, more patients in the sequential ICI-crizotinib cohort had MET-driven NSCLC and a history of smoking (see Supplementary Table 1). There was no difference between the cohorts in terms of the presence of liver conditions (none of 11 patients [0%] versus 16 of 442 [4%] [p > 0.999]) or hepatic metastases before administration of crizotinib (two of 11 patients [18%] versus 101 of 442 [23%] [p > 0.999]) (see Supplementary Table 1).
      Five of the 11 patients receiving sequential ICI and crizotinib experienced development of a grade 3/4 increase in alanine transaminase (ALT) level (cumulative incidence 45.5% [95% confidence interval (CI): 14.9–72.2]), three cases of which (27.3%) were grade 4. In comparison, 34 of the 442 patients treated with crizotinib only (8.1% [95% CI: 5.4–10.5, p < 0.0001]) experienced development of a grade 3/4 increase in ALT level, four cases of which (0.9%) were grade 4. A grade 3/4 increase in aspartate transaminase level occurred in four of the 11 patients who were receiving sequential ICI and crizotinib therapy (cumulative incidence 36.4% [95% CI: 10.0–64.2]) versus in 14 of the 442 who were receiving crizotinib only (3.4% [95% CI: 1.9–5.5, p < 0.0001]) (Table 2). Grade 5 hepatotoxicity was not observed in either cohort. The median interval between initiation of crizotinib therapy and onset of grade 3 or higher transaminitis was 38 days (range 13–49) versus 41 days (range 5–1657) for patients receiving sequential ICI-crizotinib and crizotinib only, respectively. The median interval between the last ICI dose and initiation of crizotinib was 30 days (range 21–135) among the patients in the sequential ICI-crizotinib cohort who experienced development of a grade 3/4 increase in transaminase level versus 50 days (range 10–121) among those who did not.
      Table 1Detailed Characteristics of Patients Who Received Crizotinib after an ICI (n = 11)
      IDICITKIOncogenic DriverICI LineICI Doses, nICI-CRZ Interval, dLiver MetastasisPD-L1 TPSPD-L1 AbALT/AST IncreaseCRZ-Liver Tox Interval, dLiver Tox Duration, dCRZ Interruption
      1Pembrolizumab + chemotherapyCrizotinibALK1323No95%22C3Gr 4 ALT Gr 4 AST3837Drug discontinued
      2Pembrolizumab + chemotherapyCrizotinibALK1121No70%22C3Gr 4 ALT Gr 4 AST2744Drug discontinued
      6PembrolizumabCrizotinibALK1110No60%E1L3NNoN/AN/AN/A
      7PembrolizumabCrizotinibROS12327No20%E1L3NNoN/AN/AN/A
      8Nivolumab + ipilimumabCrizotinibROS112121No<1%E1L3NNoN/AN/AN/A
      9Atezolizumab + investigational drugCrizotinibROS13225YesN/AN/ANoN/AN/AN/A
      10NivolumabCrizotinibMET amp21273No0%E1L3NGr 1 ALT Gr 1 AST27140Dosing not interrupted
      3NivolumabCrizotinibMET amp2430Yes50%E1L3NGr 4 ALT Gr 4 AST4298Drug discontinued
      4
      The patient received nivolumab, which was followed initially by capmatinib. Soon thereafter, chronic lymphocytic leukemia was diagnosed, requiring discontinuation of capmatinib. The patient subsequently received crizotinib (for lung cancer) combined with ibrutinib (for chronic lymphocytic leukemia). The increase in ALT/AST level was attributable to crizotinib (the levels improved when crizotinib was withheld and recurred with rechallenge of crizotinib).
      NivolumabCapmatinib → crizotinib + ibrutinibMET ex 1419135No0%E1L3NGr 3 ALT Gr 3 AST4961Drug discontinued
      5PembrolizumabCrizotinibMET ex 141742No>90%E1L3NGr 3 ALT Gr 2 AST1315Held for 36 d; resumed with dose reduction
      11PembrolizumabCrizotinibMET ex 143299No95%E1L3NNoN/AN/AN/A
      Note: ICI Line refers to the line of systemic therapy for ICI; ICI Doses refers to the number of ICI doses received by the patient. ICI-CRZ Interval refers to the time interval between the last dose of ICI and the start of crizotinib therapy. Liver Metastasis refers to the presence of liver metastases before the patient started taking crizotinib. CRZ-Liver Tox Interval refers to the interval between the start of crizotinib therapy and onset of liver toxicity. Gr refers to grade per the Common Terminology Criteria for Adverse Events, version 4.0.
      ID, identifier; ICI, immune checkpoint inhibitor, TKI, tyrosine kinase inhibitor; CRZ, crizotinib; PD-L1, programmed death ligand 1; TPS, tumor proportion score; Ab, antibody; ALT, alanine transaminase; AST, aspartate transaminase; Tox, toxicity; ALK, ALK receptor tyrosine kinase gene; Gr, grade; MET, MET proto-oncogene, receptor tyrosine kinase gene; amp, amplification; N/A, not applicable; ex 14, exon 14 skipping.
      a The patient received nivolumab, which was followed initially by capmatinib. Soon thereafter, chronic lymphocytic leukemia was diagnosed, requiring discontinuation of capmatinib. The patient subsequently received crizotinib (for lung cancer) combined with ibrutinib (for chronic lymphocytic leukemia). The increase in ALT/AST level was attributable to crizotinib (the levels improved when crizotinib was withheld and recurred with rechallenge of crizotinib).
      Table 2Increase in ALT/AST Level with Crizotinib after an ICI versus with Crizotinib Alone
      Increase in ALT/AST LevelPatients, nCumulative Incidence of Liver Toxicity
      TotalLiver ToxicityPoint Estimate, %(95% CI)p Value
      Grade 3/4 increase in ALT level<0.0001
       ICI → TKI11545.5(14.9–72.2)
       TKI442348.1(5.7–11.0)
      Grade 4 increase in ALT level<0.0001
       ICI → TKI11327.3(5.8–55.4)
       TKI44240.9(0.3–2.2)
      Grade 3/4 increase in AST level<0.0001
       ICI → TKI11436.4(10.0–64.2)
       TKI442143.4(1.9–5.5)
      Grade 4 increase in AST level<0.0001
       ICI → TKI11327.3(5.8–55.4)
       TKI44210.2(0.02–1.3)
      Note: Grading is per the Common Terminology Criteria for Adverse Events, version 4.0.
      Point estimate is reported at the time of last observed event.
      ALT, alanine transaminase; AST, aspartate transaminase; TKI, tyrosine kinase inhibitor; ICI, immune checkpoint inhibitor; CI, confidence interval.
      Of note, none of the five patients who received sequential ICI and crizotinib and developed grade 3 or higher transaminitis had preexisting autoimmune or liver conditions. One (patient 3 [see Table 1]) had hepatic metastases with baseline grade 1 transaminitis; all the others had normal baseline transaminase levels. Four had received an ICI as first-line therapy (see Table 1). For patients 1, 2, and 5, a high PD-L1 tumor proportion score (>50%) was returned earlier than the results of ALK/ROS1/MET testing, prompting initiation of an ICI (see Table 1). Patient 4 had recurrence of NSCLC shortly after completing adjuvant chemotherapy and began taking nivolumab before any MET testing results had been received.
      The duration of hepatotoxicity in these five patients ranged between 15 and 98 days (median 44 days). Four had a concurrent grade 1 increase in bilirubin level, and three had a grade 3 increase in alkaline phosphatase level (see Table 1). No case met the Hy’s law criteria. Four patients required permanent discontinuation of crizotinib therapy; one was able to resume taking crizotinib with a dose reduction after it had been held for 5 weeks. All cases were reversible; none required steroids, and liver biopsies were not performed. There was no concomitant pneumonitis.

      Discussion

      Programmed death 1/PD-L1 inhibitors have become viable treatment options in addition to genotype-directed TKIs in oncogene-driven NSCLC. As a growing number of ICIs gain approval for use in NSCLC, patients are increasingly likely to receive ICI therapy during their disease course. Although the toxicity profiles of TKIs are well established, little is known regarding the potential toxicities of TKIs administered after ICIs.
      In this study, we observed a higher incidence of hepatotoxicity with sequential ICI and crizotinib use compared with crizotinib alone. The actuarial rates of grade 3/4 increases in ALT and aspartate transaminase levels with sequential therapy were 45.5% and 36.4%, respectively, versus 8.1% and 3.4% with crizotinib alone (which is consistent with the rates of 3% to 10% that have been reported in trials
      • Camidge D.R.
      • Bang Y.J.
      • Kwak E.L.
      • et al.
      Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study.
      • Shaw A.T.
      • Kim D.W.
      • Nakagawa K.
      • et al.
      Crizotinib versus chemotherapy in advanced ALK-positive lung cancer.
      • Liu B.
      • Yuan M.
      • Sun Y.
      • et al.
      Incidence and risk of hepatic toxicities associated with anaplastic lymphoma kinase inhibitors in the treatment of non-small-cell lung cancer: a systematic review and meta-analysis.
      ). Therefore, prior exposure to an ICI may significantly increase the risk of crizotinib-associated hepatotoxicity. Although increased toxicities, including transaminitis, were observed in early-phase studies evaluating concurrent administration of nivolumab plus crizotinib (CheckMate 370)
      • Spigel D.R.
      • Reynolds C.
      • Waterhouse D.
      • et al.
      Phase 1/2 study of the safety and tolerability of nivolumab plus crizotinib for the first-line treatment of anaplastic lymphoma kinase translocation-positive advanced non-small cell lung cancer (CheckMate 370).
      and avelumab plus crizotinib (JAVELIN Lung 101),
      • Shaw A.T.
      • Lee S.-H.
      • Ramalingam S.S.
      • et al.
      Avelumab (anti–PD-L1) in combination with crizotinib or lorlatinib in patients with previously treated advanced NSCLC: phase 1b results from JAVELIN Lung 101 [abstract].
      this is the first study to our knowledge to evaluate the effect of sequential ICI and TKI therapy on the risk of hepatotoxicity.
      Our findings suggest that patients with ROS1/MET/ALK-driven NSCLC who receive crizotinib after an ICI need to be cautioned and closely monitored for the development of hepatotoxicity. Of note, alectinib rather than crizotinib is now the standard first-line therapy in ALK-rearranged NSCLC, and the clinical impact of sequential ICI and alectinib was not evaluated in this study. It is worth noting, however, that in a phase Ib trial of concurrent administration of alectinib and atezolizumab in ALK-rearranged NSCLC, an acceptable safety profile was observed, with a grade 3 increase in ALT level occurring in two of 21 patients (9.5%).
      • Kim D.-W.
      • Gadgeel S.M.
      • Gettinger S.N.
      • et al.
      Safety and clinical activity results from a phase Ib study of alectinib plus atezolizumab in ALK+ advanced NSCLC (aNSCLC) [abstract].
      These findings are in line with the acceptable tolerability of concurrent administration of lorlatinib and avelumab,
      • Shaw A.T.
      • Lee S.-H.
      • Ramalingam S.S.
      • et al.
      Avelumab (anti–PD-L1) in combination with crizotinib or lorlatinib in patients with previously treated advanced NSCLC: phase 1b results from JAVELIN Lung 101 [abstract].
      yet they are in contrast to the increased hepatotoxicity of crizotinib plus avelumab,
      • Shaw A.T.
      • Lee S.-H.
      • Ramalingam S.S.
      • et al.
      Avelumab (anti–PD-L1) in combination with crizotinib or lorlatinib in patients with previously treated advanced NSCLC: phase 1b results from JAVELIN Lung 101 [abstract].
      crizotinib plus nivolumab,
      • Spigel D.R.
      • Reynolds C.
      • Waterhouse D.
      • et al.
      Phase 1/2 study of the safety and tolerability of nivolumab plus crizotinib for the first-line treatment of anaplastic lymphoma kinase translocation-positive advanced non-small cell lung cancer (CheckMate 370).
      and ceritinib plus nivolumab.
      • Felip E.
      • Braud F.G.D.
      • Maur M.
      • et al.
      Ceritinib plus nivolumab (NIVO) in patients (pts) with anaplastic lymphoma kinase positive (ALK+) advanced non-small cell lung cancer (NSCLC) [abstract].
      Indeed, the tolerability of different sequential or concurrent ICI-TKI strategies may be TKI specific, urging further studies to elucidate which combinations or sequences of an ICI and a TKI may be safe and viable options for patients. As suggested by the increased hepatotoxicity seen with an ICI plus crizotinib or ceritinib—versus with alectinib or lorlatinib—the baseline level of hepatotoxicity seen with each TKI may affect the development of increased hepatotoxicity when it is used with an ICI in a concurrent or sequential approach.
      Our study had several noteworthy limitations. It was a retrospective study subject to inherent selection biases and potential confounding by unmeasured risk factors. Further, the number of patients who received sequential ICI and crizotinib therapy was small. Of note, although a higher proportion of those in the sequential ICI-crizotinib cohort had MET alterations and were smokers (possibly reflecting the association with MET alterations
      • Drilon A.
      • Ou S.-H.
      • Clark J.
      • et al.
      MA16.09. Antitumor activity and safety of crizotinib in patients with MET exon 14-altered advanced non-small cell lung cancer.
      ) than in the crizotinib-only cohort (see Supplementary Table 1), the rate of hepatotoxicity is not known to be different in patients with MET-altered tumors.
      • Drilon A.
      • Ou S.-H.
      • Clark J.
      • et al.
      MA16.09. Antitumor activity and safety of crizotinib in patients with MET exon 14-altered advanced non-small cell lung cancer.
      Additionally, it was not feasible to evaluate all sequences of available ICIs and TKIs; as we have mentioned, it is likely that toxicities arising from strategies involving sequential or concurrent administration of an ICI and TKI may be TKI specific. Finally, the mechanism by which prior treatment with an ICI may augment the risk of TKI-associated hepatotoxicity remains poorly understood. Further studies will help determine whether prior ICI use may “prime” the immune system toward a TKI-induced inflammatory response.
      In conclusion, prior immunotherapy may significantly increase the risk of crizotinib-associated hepatotoxicity. Careful monitoring for hepatotoxicity is therefore recommended in patients treated sequentially with an ICI and crizotinib. In parallel, further studies are needed to define the safety profile of different sequences of ICIs and TKIs and identify feasible treatment strategies in oncogene-driven NSCLC. Until a more fine-tuned understanding of specific ICI-TKI sequences is available, caution may be advised when clinicians face the real-world question of whether to utilize immunotherapy in patients with oncogene-driven NSCLC who may still have TKI options. In patients newly diagnosed with advanced-stage NSCLC, baseline comprehensive genotyping to identify targetable driver oncogenes should be expedited, and the corresponding results should be incorporated along with the PD-L1 status to optimally inform treatment stratification and minimize potentially preventable toxicities.

      Acknowledgments

      This work was supported by a grant from the National Cancer Institute (R01CA164273 [to Dr. Shaw]), by Be a Piece of the Solution, and by the Targeting a Cure for Lung Cancer Research Fund at Massachusetts General Hospital.

      Supplementary Data

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