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Long-term Clinical Outcome of Trastuzumab and Lapatinib for HER2-positive Metastatic Colorectal Cancer

Open AccessPublished:June 27, 2020DOI:https://doi.org/10.1016/j.clcc.2020.06.009

      Abstract

      Background

      ERBB2 amplification occurs in 5% of RAS wild-type metastatic colorectal cancer (mCRC) and it has been shown to be a target for treatment with 2 HER2-directed combinations of trastuzumab and lapatinib or trastuzumab and pertuzumab. We present long-term clinical results of trastuzumab and lapatinib (HERACLES-A trial) at 6.7 years (82 months) follow-up and focus on central nervous system (CNS) recurrences.

      Patients and Methods

      Patients had histologically confirmed KRAS exon 2 (codons 12 and 13) wild-type and HER2-positive mCRC. HER2 positivity was assessed by immunohistochemistry and in situ hybridization HERACLES diagnostic criteria. Patients were treated with intravenous trastuzumab 4 mg/kg loading dose, then 2 mg/kg once per week, and oral lapatinib 1000 mg per day until disease progression or toxicity. Patients who presented with symptoms or signs of CNS disease received brain computed tomography scan or magnetic resonance imaging.

      Results

      A total of 35 patients received trastuzumab and lapatinib and 32 were evaluable for response. One patient (3%) achieved complete response (CR), 8 (25%) partial response, and 13 (41%) stable disease. Therefore, response rate was 28%. Median progression-free survival was 4.7 months (95% confidence interval [CI] 3.7–6.1). Median overall survival was 10.0 months (95% CI 7.9–15.8). One patient achieved sustained CR still maintained at 7 years of follow-up. Progression in the central nervous system (CNS) occurred in 6 (19%) of 32 patients.

      Conclusions

      Long-term (6.7 years) follow-up analysis of HERACLES-A supports using of trastuzumab and lapatinib as treatment reference for KRAS wild-type, chemorefractory HER2-positive mCRC. In this subset of patients, prolongation of survival is accompanied by CNS recurrences that will require diagnostic and therapeutic attention in future studies.
      Clinicaltrials. Gov identifier: NCT 03225937.

      Keywords

      Introduction

      In metastatic colorectal cancer (mCRC), ERBB2 amplification occurs in 5% of RAS wild-type cases
      • Siena S.
      • Sartore-Bianchi A.
      • Marsoni S.
      • et al.
      Targeting the human epidermal growth factor receptor 2 (HER2) oncogene in colorectal cancer.
      and in the 2019 National Comprehensive Cancer Network (NCCN) Treatment Guidelines for Colon Cancer
      National Comprehensive Cancer Network
      Colon Cancer.
      this molecular alteration has been recognized as a valuable therapeutic target with 2 HER2-directed drug combinations: trastuzumab and lapatinib
      • Sartore-Bianchi A.
      • Trusolino L.
      • Martino C.
      • et al.
      Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial.
      or trastuzumab and pertuzumab.
      • Meric-Bernstam F.
      • Hurwitz H.
      • Raghav K.P.S.
      • et al.
      Pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer (MyPathway): an updated report from a multicentre, open-label, phase 2a, multiple basket study.
      With the former regimen, we recently reported briefly the original finding of a high rate of central nervous system (CNS) recurrences in this patient population.
      • Sartore-Bianchi A.
      • Lonardi S.
      • Aglietta M.
      • et al.
      Central nervous system as possible site of relapse in ERBB2-positive metastatic colorectal cancer: long-term results of treatment with trastuzumab and lapatinib.
      In the present article we detail in full the long-term clinical results of the pivotal HERACLES-A trial of trastuzumab and lapatinib in an extended population of 32 patients with mCRC at a follow-up of 6.7 years with an expanded focus on timing, characteristics, and treatment of CNS recurrences.

      Patients and Methods

      Patients and Treatment

      Patients were treated in the HERACLES-A trial
      • Sartore-Bianchi A.
      • Trusolino L.
      • Martino C.
      • et al.
      Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial.
      and had a histologically confirmed diagnosis of mCRC with KRAS exon 2 (codons 12 and 13) wild-type status and HER2 positivity, as defined by the CRC-specific HERACLES diagnostic criteria (tumors with 3+ HER2 score in >50% of cells by immunohistochemistry or with 2+ HER2 score and a HER2:CEP17 ratio >2 in >50% of cells by fluorescence in situ hybridization [FISH]).
      • Valtorta E.
      • Martino C.
      • Sartore-Bianchi A.
      • et al.
      Assessment of a HER2 scoring system for colorectal cancer: results from a validation study.
      Patients were treated with trastuzumab, intravenously at 4 mg/kg loading dose, then at 2 mg/kg once per week, and lapatinib, orally at 1000 mg per day in 21-day treatment cycles (ie, 1 weekly trastuzumab dose and 1 daily lapatinib dose). Inclusion/exclusion criteria, screening phase, treatment/dose schedules, and tumor assessments were as previously described.
      • Sartore-Bianchi A.
      • Trusolino L.
      • Martino C.
      • et al.
      Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial.

      Follow-up and CNS Relapse

      Tumor assessments were done at baseline and every 8 weeks thereafter until progression. Follow-up for overall survival (OS) was updated to 6.7 years after study treatment started. Assessments were made for death and for CNS recurrence. Patients who presented with symptoms or signs of CNS disease received brain computed tomography (CT) scan with intravenous (I.V.) contrast and, if clinically indicated, magnetic resonance imaging with I.V. contrast. HERACLES-A trial protocol did not have specific indications for CNS relapses and all cases were diagnosed and treated as per best clinical practice.

      Results

      We screened and enrolled patients with mCRC between August 27, 2012, and March 15, 2016. Screening details were previously described.
      • Sartore-Bianchi A.
      • Trusolino L.
      • Martino C.
      • et al.
      Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial.
      A total of 35 patients were enrolled and treated with trastuzumab and lapatinib (27 in the trial phase, 8 in an extension cohort). Of these, 3 were not evaluable for response (concomitant RAS mutation 2 cases, absence of target lesions assessable by RECIST, 1 case [Supplemental Figure 1 in the online version]). The characteristics of the 32 fully evaluable patients are displayed in Table 1. At the time of the end of the study (May 15, 2019), the follow-up was 82 months (6.7 years). Of the 32 patients, one had a complete and 8 (25%) had a partial response, for a total of 9 (28%) patients achieving objective response rate (ORR). Stable disease (SD) was observed in 13 (41%) patients and lasted ≥4 months in 9. Overall, disease control was achieved in 22 patients (69%), lasting ≥4 months in 18 (56%). Table 2 shows treatment-related adverse events according to Common Terminology Criteria for Adverse (CTCAE) events that occurred in at least 5% of patients or all that were grade 3 or worse. Three patients underwent the treatment for more than 1 year: of them, only 1 patient displayed fatigue grade 3 and an asymptomatic decrease in left ventricular ejection fraction grade 3 that improved and reversed to grade 1 after temporary suspension.
      Table 1Baseline Characteristics
      Clinical VariablesN = 32(%)
      Median age in years (range)62 (40-86)
      Sex
       Males28(88)
       Females4(12)
      HER2 expression by immunohistochemistry score
       3+25(78)
       2+7(22)
      Site of primary tumor
       Rectum8(25)
       Colon24(75)
      Proximal
      Located in cecum, ascending colon, liver flexure, and transverse colon.
      5(15)
      Distal
      Located in splenic flexure, descending colon, and sigmoid colon.
      19(60)
      Prior treatment
       Median number of prior lines (range)5 (2-11)
       Patients with > 3 prior lines24(75)
       Prior cetuximab or panitumumab32(100)
      a Located in cecum, ascending colon, liver flexure, and transverse colon.
      b Located in splenic flexure, descending colon, and sigmoid colon.
      Table 2Adverse Events
      Adverse EventsGrades 1-2Grade 3
      Gastrointestinal
       Diarrhea26 (81)1 (3)
       Abdominal pain5 (16)
       Nausea10 (31)
       Vomiting5 (16)
      Dermatological
       Rash17 (53)1 (3)
       Dry skin8 (25)
       Nail disorder3 (10)
       Pruritus3 (10)
       Erythema2 (6)
       Folliculitis3 (10)
      Metabolic and nutritional disorders
       Fatigue14 (44)5 (16)
       Anorexia2 (6)
      Paronychia12 (38)
      Conjunctivitis6 (19)
      Hand-foot syndrome2 (6)
      Blood bilirubin increase1 (3)
      Decrease in left ventricular ejection fraction2 (6)
      Data are n (%). Treatment-related adverse events are reported if they occurred in at least 5% of patients or were of Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or worse. All 32 patients were included in the analysis. No grade 4 or 5 adverse events occurred.
      Median progression-free survival (PFS) was 4.7 months (95% confidence interval [CI] 3.7–6.1). At 7 years after treatment initiation, 1 of 32 patients is still in complete remission, and thus potentially cured. Median OS was 10.0 months (95% CI 7.9–15.8) with the latter patient alive censored at the time of data cutoff. Figure 1 shows a swimmer plot of PFS and OS.
      Figure thumbnail gr1
      Figure 1Swimmer Plot Regarding Progression-free Survival (PFS) and Overall Survival (OS) of HER2-Positive Patients Treated With Trastuzumab and Lapatinib. Green Bars Represent Patients Who Achieved Complete Response (CR) and Partial Response (PR), whereas Yellow and Red Bars Indicate Stable (SD) and Progressive Disease (PD), Respectively. Bars With Black Line are Patients With Central Nervous System (CNS) Recurrence. Black Dots Represent PFS. Red Dots Represent Timing of CNS Recurrence
      Abbreviations: CNS PD = progression of disease in the CNS; Pts = patients.

      CNS Relapses

      Symptomatic disease progression in the CNS occurred in 6 (19%) of 32 evaluable patients. The characteristics of these patients and their CNS progression and treatments are reported in Table 3. Five of 6 patients achieved a clinical benefit from the anti-HER2 treatment (2 with partial response [PR] and 3 with SD). Figure 2 shows the treatment history of this particular cohort of patients who developed brain progression. Four patients progressed while on anti-HER treatment and median time to progression in the CNS was 7.9 months. Exclusive brain progression occurred in 3 patients, whereas in the other 3 patients the progression was generalized. Median OS was 11.4 months. Treatments consisted of stereotactic brain radiation therapy (n = 2) and neurosurgery excision (n = 1). Because of poor performance status, 2 remaining patients received best supportive care and 1 was lost to follow-up. In the patient who underwent neurosurgery for a cerebellum secondary localization, manifested 11.5 months after treatment initiation (UPN 121003), the CNS metastases maintained HER2-positivity (immunohistochemistry [IHC] 3+) and status of KRAS and BRAF wild-type as compared with a metachronous lung metastasis, analyzed before HER2-targeted treatment, and the primary tumor (Figure 3). We additionally did not find in the CNS lesion any mutations of ERBB2.
      Table 3Clinical Characteristics and Treatments of Patients Showing CNS Progression Within the HERACLES-A Trial
      Patient IDSite of CNS PDBrain PFS (mo)Timing of CNS Progression Related to Anti-HER2 TreatmentTime After Last HER2-Targeted Treatment (mo)Best Response to Anti-HER2 TreatmentBrain Metastases TreatmentOS (mo)OS After CNS Relapse (mo)
      121016
      This patient developed brain metastases after treatment with trastuzumab + lapatinib and T-DM1 given as sequential rescue treatment within the HERACLES-RESCUE study.
      NA30.5Off-treatment3.2PRNone35.34.8
      121006cerebellum, supratentorial lesions13.6On-treatment0.5PRNone13.90.3
      121003cerebellum11.5Off-treatment1.8SDSurgery29.718.2
      121019supratentorial lesions, cerebellum1.2On-treatment
      Patient remained on HERACLES-A treatment during brain radiotherapy.
      0.5SDStereotactic radiosurgery8.97.7
      121009NA4.2On-treatment0.4SDNA7.83.6
      121027supratentorial lesions2.1On-treatment0.1PDStereotactic radiosurgery5.02.9
      Abbreviations: CNS = central nervous system; NA = not available; ORR = objective response rate; OS = overall survival; PD = progressive disease; PFS = progression-free survival; PR = partial response; SD = stable disease.
      a This patient developed brain metastases after treatment with trastuzumab + lapatinib and T-DM1 given as sequential rescue treatment within the HERACLES-RESCUE study.
      b Patient remained on HERACLES-A treatment during brain radiotherapy.
      Figure thumbnail gr2
      Figure 2Treatment History of HER2-Positive Patients Who Developed Central Nervous System (CNS) Progression
      Abbreviations: CNS PD = disease progression to CNS; OSH = overall survival following HERACLES-A treatment; PFS1 = progression-free survival with first-liine treatment; PFS2 = PFS with second-line treatment; PFS3 = PFS with third-line treatment; PFS4 = PFS with fourth-line treatment; PFSH = PFS with trastuzumab and lapatinib (HERACLES-A).
      Figure thumbnail gr3
      Figure 3Representative Patient 121003 Showing Progression of a Metastatic Lesion in the Cerebellum Retaining ERBB2 Amplification in HERACLES-A Trial. (A) Representative Computed Tomography (CT) Scan of the Lung (Left) and Cerebellum Metastasis (Right) Observed in Patient 121003 after 13.6 months of Treatment With Trastuzumab and Lapatinib. (B) Corresponding Immunohistochemistry (IHC) and Fluorescence in Situ Hybridization (FISH) Analyses of Lung (Left) and Cerebellum Metastasis Obtained Through Surgical Excision (Right), Showing Maintenance of ERBB2 Amplification. Parallel Mutational Analysis Demonstrated KRAS and BRAF Wild-type in Both Specimens. Original Magnification for Hematoxylin-Eosin and HER2 Immunohistochemistry (Inner Left Picture) Staining Pictures is ×200 (Scale bar: 100 μm) and Original Magnification for FISH Pictures (Inner Right Picture) is ×630 (Scale bar: 20 μm)

      Discussion

      This long-term follow-up analysis of the HERACLES-A trial demonstrates that pharmacological double HER2 blockade with trastuzumab and lapatinib, as foreseen by preclinical models,
      • Bertotti A.
      • Migliardi G.
      • Galimi F.
      • et al.
      A molecularly annotated platform of patient-derived xenografts (“xenopatients”) identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer.
      ,
      • Leto S.M.
      • Sassi F.
      • Catalano I.
      • et al.
      Sustained inhibition of HER3 and EGFR is necessary to induce regression of HER2-amplified gastrointestinal carcinomas.
      constitutes a therapeutic reference for the treatment of mCRC where this biomarker is present.
      • Valtorta E.
      • Martino C.
      • Sartore-Bianchi A.
      • et al.
      Assessment of a HER2 scoring system for colorectal cancer: results from a validation study.
      The value of ERBB2 amplification as a therapeutic target in mCRC has been confirmed in the MyPathway trial
      • Meric-Bernstam F.
      • Hurwitz H.
      • Raghav K.P.S.
      • et al.
      Pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer (MyPathway): an updated report from a multicentre, open-label, phase 2a, multiple basket study.
      in which the combination of trastuzumab and pertuzumab was used, and both regimens achieve level 2 OncoKB designation (https://www.oncokb.org) and inclusion in the NCCN Guidelines for colon cancer. Further, the more recently presented MOUNTAINEER trial with trastuzumab and tucatinib and DESTINY-CRC01 with the antibody-drug conjugate trastuzumab deruxtecan showed the potential for improvement of these results with newer HER2-targeted agents.
      • Strickler J.H.
      • Zemla T.
      • Ou F.-S.
      • et al.
      527PDTrastuzumab and tucatinib for the treatment of HER2 amplified metastatic colorectal cancer (mCRC): initial results from the MOUNTAINEER trial.
      ,
      • Siena S.
      • Di Bartolomeo M.
      • Raghav K.
      • et al.
      A phase II, multicenter, open-label study of trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing metastatic colorectal cancer (mCRC): DESTINY-CRC01.
      In the present HERACLES-A extended population of 32 patients we observed an ORR of 28% (95% CI 14%–47%) and a median PFS of 4.7 months. These results are achieved in a heavily pretreated population in which standard therapeutic options such as regorafenib or trifluridine-tipiracil do not provide meaningful ORR.
      • Grothey A.
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      Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial.
      ,
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      Randomized trial of TAS-102 for refractory metastatic colorectal cancer.
      Interestingly, we documented a sustained complete response (CR) still maintained at 7 years of follow-up (Supplemental Figure 2 in the online version). These results confirm that the benefit obtained by targeting oncogenic addictive products such as HER2 can lead to unprecedented clinical benefit and survival. HERACLES-A data presented here compare indeed favorably with the other 2 therapeutic strategies for biomarker-defined mCRC populations, such as triple BRAF-directed therapy
      • Kopetz S.
      • Grothey A.
      • Yaeger R.
      • et al.
      Encorafenib, binimetinib, and cetuximab in BRAF V600E–mutated colorectal cancer.
      and microsatellite instability-confined treatment with immune checkpoint inhibitors.
      • Overman M.J.
      • Lonardi S.
      • Wong K.Y.M.
      • et al.
      Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer.
      In this regard, from a clinical standpoint, HER2-targeted treatment seems to reconcile the strengths of targeted oncology against oncogenes (rapid and deep induction of tumor shrinkage) with those of immunotherapy (durability of responses and the potential for cure).
      Treatment-prolonged survival in this cohort of patients with chemorefractory HER2-positive mCRC resulted in an unexpectedly high occurrence of CNS metastases in approximately one-fifth of patients. This incidence rate is 4 times higher than usually reported in mCRC.
      • Tan R.Y.C.
      • Camat M.D.
      • Ng M.
      • et al.
      HER2 positive rates are enriched amongst colorectal cancer brain metastases: a study amongst 1920 consecutive patients.
      Several considerations can be made to explain this finding: a potential biological tropism toward CNS of ERBB2-amplified cells; a limitation of trastuzumab and lapatinib to cross the blood–brain barrier (BBB); or the increased likelihood in patients with long survival outcomes of developing involvement of rarer anatomic sites than observed in the general population of mCRC.
      The hypothesis that ERBB2 amplification drives a higher propensity to spread to CNS has been already documented for breast
      • Lin N.U.
      • Amiri-Kordestani L.
      • Palmieri D.
      • Liewehr D.J.
      • Steeg P.S.
      CNS metastases in breast cancer: old challenge, new frontiers.
      ,
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      • Zahrieh D.
      • Price K.N.
      • et al.
      Identifying breast cancer patients at risk for Central Nervous System (CNS) metastases in trials of the International Breast Cancer Study Group (IBCSG).
      and gastric cancer.
      • Yoon H.H.
      • Lewis M.A.
      • Foster N.R.
      • et al.
      Central nervous system relapse in patients with untreated HER2-positive esophageal or gastroesophageal junction adenocarcinoma.
      ,
      • Limon D.
      • Gal O.
      • Gordon N.
      • et al.
      Brain metastasis in gastroesophageal adenocarcinoma and HER2 status.
      Approximately only 1% to 4% of patients with mCRC are reported to develop CNS metastases.
      • Nozawa H.
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      • et al.
      Brain metastasis from colorectal cancer: predictors and treatment outcomes.
      ,
      • Mege D.
      • Sans A.
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      Brain metastases from colorectal cancer: characteristics and management.
      However, limited data are available about the correlation between ERBB2 amplification and tendency to CNS metastasis. Tan et al.
      • Tan R.Y.C.
      • Camat M.D.
      • Ng M.
      • et al.
      HER2 positive rates are enriched amongst colorectal cancer brain metastases: a study amongst 1920 consecutive patients.
      recently pointed out that 20% of 40 patients with mCRC developing CNS metastases were characterized by ERBB2 amplification in the primary tumor. In another recent publication,
      • Mitra D.
      • Clark J.W.
      • Shih H.A.
      • et al.
      Enrichment of HER2 amplification in brain metastases from primary gastrointestinal malignancies.
      14 patients with mCRC undergoing craniotomy because of CNS metastasis were tested by IHC and FISH for ERBB2 amplification and 3 of them (21%) resulted positive with 100% concordance with primary tumor. These data, together with present findings from a selected population of HER2-positive patients with mCRC, support the hypothesis that ERBB2 amplification, as also DNA damage response pathway defects,
      • Sun J.
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      Genomic signatures reveal DNA damage response deficiency in colorectal cancer brain metastases.
      is a mechanism that drives higher propensity to spread to CNS.
      Another explanation for the high incidence of CNS progression might be because of the limited intracranial activity of anti-HER2 therapies, particularly trastuzumab.
      • Palmieri D.
      • Bronder J.L.
      • Herring J.M.
      • et al.
      Her-2 overexpression increases the metastatic outgrowth of breast cancer cells in the brain.
      Indeed, pharmacokinetics evidence obtained from phase I trials involving anti-HER2 drugs demonstrated different capability to bypass the BBB due to their dimension (ie, molecular mass >450 kDa) or their hydrophilic nature.
      • Eichler A.F.
      • Loeffler J.S.
      Multidisciplinary management of brain metastases.
      ,
      • Steeg P.S.
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      • Smith Q.R.
      Brain metastases as preventive and therapeutic targets.
      Trastuzumab, when administered as an I.V. infusion, poorly crosses the BBB. In radiotherapy-naïve patients, trastuzumab concentrations have been reported to be 420-fold lower in cerebrospinal fluid (CSF) than in serum.
      • Stemmler H.-J.
      • Schmitt M.
      • Willems A.
      • Bernhard H.
      • Harbeck N.
      • Heinemann V.
      Ratio of trastuzumab levels in serum and cerebrospinal fluid is altered in HER2-positive breast cancer patients with brain metastases and impairment of blood-brain barrier.
      Even after radiotherapy, the blood/CFS trastuzumab concentration remains low (1:49).
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      • Schmitt M.
      • Willems A.
      • Bernhard H.
      • Harbeck N.
      • Heinemann V.
      Ratio of trastuzumab levels in serum and cerebrospinal fluid is altered in HER2-positive breast cancer patients with brain metastases and impairment of blood-brain barrier.
      Lapatinib is a small molecule reversible tyrosine kinase inhibitor designed to target both HER1 (epidermal growth factor receptor) and HER2. Being a small molecule (molecular weight <1 kDa), lapatinib should be able to cross the BBB and reach CNS deposits.
      • Taskar K.S.
      • Rudraraju V.
      • Mittapalli R.K.
      • et al.
      Lapatinib distribution in HER2 overexpressing experimental brain metastases of breast cancer.
      In a preclinical study on healthy animals, however, the ability of lapatinib to cross the BBB was limited due to efflux transporter P-glycoprotein,
      • Polli J.W.
      • Humphreys J.E.
      • Harmon K.A.
      • et al.
      The role of efflux and uptake transporters in [N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine (GW572016, lapatinib) disposition and drug interactions.
      a selective gatekeeper of the BBB and thus a primary obstacle to drug delivery into the brain. Several clinical trials evaluated the CNS efficacy of lapatinib obtaining conflicting results.
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      Lapatinib plus capecitabine for HER2-positive advanced breast cancer.
      ,
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      Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer.
      Finally, another reason explaining why HER2-positive tumors seem to develop more CNS metastases is the prolonged survival obtained thanks to the anti-HER2 treatment itself. This gain in survival might indeed allow the unmasking of brain deposits otherwise clinically silent.
      • Lin N.U.
      • Winer E.P.
      Brain metastases: the HER2 paradigm.
      ,
      • Pestalozzi B.C.
      • Brignoli S.
      Trastuzumab in CSF.
      In HERACLES-A, we observed a median OS of 10.0 months, with 1 patient still in CR after 7 years and this survival time from the initiation of HER2-targeted treatment must be added to the time elapsed since the diagnosis of metastatic disease, which was considerable in HERACLES-A (patients had received a median of 4 previous treatment lines before enrollment). Indeed, the median OS for the entire cohort of 32 patients since the diagnosis of stage IV is 42.3 months, higher than expected (Supplemental Table 1 in the online version).
      Our analysis regarding CNS involvement in HERACLES-A has some limitations. First, we did not perform a brain imaging on the entire cohort of HER2-positive patients with mCRC but only in symptomatic patients, so that we could not exclude an even higher incidence in this population. Second, we compared our cohort with historical data on incidence of brain metastases in patients with mCRC patients and not with patients with HER2-positive tumors who did not receive trastuzumab/lapatinib or patients with HER2-negative mCRC.
      Altogether our findings support the hypothesis that, in HER2-positive patients with mCRC treated with trastuzumab and lapatinib, CNS represents a sanctuary of disease progression. Based on this, we recommend to include brain imaging for staging and tumor assessment in these patients.

      Conclusion

      In conclusion, updated analysis of HERACLES-A trial confirms trastuzumab and lapatinib as a HER2-directed combination of reference for KRAS wild-type, chemorefractory HER2-positive mCRC. We also document that CNS represents a sanctuary site of relapse, a finding that calls for inclusion of brain imaging for staging and tumor assessment in this patient population. Further studies will shed light on the mechanisms underlying this tropism and will investigate the potential of new-generation tyrosine kinase inhibitors with capability of CNS penetration and possibly clinical activity.
      • Strickler J.H.
      • Zemla T.
      • Ou F.-S.
      • et al.
      527PDTrastuzumab and tucatinib for the treatment of HER2 amplified metastatic colorectal cancer (mCRC): initial results from the MOUNTAINEER trial.
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      Tucatinib with capecitabine and trastuzumab in advanced HER2-positive metastatic breast cancer with and without brain metastases: A non-randomised, open-label, phase 1b study.
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      Clinical Practice Points

      • HERACLES-A pivotal multicenter phase-II trial demonstrated trastuzumab and lapatinib as an active combination in treating HER2-positive chemorefractory mCRC.
      • These results document that the benefit obtained by targeting oncogenic addictive products such as HER2 can lead to unprecedented clinical benefit and survival. We report a sustained CR maintained at 7 years of follow-up. Interestingly, a high prevalence of CNS recurrences indicated this site as a sanctuary of relapse in this subset of HER2-positive patients with mCRC.
      • Trastuzumab and lapatinib combination was confirmed as a reference therapeutic option for HER2-positive mCRC in advanced line. In this population, CNS represents a sanctuary of disease progression, therefore we recommend to include brain imaging for staging and tumor assessment.

      Disclosures

      A. Sartore-Bianchi has acted as a consultant/advisory member for Amgen, Bayer, and Sanofi. S. Siena is advisory board member for Amgen, Bayer, BMS, Celgene, Incyte, Merck, Novartis, Roche, Seattle Genetics. A. Amatu is advisory board member for Amgen and Bayer. F. Ciardiello received honoraria or consultation fees for speaker, consultancy, or advisory roles: Amgen, Bayer, Bristol-Myers Squibb, Celgene, Merck Serono, Pfizer, Roche, Servier; direct research funding as the principal investigator for institutional research projects: Amgen , Bayer , Merck Serono , Roche , Ipsen ; institutional financial interests, financial support for clinical trials or contracted research: Merck Serono, Roche, Symphogen, Array; leadership Positions in Professional Societies (nonfinancial interests): ESMO Past-President, President of the Associazione Italiana Oncologia Toracica.

      Acknowledgments

      The authors are supported by grants from the following: Associazione Italiana Ricerca Cancro grant AIRC 5 × mille [Project ID 51000] Special Program Molecular Clinical Oncology , AIRC Investigator Grant [Project ID 20685] to Livio Trusolino, Alberto Bardelli, and S. Siena, and Fondazione AIRC under 5 per Mille 2018 - ID. 21091 program – P.I. Bardelli Alberto, Group Leaders L. Trusolino and S. Salvatore, S. Marsoni; AIRC IG 2018 - ID. 21923 project - PI A. Bardelli; Fondazione Piemontese per la Ricerca sul Cancro-ONLUS 5 per mille 2014 e 2015 Ministero della Salute to A. Bardelli; CORDIS Community Research and Development Information Service , Horizon 2020 [Project ID 635342] grant Molecularly Guided Trials with Specific Treatment Strategies in Patients with Advanced Newly Molecular Defined Subtypes of Colorectal Cancer (MoTriColor) to A. Bardelli and S. Siena; Fondazione Oncologia Niguarda Onlus, grant Terapia Molecolare dei Tumori to A. Sartore-Bianchi and grant Studies to Develop Therapies Against Colorectal Cancer in Young Adults 12018 to A. Sartore-Bianchi and S. Siena; Progetto NET-2011-02352137 Ministero della Salute ; Fondazione Regionale Ricerca Biomedica (FRRB) , Grant IANG-CRC CP_12/2018 to SS.

      Supplemental Data

      Figure thumbnail fx1
      Supplemental Figure 1Flow-Chart of Patients Treated With Trastuzumab and Lapatinib and Evaluable for Response in HERACLES-A Trial
      Figure thumbnail fx2
      Supplemental Figure 2Sustained Complete Response With Trastuzumab and Lapatinib Therapy in a 63-Year-old Woman With Chemoresistant HER2-Positive Metastatic Colorectal Cancer. Treatment With HER2 Targeted Agents is Ongoing in November 2019. (A) Representative Computed Tomography (CT) Scan of Bilateral Lung Metastases in Patient UPN 121015 at Baseline in December 2013. (B) Representative CT Scan Imaging of Maintained Lung Complete Response in August 2019 after 6 years of Treatment With Trastuzumab and Lapatinib
      Supplemental Table 1OS From Diagnosis of Stage IV of the Entire Cohort of HER2-Positive Patients With Metastatic Colorectal Cancer Treated With Lapatinib and Trastuzumab Within HERACLES-A Trial
      Patient IDOS (mo)
      12100155.2
      12100244.1
      12100378.5
      12100481.6
      12500534.3
      12100651.9
      12400726.2
      12100936.1
      12101110.8
      12101259.4
      12101329.1
      12201430.6
      12101595.4
      12101662.2
      12501749.1
      12101860.1
      12101924.3
      12202084.7
      12402150.1
      12202247.1
      12102394.9
      12102422.4
      12202545.2
      12102639.9
      12102736.4
      12102830.4
      12202940.5
      12403018.1
      12103129.1
      12503225.6
      12103353.9
      12103519.7
      Median OS42.3
      Abbreviation: OS = overall survival.

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