NIVOLUMAB Plus IPILIMUMAB and TEMOZOLOMIDE in Microsatellite Stable, MGMT Silenced Metastatic Colorectal Cancer
Condition: Metastatic Colorectal Cancer
MeSH terms: Colorectal Neoplasms
Study type: Interventional
Phase: Phase 2

Summary: 
      This is a Phase II, multicenter, single-arm trial designed to evaluate the efficacy and
      safety of nivolumab (NIVO), ipilimumab (IPI) and temozolomide (TMZ) combination in 27
      patients with MSS, MGMT-silenced mCRC with initial clinical benefit following lead-in
      treatment with single-agent TMZ.

      Immune checkpoint inhibitors have been shown to trigger durable antitumor effects in a subset
      of patients. A high number of tumor mutations (so called 'tumor mutational burden') has
      recently been found associated with increased immunogenicity (due to a high number of
      neoantigens) and improved treatment efficacy across several different solid tumors. In mCRCs,
      only a small fraction of tumors (<5%) display a high mutational load and are usually
      associated with inactivation of mismatch repair genes such as MLH1, MSH2 and MSH6. Checkpoint
      inhibitors may have increased activity in dMMR/microsatellite instability-high (MSI-H)
      tumors, a hypothesis which was tested in various Phase II trials with positive results. On
      the opposite, mismatch repair proficient colorectal cancer is unresponsive to immune
      checkpoint inhibitors.

      Previous reports indicate that acquired resistance to TMZ may emerge through the induction of
      a microsatellite-instability-positive phenotype and recent data showed that inactivation of
      MMR, driven by acquired resistance to the clinical agent temozolomide, increased mutational
      load, promoted continuous renewal of neoantigens in human colorectal cancers and triggered
      immune surveillance in mouse models.

      On all of the above grounds, the investigators hypothesize that treatment of microsatellite
      stable MGMT hypermethylated CRCs with alkylating agents could reshape the tumor genetic
      landscape by increasing the tumor mutational burden, leading to achieve potential
      sensitization to immunotherapy.
    

Detailed description: 
      In advanced CRC, the occurrence of chemorefractory disease poses a major therapeutic
      challenge for presence of an adequate performance status to potentially receive further
      treatments. Patients who progress after all approved treatments may be generally considered
      suitable for new investigational drugs or strategies. Thus, in the era of personalized
      medicine, tumor molecular profiling may lead to the identification of therapeutic targets or
      predictive biomarkers for pharmacological intervention. The DNA repair gene
      O6-methylguanine-DNA methyltransferase (MGMT) is responsible of the elimination of alkyl
      groups from the O6-position of guanine. If inactive, it may be involved in early steps of
      colorectal tumor genesis leading to an increase of G-to-A point mutations. Epigenetic
      silencing of MGMT during colorectal tumor genesis is associated with hypermethylation of the
      CpG island in its promoter. This transcriptional gene silencing is responsible for diminished
      DNA-repair of O6-alkylguanine adducts, with the consequence of enhancing chemosensitivity to
      alkylating agents including dacarbazine and its oral prodrug temozolomide (TMZ). Previous
      phase II studies showed that TMZ induced an average objective response rate by RECIST
      criteria in 10% of heavily pre-treated patients with advanced CRC carrying MGMT promoter
      methylated tumors. Thus, MGMT methylation by methylation-specific PCR (MSP) used for patients
      screening seemed to be a necessary but not sufficient condition to identify response to TMZ.
      Digital PCR quantification of MGMT methylation refined patients' selection, with benefit
      restricted to those with highly hyper-methylated tumors. Further analysis showed that MGMT
      negative/low expression by immunohistochemistry (IHC) is found in about one third of
      MSP-methylated samples and is associated with increased response rate. However, even in
      responding mCRC patients, acquired resistance to single agent TMZ emerges rapidly and almost
      invariably within 6 months from treatment initiation.

      Immune checkpoint inhibitors have been shown to trigger durable antitumor effects in a subset
      of patients. A high number of tumor mutations (so called 'tumor mutational burden') has
      recently been found associated with increased immunogenicity (due to a high number of
      neoantigens) and improved treatment efficacy across several different solid tumors. Early
      clinical testing indicated that only 1 of 33 CRC patients had a response to anti PD-1
      treatment, in contrast to substantial fractions of patients with melanomas, renal-cell
      cancers, and lung tumors who showed benefit from PD-1 blockade. Similarly, anti CTLA-4
      treatment up today brought to unsatisfactory results in unselected mCRC patients. The
      probability of response has been ascribed to a high mutational burden (that is an elevated
      number of somatic mutations), which translates in increased number of neo-antigens. In mCRCs,
      only a small fraction of tumors (<5%) display a high mutational load and are usually
      associated with inactivation of mismatch repair genes such as MLH1, MSH2 and MSH6. Molecular
      alterations in these genes occur as an initial step in colon tumor genesis leading to the
      microsatellite instability (MSI) phenotype. Indeed, mismatch repair-deficient (dMMR)
      colorectal cancers have 10 to 100 times as many somatic mutations as mismatch
      repair-proficient colorectal cancers. Moreover, mismatch repair-deficient cancers contain
      prominent lymphocyte infiltrates, a finding consistent with an immune response. Thus,
      checkpoint inhibitors may have increased activity in dMMR/microsatellite instability-high
      (MSI-H) tumors, a hypothesis which was tested in various Phase II trials with positive
      results. On the opposite, mismatch repair proficient colorectal cancer is unresponsive to
      immune checkpoint inhibitors.

      Previous reports indicate that acquired resistance to TMZ may emerge through the induction of
      a microsatellite-instability-positive phenotype. On the other hand, TMZ by itself has been
      shown to induce an increase of mutational load in other MGMT deficient solid tumors such as
      melanoma or glioblastoma. In parallel, other studies have demonstrated that alkylating
      agents' side effects can influence the immune cell compartment by selectively depleting the
      immuno-suppressive T regulator lymphocytes (Tregs), and activating the immuno-active T
      cytotoxic lymphocytes (Tc) and natural killers (NK). The investigators recently showed that
      inactivation of MMR, driven by acquired resistance to the clinical agent temozolomide,
      increased mutational load, promoted continuous renewal of neoantigens in human colorectal
      cancers and triggered immune surveillance in mouse models.

      On all of the above grounds, the investigators hypothesize that treatment of microsatellite
      stable MGMT hypermethylated CRCs with alkylating agents could reshape the tumor genetic
      landscape by increasing the tumor mutational burden either directly (by inducing G>A
      mutations) or/and indirectly (by inactivating DNA repair genes such as MLH1, MSH2 or MSH6,
      which in turn could lead to hypermutated phenotype) therefore enhancing formation of cancer
      neoantigens and immunogenicity. TMZ treatment can also modulate the repertoire of immune
      cells (Tregs, Tc, NK) favoring T cell activation. To achieve potential sensitization to
      immunotherapy by means of TMZ-induced MSI-like status, treatment with TMZ should be active
      (i.e. inducing a SD/PR/CR).
    

Intervention name(s): Temozolomide; Nivolumab; Ipilimumab
Intervention type(s): Drug; Drug; Drug
Intervention description(s): temozolomide 150 mg/sqm daily on days 1-5 every 4 weeks; nivolumab 480 mg i.v. every 4 weeks; low-dose ipilimumab 1 mg/Kg i.v. every 8 weeks
Intervention MeSH terms: Nivolumab; Ipilimumab; Temozolomide
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: nivolumab; ipilimumab; temozolomide; microsatellite stable; MSS; MGMT