Therapy of small-cell lung cancer (SCLC) with a topoisomerase-I inhibiting antibody-drug conjugate (ADC) targeting Trop-2
The present invention relates to treatment of SCLC with therapeutic ADCs comprising a drug attached to an anti-Trop-2 antibody or antigen-binding antibody fragment. Preferably, the drug is SN-38. More preferably, the antibody is an hRS7 antibody and the ADC is sacituzumab govitecan. The ADC may be administered at a dosage of between 4 mg/kg and 16 mg/kg, preferably 4, 6, 8, 9, 10, 12, or 16 mg/kg, mostly preferably 8 to 10 mg/kg. When administered at specified dosages and schedules, the ADC can reduce solid tumors in size, reduce or eliminate metastases and is effective to treat cancers resistant to standard therapies, such as radiation therapy, chemotherapy or immunotherapy. Surprisingly, the ADC is effective to treat cancers that are refractory to or relapsed from irinotecan or topotecan. Preferably, the ADC is administered as a combination therapy with one or more other anti-cancer treatments, such as carboplatin or cisplatinum.
1. A method of treating small cell lung cancer (SCLC) comprising (i) administering to a human patient with SCLC an anti-Trop-2 antibody-drug conjugate (ADC) wherein the anti-Trop-2 ADC is sacituzumab govitecan, and (ii) administering to the patient cisplatin or carboplatin;
wherein the ADC and cisplatin or carboplatin are administered as a second-line or later therapy to patients who have received previous cancer treatment for the SCLC.
2. The method of claim 1 , wherein the cancer is metastatic (mSCLC).
3. The method of claim 1 , wherein the patient has previously relapsed from or been resistant to treatment with a standard anti-cancer agent.
4. The method of claim 1 , wherein the patient has previously relapsed from or been resistant to treatment with topotecan or irinotecan.
5. The method of claim 1 , wherein the SCLC is sensitive to chemotherapy with platinum-containing agents.
6. The method of claim 1 , wherein the SCLC is resistant to chemotherapy with platinum-containing agents.
7. The method of claim 1 , wherein the treatment results in a reduction in tumor size of at least 15%, at least 20%, at least 30%, or at least 40%.
8. The method of claim 2 , further comprising reducing in size or eliminating the metastases.
9. The method of claim 1 , wherein the cancer is refractory to other therapies but responds to the ADC.
10. The method of claim 1 , wherein the ADC dosage is administered to the human subject once or twice a week on a schedule with a cycle selected from the group consisting of: (i) weekly; (ii) every other week; (iii) one week of therapy followed by two, three or four weeks off; (iv) two weeks of therapy followed by one, two, three or four weeks off; (v) three weeks of therapy followed by one, two, three, four or five weeks off; (vi) four weeks of therapy followed by one, two, three, four or five weeks off; (vii) five weeks of therapy followed by one, two, three, four or five weeks off; and (viii) monthly.
11. The method of claim 10 , wherein the cycle is repeated 4, 6, 8, 10, 12, 16 or 20 times.
12. The method of claim 1 , wherein the ADC is administered in combination with one or more therapeutic modalities selected from the group consisting of an unconjugated antibody, an immunoconjugate, gene therapy, chemotherapy, a therapeutic peptide, cytokine therapy, localized radiation therapy, surgery, interference RNA therapy, a drug, a toxin and a cytokine.
13. The method of claim 12 , wherein the drug, toxin or chemotherapeutic agent is selected from the group consisting of 5-fluorouracil, afatinib, aplidin, azaribine, anastrozole, anthracyclines, axitinib, AVL-101, AVL-291, bendamustine, bleomycin, bortezomib, bosutinib, bryostatin-1, busulfan, calicheamycin, camptothecin, carboplatin, 10-hydroxycamptothecin, carmustine, celebrex, chlorambucil, cisplatinum (CDDP), Cox-2 inhibitors, irinotecan (CPT-11), SN-38, carboplatin, cladribine, camptothecans, cyclophosphamide, crizotinib, cytarabine, dacarbazine, dasatinib, dinaciclib, docetaxel, dactinomycin, daunorubicin, doxorubicin, 2-pyrrolinodoxorubicine (2P-DOX), cyano-morpholino doxorubicin, doxorubicin glucuronide, epirubicin glucuronide, erlotinib, estramustine, epidophyllotoxin, erlotinib, entinostat, estrogen receptor binding agents, etoposide (VP16), etoposide glucuronide, etoposide phosphate, exemestane, fingolimod, flavopiridol, floxuridine (FUdR), 3′,5′-O-dioleoyl-FudR (FUdR-dO), fludarabine, flutamide, farnesyl-protein transferase inhibitors, fostamatinib, ganetespib, GDC-0834, GS-1101, gefitinib, gemcitabine, hydroxyurea, ibrutinib, idarubicin, idelalisib, ifosfamide, imatinib, L-asparaginase, lapatinib, lenolidamide, leucovorin, LFM-A13, lomustine, mechlorethamine, melphalan, mercaptopurine, 6 -mercaptopurine, methotrexate, mitoxantrone, mithramycin, mitomycin, mitotane, navelbine, neratinib, nilotinib, nitrosurea, olaparib, plicomycin, procarbazine, paclitaxel, PCI-32765, pentostatin, PSI-341, raloxifene, semustine, sorafenib, streptozocin, SU11248, sunitinib, tamoxifen, temazolomide (an aqueous form of DTIC), transplatinum, thalidomide, thioguanine, thiotepa, teniposide, topotecan, uracil mustard, vatalanib, vinorelbine, vinblastine, vincristine, vinca alkaloids and ZD1839.