Metastatic Breast Cancer: T-DM1
`Conjugate Superior to Standard
`Treatment with Capecitabine-Lapatinib
`
`BY ROBERT H. CARLSON
`
`
`
`The most common adverse events
`of grade 3 or higher for capecitahine—
`lapatinib were diarrhea (20.7% vs.
`l.6% for T-DMI): hand-foot syndrome
`(16.4% vs. 0% respectively); and vomiting
`(4.5% vs. 0.8%).
`In her conclusion, Blackwell noted that
`it has been 14 years since trastttzumab was
`introduced at
`the 1998 annual ASCO
`meeting. “Today. the same antibody has
`been improved in a way that we expect
`to benefit patients and lessen the toxic-
`ity of traditional chemotherapy through
`use ofau antibody-drug conjugate." she
`said. “Targeted therapy for cancer has
`progressed another step forward with the
`EMILIA study."
`
`Discussant: ’lmportant New
`Weapon’
`"T—DMI
`is an important new weapon
`in the therapeutic armamentarium for
`breast cancer." said the Discussant for the
`study. Louis M. \X’einer, MD, Director of
`Georgetown-Lombardi Comprehensive
`Cancer Center.
`
`
`
`LOUIS M. WEINER, MD: "The improved
`survival is particularly notable. since
`effective palliative treatment of
`metastatic breast cancer has rarely been
`associated with substantially improved
`survival in the refractory setting. The
`results of this trial suggest that median
`survival will be significantly prolonged in
`women treated with T-DM1."
`
`He congratulated the EMILIA inves-
`tigators for designing, implementing. and
`analyting a Phase lll trial that convincingly
`demonstrated the superiority OFT-Db“
`therapy compared with a standard regimen.
`”Stated simply. T-DMI really works
`in this patient population.” he said. “The
`improved survival is particularly notable.
`continued rm [mgr 28
`
` R
`
`t
`-§
`i
`3Ss
`5’.
`41
`
`8‘
`
`'
`
`KIMBERLY L. BLACKWELL. MD: "T-DM1
`is a brand new way of treating breast
`cancer. and I think it is the first of many
`antibody-drug conjugates to follow
`that will link a potent anticancer agent
`to a targeted delivery system of an
`antibody."
`
`for those receiving T-DM 1. a 17.9% abso-
`lute difference.
`
`Median progression-free survival was
`6.4 months for capecitabine'laparinib with
`304 death events, vs. 9.6 months and 265
`events For T—DM], an absolute improve-
`ment in median PFS 013.2 months.
`
`”Targeted therapy for
`
`cancer has progressed
`
`another step forward
`
`with the EMILIA study.”
`
`And median overall survival at interim
`analysis was 23.3 months for capecitabine’
`lapatinib with 12‘) events. There were 94
`events with T-DMl but median survival
`has not yet been reached.
`
`Safety
`Safety also favored T—DM 1 including time
`to symptom progression and other patient-
`reported outcomes.
`l‘ewer
`significantly
`There were
`treatment—related adverse events with
`T-DM 1. Blackwell said. including at 40.8
`percent rate of grade 3 or higher adverse
`events with T—DMl vs. 57.0 percent for
`capecitabine-lapatinib.
`The tnost common adverse events
`
`of grade 3 or higher for T-DMl were
`thromhocytopenia (12.9% vs. 0.2% for
`capecitabine-lapatinib) and increased
`aspartate aminotransferase (AST) (4.3%
`vs. 0.8%. respectively).
`
`”The immunoconjugate,
`
`T-DM1, is in a sense
`
`a smart bomb, a way
`
`to deliver cytotoxic
`
`chemotherapy where
`
`you want it to be,
`
`and largely, but not
`
`completely, avoid
`
`post-toxicity.”
`
`HICAGO—Trastuzumab has
`again proved its versatility in
`breast cancer.
`this time in com-
`bination with the powerful cyto-
`toxic emtansine (T—DMI) to trmt women
`. with HER2—positive locally advanced or
`metastatic breast cancer previously treated
`with trastuzumab and a taxane.
`
`As presented here at the plenary session
`of the ASCO Annual Meeting (Abstract
`1.8/11), primary results from the Phase III
`EMILIA trial showed that the antibody-
`drug conjugate of T—DMI was superior
`to the standard capecitabine-lapatinib
`regimen in both progression-free survival
`(PFS)—a hazard ratio of 0.650—and
`overall survival. with a hazard ration of
`0.621 at 24 months.
`Lead author Kimberly L. Blackwell,
`MD, Director of the Breast Cancer Clinial
`Program and Professor of Medicine at
`Dulce Cancer Institute, reported an ab-
`solute improvement in median PPS of
`3.2 months with T-DMI, and an abso~
`lute improvement in overall survival of
`17.9 percent.
`She explained that emtansine has been
`shown to be 25 to 500 times more potent
`than paclitaxel in in—vitro assays, and the
`combination—T—DM l—incorporates the
`antitumor activities of trastuzumab and
`
`the HERZ-targeted delivery of DM 1 .
`Capecitabine—lapatinib is currently the
`only approved combination for trastu-
`zumab—refractory HER-Z-positive meta-
`static breast cancer.
`“T-DMI is a brand new way of treating
`breast cancer, and 1 think it is the first of
`many antibody-drug conjugates to follow
`that will link a patent anticancer agent to
`a targeted delivery system of an antibody.”
`she said.
`-
`
`213 Sites in 26 Countries
`EMILIA was conducted in 213 sites in
`26 countries. Patients received T-DMl at
`3.6 mglkg 1V every three weeks. or oral
`capecitabine at 1000 mg/m2 twice daily
`on days 1-14 every three weeks plus oral
`lapatinib at 1.250 mg daily. Either regimen
`was continued until progressive dismse or
`unmanageable toxicity.
`A total of 991 patients were enrolled
`and 978 received treatment. All patients
`with metastatic disease had received a prior
`taxane and rrastuzumab.
`The median duration of follow-
`up was 12.9 months for patients re-
`ceiving T-DM] and 12.4 months for
`capecitabine—lapatinib.
`The overall survival rate was 47.5 per-
`cent at 24 months for patients receiving
`capecitabine-lapatinib versus 65.4 percent
`
`IMMUNOGEN 2123.139. 1
`Phigenix v. Immunogen
`|PR2014-00676
`
`.oornlg
`ogy—times
`
`
`
`oncologytimes-july10,20120oncol
`
`IMMUNOGEN 2123, pg. 1
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`Bevacizumab Extends PFS
`
`But, Says Discussant: Stop Phase III Trials of Molecularly Targeted
`Agents in Ovarian Cancer!
`BY ROBERT H. CARLSON
`
`
`
`
`
`
`
`to be. and largely. but tint
`you want it
`completely, avoid post—toxicity."
`He said it is very gratifying to see that
`this drug outperformed two oral agents
`given in combination. capccitabine and
`Iapatinib. a standard treatment. “When
`I say outperformed,
`it controlled breast
`cancer for a longer period of time. At
`first glance.
`this will
`likely translate to
`an overall survival advantage with longer
`follow-up."
`Seidman said he has personal cxpe-
`riencc with T-DM] in clinical
`trials at
`Memorial Sloan—Kettering: "It is kind and
`gentle. This is not your grandmother's
`chemotherapy."
`He said he has heard that T-DM I may
`be approved by the FDA sometime in 2012.
`
`Also Important: Pertuzumab
`to
`Seidman added that it
`is
`important
`look at a study about pertuzunrab. another
`HERZ-targeted agent also developed by
`Gcncntcch and Roche—the MARIANNE
`trial ofT-DMl antl pcrtuztunab (clinical-
`h'ialt.gov/c12/sbow/NCT01 120184).
`“The MARIANNE Phase II] trial re-
`sults are awaited to define a possible role
`for the combination nfT-DM] and pertu—
`zuniab as first—line combination therapy ol-
`HER2 metastatic breast cancer. " he said.
`”Perttrzuntab may actually enter our
`clinics and be used commercially even
`before TDM-L So in a sense We have .in
`'ernlmrrassment of riches' right now for
`l'lER—Z-positive breast cancers."
`He noted that researchers are refining
`targeted therapy by finding new targets
`and developing new molecules to hit those
`targets. by better profiling patients with
`gene signatures. and finding combination
`therapies for dual inhibition—“\‘Uc'rt: also
`finding that cancer cells. as they have been
`for many years, are often smarter than the
`doctors who treat them." fl
`
`oncologytimes0july10,20120oncology—times.comlg Platinum-Resistant Ovarian Cancer:
`
`
`defined patients with serous cancer. and
`because there is no strong predictive bio-
`marltcr in epithelial ovarian cancer.
`
`.10 percent ofwumcn who have primary
`HlCAGO—For patients with
`platinum-resistant
`recurrent
`platinum-resistant disease, as well as those
`ovarian cancer. a combination of
`whose disease later becomes platinum
`resistant.
`bevacizumab and standardvoF—carc
`Pujade—laurainc. Professor of Medicine
`New Standard Option
`chemotherapy cuts the risk of disease pro—
`“Bevacizumab combined with chemother—
`at Université Paris Descartes, said AURELIA
`gression almost in halfcompated with che-
`is the first randomized Phase III trial
`in
`apy should be considered a new standard
`motherapy alone. This and other outcomes
`from the randomized Phase III AURELIA
`platinum-resistant ovarian cancer to dem-
`option in platinum—resistant ovarian
`trial from France Were described here at
`cancer." said Eric Pujade-Lattraine, MD,
`onstrate benefit with biologic therapy and
`benefit with a combination regimen vs.
`the American Society ofCIiniml Oncology
`PhD. who presented the data on behalfoi
`monotherapy.
`the AURELIA investigators and the Group
`Annual Meeting (Abstract 1.345002).
`He noted that bcvacizumab cfiicacy
`d'lnvestigateurs Nationaux pour l’Etude
`But in a provocative turn, the Discussant
`des Cancers Ovariens (GINECO).
`with platinum in front-line therapy
`the study recommended stopping
`for
`has already been demonstrated in the
`He said the results are very significant
`Phase [11 trials ofmolecularly targeted agents
`because the addition of bevacizumab
`Gynecologic Oncology Group 0218 and
`in ovarian cancer boo-use there are no large
`continued rm page .29
`offers a new treatment option for the
`groups of homogeneously genomically
`
`Trastuzumab has again
`
`proved its versatility
`
`in breast cancer, this
`
`time in combination
`
`with the powerful
`
`cytotoxic emtansine
`to treat women with
`
`HERZ-positive locally
`advanced or metastatic
`
`breast cancer
`
`previously treated with
`trastuzumab and a
`
`taxane.
`
`-* EM l LIA
`
`continuedfi‘am page 26
`
`since eflectis’e palliative treatment of meta-
`static breast anccr has rarely been associ-
`ated with substantially improved survival
`in the refractory setting. The results of this
`trial suggest that median survival will be
`significantly prolonged in women treated
`with T—DM l ."
`He said more work will be needed to
`determine if the benefits oFT-DMl-based
`therapy are restricted to patients with
`HER-2 gene amplification, or if patients
`with lesser degrees of HER-2 overexpres-
`sion can be eficctively treated as well.
`"The utility of T—DMI
`in trastu—
`zumab-resistanr disease raises obvi-
`ous questions about
`the ultimate role
`of trastuzumab that justify thoughtful
`clinical investigations that are underway."
`he concluded.
`
`Speaking of his own experience with
`T-DM1 at Memorial Sloan-Kettering
`Cancer Center, ANDREW SEIDMAN, MD,
`said. "It is kind and gentle. This is not
`your grandmother's chemotherapy."
`
`'New Type of Precision Medicine'
`Asked for a comment about the study,
`Andrew Seidman, MD, a breast cancer
`researcher and attending physician at
`Memorial Sloan-Kettering Cancer Center.
`called the results “welcome news."
`Seidman. also Professor of Medicine
`at Weill-Cornell Medical College, said
`Blackwell’s overview of the EMlLlA trial
`
`highlights one of the most important strid-
`ics in breast cancer at this meeting—"a new
`type of precision medicine for breast can-
`cer that is using an old friend. trastuzumzrb.
`as a delivery vehicle for a potent q'totoxic
`agent."
`"The irnmunoconjugate. T-DMl. is in
`a sense a smart bomb," he said. “
`It's a way
`to deliver cytotoxic chemotherapy Where
`
`"Old Friend'
`
`events, most would agree that it is a
`
`30th Dr. Blackwell in her presen-
`I’ta‘tion and Dr. Séidman in his
`interview called trasttrzun'iab"
`old friend" Inane-mailexchangen.‘
`soidm'an explained
`” ”Trastuzumab is indeed an old
`friend Since approximately 1999;
`*
`_ [kind and gentle agent."
`
`{or women with HER-driven meta-
`static breast cancer, and doing the
`same for women with earlier stage
`disease as adjuvant therapy since
`2005. Friends treat us with kindness.
`and other than uncommon cardiac
`
`IMMUNOGEN 2123, Pg. 2
`Phigenix v. Immunogen
`|PR2014-00676
`
`IMMUNOGEN 2123, pg. 2
`Phigenix v. Immunogen
`IPR2014-00676
`
`