Discussion of the Pediatric and Medical Oncology Session
Connective Tissue Oncology Society Meeting, New York, 2 November
2013
Patrick Schöffski
Head, Department of General Medical Oncology, University Hospitals Leuven, and Laboratory of Experimental Oncology, KU
Leuven, Belgium
Instructions received from Bob Maki• Discuss 4 presentations in
10-15 minutes• Do not reiterate presented
data• Add a few personal
comments• Provide perspective to
further address the topics
• “You talk! I’ll have lunch and listen to some John Coltrane”
Featured presentations1. B. Bui-Nguyen et al.: Results of EORTC/SARC
Phase 2/3 clinical trial with doxorubicin and two different trabectedin schedules in soft tissue sarcoma (STS)
2. B. Weiss et al.: Results of Phase 2 clinical trial with sirolimus in NF1-related plexiform neurofibromas
3. A. Gupta et al.: Evaluation of cancer survivor and care provider preferences for male fertility preservation
4. K. Paz: Use of mouse models for individualized treatment of advanced STS
Discussion1. B. Bui-Nguyen et al.: Results of EORTC/SARC
Phase 2/3 clinical trial with doxorubicin and two different trabectedin schedules in soft tissue sarcomas (STS)
2. B. Weiss et al.: Results of Phase 2 clinical trial with sirolimus in NF1-related plexiform neurofibromas
3. A. Gupta et al.: Evaluation of cancer survivor and care provider preferences for male fertility preservation
4. K. Paz: Use of mouse models for individualized treatment of advanced STS
Conflict of interest/personal bias• Received travel support from PharmaMar to
attend this meeting, translational research grants and honoraria for advisory functions in the past
• Member of EORTC STBSG but have entered only one patient in this trial, who is still receiving trabectedin
Concept of EORTC 62091/SARC020• Purpose of the
randomized Phase 2 part of EORTC 62091/SARC020 was to identify the best schedule of trabectedin administration (“pick the winner”) in preparation of a pivotal head-to-head first line comparison of the minor groove binder with doxorubicin in metastatic STS (various histotypes)
Ecteinascidia turbinata
Important findings
• Futility analysis for the Phase 2 portion of the trial did not support the superiority hypothesis of trabectedin over doxorubicin
• Poor PFS outcome for trabectedin in both experimental arms (median 2.76 and 3.09 months)
• Treatment discontinuation rates were unexpectedly high with both schedules
• According to the statistical assumptions the safety of trabectedin was deemed “unacceptable”
• Pivotal Phase 3 comparison of trabectedin with doxorubicin will not be pursued
Take-home message for us• Doxorubicin-based chemotherapy remains the
(poorly active and unsatisfactory) standard of care in advanced STS
• The use of trabectedin in advanced STS outside of clinical trials remains restricted to patients failing anthracyclins, depending on the drug’s approval/ reimbursement status in different countries
• If indicated, trabectedin should always be given in STS as a 24 hour i.v. infusion every three weeks
• Safety/toxicity of the drug must be monitored closely
Personal comments• Second randomized Phase 2 trial in STS
suggesting advantage of one trabectedin schedule over another
• Excellent example of an “adaptive seamless Phase 2/3 study design” with an unfortunate outcome
• The (negative) results of the Phase 2 part of the study prevented the sponsor from embarking on a costly Phase 3 exercise and protected STS pts from being treated with an inferior treatment – success!
• Based on personal experience with trabectedin in 300+ pts I tend to disagree with the outcome of the trial that the safety of the drug is “unacceptable”
Future perspective• I continue recommending this very important
drug for “L-sarcomas” and some other histological subtypes
• Trabectedin is facing more competition, given the success of pazopanib, the off label use of other drugs and increasing trial activity in refractory STS
• Era of non-histotype-specific STS chemotherapy trials is history, especially when testing drugs that showed selective effects in defined STS subtypes - let’s start using our knowledge of sarcoma biology and drug pharmacology and run more rational trials!
Discussion1. B. Bui-Nguyen et al.: Results of EORTC Phase
2/3 clinical trial with doxorubicin and two different trabectedin schedules in soft tissue sarcomas (STS)
2. B. Weiss et al.: Results of Phase 2 clinical trial with sirolimus in NF1-related plexiform neurofibromas
3. A. Gupta et al.: Evaluation of cancer survivor and care provider preferences for male fertility preservation
4. K. Paz: Use of mouse models for individualized treatment of advanced STS
Conflict of interest/personal bias• No conflict of interest• Disappointed about the
poor efficacy of “established” systemic treatments for NF1-related mesenchymal neoplasms in the clinic
• Strongly believe that NF1-related benign/malignant tumors represent important unmet medical needs and trial activity in this field should be supported
Neurofibromas in NF1 patient
Concept of trial• Increased mTOR activation is observed in NF1-
deficient cells and tumors from NF1 pts • mTOR inhibitor sirolimus studied in young NF1
pts with inoperable plexiform neurofibromas (PN)
• Benign condition causing serious, life-threatening morbidity; no established systemic therapy
• Aim was (a) to determine if sirolimus is able to increase time to disease progression in progressive PN or (b) to induce responses in the absence of documented radiographic progression at baseline
Important findings• Sirolimus was well tolerated
over over prolonged periods, with a very limited number of predefined SAEs
• Treatment resulted in a statistically significant longer TTP as compared to a historical control group from another trial
• Rapamycin treatment did not result in shrinkage of PN in either stratum of the trial
Take-home message for us• PN as a benign condition can cause serious
morbidity if the lesions have a mass effect and are located in “problematic” anatomical regions
• Sirolimus will unlikely be able to prevent or treat (but possibly postpone) serious, potentially life-threatening complications of PN, as the drug does not induce objective responses
• While sirolimus can be given over prolonged periods of time with acceptable toxicity, the trial does not definitively answer the question whether mTOR inhibition really delays disease progression, due to the use of historical controls
Personal questions• How useful are efficacy data from clinical
studies that compare outcomes of trial patients with historical control groups, even if patient selection criteria are similar?
• To what extent do we have to prolong time to progression in pts with a benign mesenchymal neoplasm to conclude that the magnitude of the treatment effect is clinically relevant?
Future perspective• Appreciate how challenging it is to run
randomized trials in this orphan clinical setting: we have to be more flexible with the design and interpretation of trials in this disease
• Authors suggest combining mTOR inhibitors with other targeted therapies as future direction
• That drugs currently tested in ongoing trials are unlikely ideal combination partners: pegylated interferon alpha, everolimus, sunitinib, nilotinin, methotrexate, temozolomide, vinblastin, celecoxib...
• Combinations will likely increase treatment-related morbidity, which may be a limiting factor in PN pts
Discussion1. B. Bui-Nguyen et al.: Results of EORTC Phase
2/3 clinical trial with doxorubicin and two different trabectedin schedules in soft tissue sarcomas (STS)
2. B. Weiss et al.: Results of Phase 2 clinical trial with sirolimus in NF1-related plexiform neurofibromas
3. A. Gupta et al.: Evaluation of cancer survivor and care provider preferences for male fertility preservation
4. K. Paz: Use of mouse models for individualized treatment of advanced STS
Conflict of interest/personal bias• Strongly believe that cancer survivorship
issues and fertility preservation are very important topics
• Disappointed about the poor evidence for “established” means of fertility prevention in oncology
• I see cancer pts and their children on a weekly basis and realize how much the kids contribute to the QoL of the patient during treatment/recovery/follow-up
Morris, 12 Mara, 9 Jan, 9 (Note to CTOS meeting organizers: invite the kids on the left as discussants, they have strong opinions on virtually every topic. Can provide you with their contacts!)
Concept of project• Empirical, qualitative and
quantitative study to assess the preference of care providers, parents, and teenage cancer survivors regarding experimental methods for fertility preservation
• Focus on harvesting immature human germ cell tissue via testicular biopsy in pre-pubertal boys, for whom there are no established means for fertility preservation
• Known that primordial germ cells are very susceptible to toxicity (e.g. due to alkylators) but do not produce mature spermatocytes yet
Important findings• More than 2/3 of all interviewed participants
(care givers, cancer survivors, parents) supported the concept of performing testicular biopsies for clinical and/or research purposes
• Vast majority of parents and cancer survivors want to get information on option of a testis biopsy before cancer treatment begins so they have a choice
• Important factors for decision-making: risk of infertility, complications from biopsy, evolution of technology, cost of storing tissue…
Take-home message for us• Patients, families and caregivers expect us to
be more pro-active with regard to fertility preservation, not only in fertile young male and female adults, but also in prepubertal male children
• We have a clear mandate to perform further research in this field, to develop and validate the methodology
Personal comments• This is a very important and well conducted
research project that will have a significant impact on supportive care in young male pts preparing for cancer treatment
1972 landmark contribution of a famous New Yorker to the research field of male fertility
Future perspective• We deserve prospective clinical trials in this
field, and these do require close multidisciplinary interaction between pediatricians, oncologists, radiation oncologists, urologists, fertility experts, and patient advocates
• There is also a need to lobby for insurance coverage for efficient means of fertility prevention in pre- and postpubertal cancer patients receiving interventions that potentially interfere with fertility
• We need better systemic therapies for sarcoma with less negative impact on the reproductive system
Discussion1. B. Bui-Nguyen et al.: Results of EORTC Phase
2/3 clinical trial with doxorubicin and two different trabectedin schedules in soft tissue sarcomas (STS)
2. B. Weiss et al.: Results of Phase 2 clinical trial with sirolimus in NF1-related plexiform neurofibromas
3. A. Gupta et al.: Evaluation of cancer survivor and care provider preferences for male fertility preservation
4. K. Paz: Use of mouse models for individualized treatment of advanced STS
Conflict of interest/personal bias• Gave advice to Champions Oncology in the
context of GIST treatment and had early discussions around their planned clinical validation trial in sarcoma
• Personal bias against traditional (in vitro) methods for response prediction in oncology
• Strongly believe in the use of xenografts in sarcoma oncology for research purposes
• Also believe we have an ethical responsibility to protect experimental animals as good as possible
Concept of analysis
• Review of the current feasibility experience at Champions Oncology with establishing patient-derived sarcoma xenografts with the aim to personalize treatment
• Process combines molecular characterization of engrafted tissue, in vivo drug testing and treatment recommendation
• Prospective assessment of treatment outcome in 6 pts receiving “TumorGraft”-guided systemic therapies (plus 5 retrospective, anecdotal cases)
Key findings • Successful engrafting
of sarcoma tissue in mice from 22 out of 29 (76%) human donors (number of animals not reported)
• Only 6 out of the 29 pts (20%) actively treated
• High predictive accuracy of in vivo testing: company reports an “absolute” correlation between in vivo efficacy and clinical outcome, both in terms of drug resistance and sensitivity
• All patients responded by standard criteria
Take-home message for us• Data support the technical feasibility of
establishing patient-derived xenograft sarcoma models as an investigational platform for the purpose of therapeutic decision-making
• Early experience suggests that only a fraction of pts have a chance to benefit from the xenografting exercise (no engraftment of their tumor, no relapse, early death, many other reasons…)
• Validation studies planned in 5 different malignancies, including sarcomas
Ready for prime time in sarcoma?• Plenty of good reasons to support the idea
that in vivo modelling is better than traditional in vitro response prediction, as personalized “avatars” are believed to maintain the tumor genotype and heterogeneity, growth factor/tumor and tumor/ vascular interactions of the original cancer,
but…
...more questions than answers• Animals have no functional immune system,
which plays an important role in the host/tumor interaction
• Genetic stability of sarcomas may be different in the host than in the experimental animal
• Logistics of shipment of fresh tissue to central laboratory may be a limiting factor for disseminating the technology, which is required for validation
• Full scale validation of the concept in sarcoma (= documented survival benefit achieved by “TumorGraft”-guided therapy) likely non-feasible: orphan setting, heterogeneous disease, variable natural course, costs and time as limiting factors
Conceptual issues• Current reality in sarcoma is that most pts get
all available (= approved, reimbursed) drugs anyway, without any guidance from in vivo-modelling
• Considerable doubt that applying “optimal” sequence of available drugs based on “TumorGraft”-guided therapy will translate into a clinically relevant survival gain (or cost savings for health care systems)
• Off label use of compounds as shown is not in line with current thinking of insurance providers and regulators and only an option for individual pts in countries with very liberal health care systems
Future perspective• Advanced mesenchymal malignancies are
very useful for developing the methodology• Sarcoma is unlikely the right indication for
formal validation of the concept of using patient-derived xenograft models for therapeutic decision-making
• Real time molecular characterization of fresh tumor biopsies at time of disease progression or relapse of the patient may be considered as an alternative, more pragmatic (but yet to be validated) approach
• Thanks to all authors and their coworkers for their excellent contribution to this session of CTOS 2013
Thanks to Bob, Shreyas and the CTOS/SARC team for putting together a truly outstanding program this year!
Acknowledgements
