Virtual Tumor Board

A Multidisciplinary Approach to Cancer Treatment

Edited by Keith A. Delman, MD

Metastatic Melanoma
Ragini R. Kudchadkar, MD1; Michael C. Lowe, MD2; Mohammad K. Khan, MD, PhD3;
Stephanie M. McBrien, BSN, RN, OCN1
Emory Winship Cancer Institute, Atlanta, Georgia

Case Presentation and Overview

W.V. is a 39-year-old Caucasian male who, on July 4, complication. CT scans of the body and MRI scans of
2017, presented with right arm numbness while run- the brain remained stable during this time. For surveil-
ning a 10-K race. Magnetic resonance imaging (MRI) lance and to monitor tumor response to treatment,
of the brain revealed a 3-cm, peripherally enhanced CT scans were used rather than positron emission
mass (Fig. 1), and computed tomography (CT) with ­tomography (PET)/CT scans because the small pul-
contrast of the chest, abdomen, and pelvis revealed monary nodules were below the limits of PET detec-
subcentimeter (2-4 mm) pulmonary nodules with no tion and were better imaged by dedicated CT scans.
other sites of disease. On July 7, 2017, he underwent One month after the completion of nivolumab, CT
craniotomy with resection of a parietal tumor. Frozen scans showed enlargement of a left upper lobe pul-
section was initially suspicious for primary glioma; monary nodule, and the patient subsequently under-
however, final pathology showed metastatic mela- went video-assisted thoracoscopic surgery wedge
noma that was positive for S100, MITF, and SOX10 resection. Pathology showed metastatic melanoma
by immunohistochemistry. There was no history of 1 cm in size. It was noted on pathology that 15% of
prior melanoma or nonmelanoma skin cancers, and nucleated cells in the periphery and 5% of cells in the
no primary tumor was identified on a total body skin center were CD8-positive lymphocytes. Although the
examination. In addition, a standard comprehensive significance of this observation is unclear, preliminary
examination for mucosal, ocular, and other occult data demonstrate better outcomes for patients who
sources was performed, and no definitive primary have increased CD8 infiltration of their melanoma.1
was identified. The tumor was positive for the BRAF After he underwent video-assisted thoracoscopic
V600E mutation by next-generation sequencing. The surgery resection, the patient was followed with a ­ ctive
patient subsequently underwent radiation to the post- surveillance. In August 2019, slow but steady growth
operative bed, receiving 30 grays (Gy) in 5 fractions. was noted in the subcentimeter pulmonary nodules
In August 2017, the patient began systemic ther- over an approximately 18-month period. All nodules
apy with ipilimumab 3 mg and nivolumab 1 mg/kg. He had grown by approximately 2 to 3 mm, with the larg-
received 2 doses of therapy, which was then discon- est measuring 1 cm. After discussion with the patient,
tinued because of the development of colitis. After a he was started on encorafenib and binimetinib on
6-week course of steroids, he was initiated on main- October 1, 2019. At the time of publication, the patient
tenance nivolumab at 480 mg intravenously every was tolerating treatment without complications and
4 weeks. He received 1 year of nivolumab without has had a near complete response to treatment.

1
Department of Hematology/Oncology
2
Department of Surgery
3
Department of Radiation Oncology

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BRAF/MEK inhibitors. Key clinical factors for decision
making include age and performance status, the pres-
ence or absence of brain metastases, and medical co-
morbidities (history of transplantation or autoimmune
disease). Patient input into this decision making is crit-
ical because the side-effect profiles of both options
are quite different. In addition, one should consider
the patient’s symptomatology from cancer and over-
all disease burden. The rapid responses and high re-
sponse rate of targeted therapy often lead clinicians
to choose BRAF and MEK inhibitor therapy in patients
with symptomatic disease.
At the time of diagnosis, this patient had an excel-
lent performance status of 0. He had no known med-
ical problems before the diagnosis but, upon imaging
to evaluate for other sites of disease, it was noted
that he had radiologic features of ankylosing spon-
dylosis, although he was largely asymptomatic. Given
imaging findings that were suspicious for ankylosing
spondylosis, the patient was evaluated by a rheuma-
tologist, who confirmed the diagnosis. However, be-
FIGURE 1. Brain Magnetic Resonance Imaging Shows Contrast- cause of this diagnosis and because the patient did
Enhancing Lesions in the Left Frontoparietal Lobe.
not have technically measurable disease according
to Response Evaluation Criteria in Solid Tumors, he
Medical Oncology Perspective: did not qualify for the treatment-naive trials available
Systemic Therapy Decision Making at that time. From our standpoint, this fact and the
presence of brain metastases were key in choosing a
At presentation, this is a young male with stage IV, systemic treatment.
BRAF-mutated melanoma to the brain from an un- Single-agent anti–PD-1 drugs, combination im-
known primary. The first branching point of discussion munotherapy, as well as dabrafenib and trame-
is whether this is an adjuvant, resected, stage IV mela- tinib have data showing activity in central nervous
noma versus an active melanoma with lung metasta- system (CNS) disease. Ipilimumab at 3 mg/kg and
ses. Approved therapies for adjuvant, fully resected nivolumab at 1 mg/kg have shown equivalent intra-
melanoma include single-agent, anti–PD-1 agents cranial and ­extracranial responses in patients with
(nivolumab; pembrolizumab) or BRAF and MEK inhibi- asymptomatic brain metastases who were not
tors (dabrafenib and trametinib). It should be noted receiving systemic steroids.2 Long and colleagues
that the numbers of patients with resected brain also demonstrated a high response rate for this
metastases in adjuvant trials are limited, although
­ combination, with a 46% intracranial response rate.3
some trials have included patients with resected stage Updated data from the 204 study4 also demon-
IV disease. For active stage IV disease, approved ther- strated durable responses intracranially from combi-
apies include nivolumab or pembrolizumab as a single nation immunotherapy. Single-agent pembrolizumab
agent, anti–PD-1 therapies, combination CTLA-4 and showed an objective response rate of 25% in mel-
PD-1 antibodies (ipilimumab and nivolumab), as well as anoma brain metastases.5,6 Single-agent nivolumab
BRAF and MEK inhibitors (dabrafenib and trametinib, showed an intracranial response rate of 20%.3 From
or encorafenib and binimetinib, or vemurafenib and these early and small studies, one can conclude
cobimetinib). that immunotherapy has activity in controlling CNS
Subcentimeter lung nodules are difficult to inter- metastases of melanoma and that combination
pret—they are too small to biopsy or to be detected therapy has a higher activity rate in the CNS than
by PET/CT. The patient did not have prior imaging single-agent therapy.
studies to compare, nor did he have any obvious rea- Dabrafenib and trametinib also demonstrated
sons for having multiple lung nodules (ie, prior infec- ­activity in the CNS in the Dabrafenib and Trametinib
tions, smoking, active asthma). Given the brain lesion Before and After Surgery in Treating Patients With
and the number of nodules, we were highly suspicious Stage IIIB-C Melanoma With BRAF V600 Mutation
that the patient had active, stage IV disease; there- (COMBI-MD) study.7 Although that study demon-
fore, we elected to proceed with therapeutic options strated a high intracranial response rate for dabrafenib
for active disease. and trametinib of 58%, the duration of response was
The second point of decision making is whether quite limited, with a median progression-free survival
to pursue immunotherapy or targeted therapy with of 6.5 months in patients with previously untreated,

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It is essential to educate patients and caregivers
TABLE 1. Considerations in Therapeutic
about how to recognize symptoms and the need
Decision-Making
to contact their health care provider early in course
IMMUNOTHERAPY THERAPY of symptoms. Teaching by a team is most effective
(using nursing staff and pharmacists, if possible) to
Pros Brain activity 52% 5-y OS provide a broad, patient-focused education about
Cons Interaction with ankylosing High risk of ­immune-related adverse events (Table 1).
spondylosis autoimmune After progression on immunotherapy with an in-
side effects crease in the number of lung nodules, the patient was
Abbreviation: OS, overall survival.
initiated on encorafenib and binimentinib. There are 3
combination BRAF/MEK inhibitors on the market cur-
rently (dabrafenib plus trametinib, vemurafenib plus
cobimetinib, and encorafenib plus binimentinib). There
asymptomatic brain disease. As a result, in patients is no known, definitive efficacy advantage to using one
with a good performance status, with no urgent combination over another, although no trials have com-
symptomatology, without contraindications, and with- pared these drugs head-to-head. Side-effect profiles
out trial options, immunotherapy is our preferred ini- do vary, with a higher incidence of fevers using com-
tial approach. bined dabrafenib and trametinib and a higher incidence
Although all CNS data are from studies with relatively of rashes using combined vemurafenib and cobimetinib
small numbers of patients, there is still strong evidence compared with encorafenib and binimentib. Encorafenib
that both immunotherapy therapy and targeted ther- and binimetinib can be taken with food, which may be
apy can control CNS disease. On the basis of the data more convenient for patients and thus was chosen for
we have to date, the highest response rate is with either this patient. The follow-up regarding our patient’s toler-
ipilimumab and nivolumab or dabrafenib and trametinib. ance of therapy and response to treatment was not yet
Given the durability seen in updates from the CheckMate available at the time of this publication.
204 study (An Investigational Immunotherapy Study
to Evaluate Safety and Effectiveness in Patients With
Melanoma That Has Spread to the Brain, Treated With
Medical Oncology Nursing
Nivolumab in Combination With Ipilimumab, Followed Perspective
by Nivolumab by Itself), it appears that combined ipili-
mumab and nivolumab may also have the best durabil- In between laboratory work, clinic, and treatment ap-
ity of response in this population. This was the primary pointments, nurses are frequently on the front lines
reason to choose this therapy for our young, healthy, when it comes to patient communication and initial
asymptomatic patient. This choice also comes with contact. Telehealth nursing as well as communication
great toxicity risk, which was discussed in detail with through patient portals are increasingly common forms
the patient to ensure that the decision for a treatment of patient-to-clinician toxicity reporting.10 Patients may
with high toxicities was congruent with the patient’s also present in person via walk-in nursing appoint-
goals of treatment. ments. This patient’s preferred method of communica-
Key factors to discuss with patients are the perma- tion has been through portal messages. Education has
nence of some of the immunotherapy toxicities, the risk been provided to the patient regarding contact through
of hospitalization, as well as the risk of rare but very seri- the portal occurring during business hours only, and he
ous complications. For younger patients, fertility should knows that any urgent concerns after hours or over the
also be discussed, although there are few data on how weekend should not be sent electronically.
long-term fertility is affected by immunotherapy. The patient initially started treatment with combi-
For combined ipilimumab and nivolumab, the risk of nation ipilimumab 3 mg/kg and nivolumab 1 mg/kg.
grade 3 and 4 toxicities is approximately 50%, with 20% Before any patient’s first dose of immunotherapy,
of patients requiring hospitalization. The endocrinop- nursing has the opportunity to stress both the side
athies will likely be permanent, lifelong conditions of effects most frequently seen as well as those that
which all patients should be aware and include thyroid pose the highest clinical risk to patients, regard-
dysfunction, hypophysitis, adrenal insufficiency, and less of how commonly they occur. With all immu-
(rarely) type 1 diabetes. More common toxicities that notherapies, but with this combination in particular,
may require a 4-week to 8-week course of high-dose the nursing team should spend a significant part of
steroids are pneumonitis, colitis, and hepatitis. Rash and direct patient education focused on immunother-
pruritus are common, although severe cases are rare. apy-induced colitis. Not only is this a frequently
Cardiac complications such as myocarditis are rare but reported toxicity, but, untreated, this can lead to
can be fatal. In addition, neurologic complications must hospitalization, perforation of the bowel, and sep-
be taken seriously, as myasthenia gravis, peripheral sis.11 The nurse can present information early on to
neuropathy, and Guillain-Barre have been reported.8,9 prevent later complications of colitis and stress the

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importance of early reporting of diarrhea to the clin- insufficiency (weakness, dizziness upon standing,
ical team. This patient was provided this education ­decreased appetite, just to mention a few) should be
and reached out through the patient portal when addressed. Also, as the patient starts to taper, educa-
the first episodes of diarrhea occurred. tion should be provided on the possibility of the need
In many oncology patients who are receiving che- for a cortisol-stimulation test. If, upon completing
motherapy or other forms of treatment, diarrhea the steroid course, the morning cortisol level is low,
protocols may differ. With immunotherapy, our ap- the provider will order this test to determine whether
proach to assessing patients with diarrhea leads to the patient has developed adrenal insufficiency. This
early diagnosis of autoimmune colitis. Similar assess- ­patient reported fatigue, myalgia, and other nonspecific
ment questions should be used, including focus on symptoms in mid-January 2018; a cortisol-stimulation
consistency (diarrhea, by definition, is liquid-like) and test was performed at that time to rule out adrenal
frequency. In addition, the nurse should establish the insufficiency and, fortunately, the results were normal.
patient’s baseline before the change in bowel move- For care teams that do not predominantly work
ments. Like with chemotherapy-induced diarrhea, with immunotherapy, one of the most important take-
infectious causes should be ruled out, so the pro- aways is to remember that standard protocols devel-
vider may order stool studies while simultaneously oped for chemotherapy patients often do not apply.
addressing the possibility of colitis. Immunotherapy- Immunotherapy causes different, albeit serious, side
induced colitis may come on quickly with frequent effects that should be addressed urgently to pre-
bowel movements, but it can also start with abdominal vent greater damage. Nurses on the front lines play
cramping or “churning.” These early signs can often a crucial role in the recognition and managements of
predict the start of diarrhea shortly thereafter. ­immunotherapy-induced toxicities.
To manage this patient’s diarrhea, loperamide in
combination with budesonide was prescribed initially.
However, the diarrhea continued, and, at the begin- Surgical Oncology Perspective:
ning of October 2017, the patient was prescribed Timing of Surgery and Systemic
high-dose steroids at 1 mg/kg. With persistent colitis, Therapy
the team expects a longer steroid course as well as a
slow taper once the colitis is on its way out. Nursing
Guidelines to Consider
should educate the patient about prophylactic medi-
cations that should be taken alongside a longer term National Comprehensive Cancer Network (NCCN)
steroid course: an antibiotic, antiviral, and antifungal. guidelines for the management of metastatic mela-
With this patient, additional written information was noma are based on the extent of disease. For pa-
sent through the portal, which can help patients recall tients with limited and resectable metastases, upfront
conversations held in clinic. The portal message reads surgery should be considered as an option. This is a
“…we will call in an antibiotic (Bactrim [sulfamethoxa- considerable shift in the treatment paradigm given
zle and trimethoprim]; Sun Pharmaceutical Industries that, historically, patients with metastatic disease
Ltd), antiviral (acyclovir), and antifungal (fluconazole) were ­almost uniformly started on systemic therapy.
to protect you while we suppress your immune sys- In general, exceptions included the need to obtain tis-
tem with the steroids. This is a standard practice that sue for diagnosis and operations that provided pallia-
we do to prevent any microorganisms that might take tive benefits. More and more data are emerging that
advantage while we use the steroid to bring down support the role of upfront surgery for patients with
your heightened immune system. Rather than a treat- limited and resectable metastatic melanoma, particu-
ment, this is a preventative measure.” This explana- larly from the adjuvant clinical trials showing signifi-
tion can assist in medication compliance, so that the cant improvements in recurrence-free and/or overall
patient understands what each medication is and why survival (OS) with systemic therapies after complete
it was prescribed. In addition, the provider team will surgical resection.
likely prescribe a proton-pump inhibitor in anticipation
of acid reflux caused by the high-dose steroids. Trials to Consider
In this patient’s case, the colitis responded to the There are no randomized clinical trials evaluating the
steroids. However, it is important to educate patients role of upfront surgery compared with conventional
on next steps should the steroids not work. Some treatment using systemic therapies. However, numer-
patients require infliximab infusions for immunother- ous prospective trials and retrospective data sets
apy-induced colitis that is nonresponsive to steroids.11 suggest that upfront surgery may provide a benefit
Another educational point to stress is the importance over upfront systemic therapy, or at least compared
of reporting any symptoms while a patient tapers with systemic therapy alone. In SWOG study 9430, 64
off high-dose steroids. This is true for colitis as well patients with completely resected metastases were
as any other autoimmune toxicity requiring a course followed prospectively; the 3-year and 4-year survival
of high-dose steroids. Symptoms related to adrenal rates were 36 and 31%, respectively, suggesting that

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patients with stage IV disease who are able to un- metastases portend a worse survival, it is reasonable
dergo surgery have a survival advantage compared to offer surgery only for patients with CNS metastases
with historic controls.12 Of 291 patients who developed who are in need of diagnosis or palliation.
distant metastatic disease during long-term f­ ollow-up
on Multicenter Selective Lymphadenectomy Trial I Specific Case Considerations
(MSLT-I), 161 underwent surgery as part of their treat- In this patient with multifocal, systemic metastases,
ment. The median survival for patients who under- including brain and lung, surgery played an integral
went surgery for distant metastatic melanoma was part in the treatment algorithm. The initial operation
15.8 months compared with 6.9 months for those who established the diagnosis of melanoma, and because
did not undergo surgery.13 Although some bias ex- there was no evidence of clear-cut, significant disease
ists toward surgery in more medically fit patients, the outside the brain at presentation, the patient appro-
consistent survival improvement with surgery in these priately underwent adjuvant radiation and systemic
studies argues for more prospective trials comparing therapy. When there appeared to be progression of
upfront surgery versus systemic therapy. disease in the lung, surgery served the dual purpose
SWOG study 1801 (clinicaltrials.gov identifier of diagnosis of recurrence and therapeutic resection.
NCT03698019) is an actively enrolling, international Removal of all clear and clinically significant, known
trial randomizing patients who have resectable stage disease allowed the patient to remain off systemic
III and IV melanoma14 (the American Joint Committee therapy for a considerable period of time. This case
on Cancer’s AJCC Cancer Staging Manual, eighth edi- highlights the need to involve surgeons in every as-
tion, M1a, M1b, and M1c) to receive neoadjuvant therapy pect of the care for patients with stage IV melanoma.
with pembrolizumab versus upfront surgery. All patients
­receive adjuvant pembrolizumab; the primary endpoint
is event-free survival. This trial not only will evaluate the Radiation Oncology Perspective:
role of neoadjuvant therapy in the metastatic setting Radiation Role in Control of CNS
but also likely will provide the most definitive data to Disease
date on the role of surgery for patients with metastatic
melanoma in the era of effective systemic therapies. Of
note, this trial excludes patients with CNS metastases, Guidelines to Consider
and very few of the patients in the previously men- NCCN 2019 cutaneous melanoma guidelines state that,
tioned trials included these patients. Given that CNS for melanoma metastases, stereotactic radiosurgery

FIGURE 2. Radiation Treatment Plan. The patient received 6 Grays in 5 fractions using hypofractionated stereotactic radiosurgery.

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(SRS) is considered an acceptable standard of care. interact with emerging immunotherapy agents as well
Because the patient had a 5.51-cm3 parasagittal cavity, as BRAF inhibitors; therefore, receipt of radiation at the
the recommendation was for a radiation dose of 30 Gy same time should be coordinated carefully through mul-
in 5 fractions (Fig. 2). In this young patient, the altered tidisciplinary input. In our case, we elected to proceed
radiation dose was chosen to limit the risk for late side with radiation and dual checkpoint therapy around the
effects, especially radiation-induced necrosis. Whole- same time with the hope that the combination would
brain radiation (WBRT) was not offered to minimize be synergistic based on preclinical work that included
the risks for neurocognitive impacts because it has not a small number of patients.19 This preclinical work sug-
been shown to improve OS for these patients. gested that the combination of radiation, anti–CLTA-4,
and anti–PD-L1 therapies would promote response and
Trials to Consider antimelanoma tumor immunity through distinct mech-
Because MRI characteristics were not definitive anisms. Future trials in melanoma should investigate
and the patient did not have a previous diagno- immunotherapy combination approaches that i­nclude
sis of melanoma, the differential on the presenting radiotherapy. For our patients who are receiving
brain lesion was broad. As such, surgical excision anti–PD-1 therapy, we have supported the practice of
was needed for diagnostic purposes in our case. concurrent radiation. There are some early, retrospec-
An older, prospective, randomized trial compared tive data from our institution suggesting that that the
biopsy followed by WBRT versus surgical excision ­simultaneous delivery of concurrent anti–PD-1 therapy
followed by WBRT (36 Gy in 12 fractions) for a single and SRS appears to be safe.20 Our current prospective
metastasis to the brain and found that surgical exci- trial (clinicaltrials.gov identifier NCT02858869) of SRS
sion improved: 1) median survival from 15 weeks to and pembrolizumab, which is evaluating the safety of
40 weeks (P < .01), 2) the local recurrence rate from this combination, is ongoing. We hope to have some
52% down to 20% (P < .01), 3) the time to neuro- preliminary results from that trial by the end of 2020.
logic death from 26 weeks to 62 weeks (P < .01), and Regarding the concurrent use of radiotherapy and dual
4) functional independence from 8 weeks to checkpoint inhibitors, there are limited data, and this
38 weeks (P < .01).15 Safe surgical resection of larger should be approached on a case-by-case basis. For
lesions (typically approximately 3.5 cm) and those BRAF inhibitor (BRAFi) therapy, we have avoided using
that are causing neurologic symptoms secondary to concurrent radiotherapy and BRAFi therapy because
mass effect is also recommended. of concerns about increased toxicity. We have typically
Patchell et al16 demonstrated that the addition of stopped BRAFi therapy from 1 to 3 days before radio-
radiation after surgery for a single brain metastasis therapy and then resumed it from 1 to 3 days after the
improved control of the tumor cavity and prevented completion of radiotherapy.
additional tumors from developing in the brain. The After SRS, the patient was brought back for
probability of recurrence after surgery was 46%. This post-SRS MRI scans at 4 to 6 weeks and then every
was improved to only 10% with the addition of radiation. 3 months. The primary concern with SRS was radiation
WBRT also reduced the probability of additional brain necrosis. This patient did develop radiation necrosis
metastases developing from 70% down to 18% but, as 1.5 years after treatment and presented with new-on-
noted above, is associated with significant sequelae set seizure. This was successfully managed with a
and thus is not a preferred approach. Aoyama et al17 short course of steroids and antiepileptic medication.
randomized 132 patients to receive SRS plus WBRT ver-
sus SRS alone. There was no difference in OS between
the 2 arms. Thus, SRS alone without offering WBRT Conclusions
was deemed acceptable, especially considering the
associated toxicity of WBRT. This concern was further Multidisciplinary teams are essential to the care of
demonstrated by Chang et al18 in a study that random- patients with metastatic melanoma. Before the ad-
ized patients who had ≤3 brain metastases to receive vent of modern systemic therapies for melanoma,
SRS alone with or without the addition of WBRT. Their surgery and radiation remained the standard of care.
trial demonstrated that the addition of WBRT decreased Now, surgery and radiation have taken on different
neurocognitive function without extending OS. roles, and the timing of systemic therapy with these
Preoperative and postoperative MRIs were used to modalities must be discussed by a multidisciplinary
assess for gross total resection of the brain metasta- team. The patient’s medical history, presentation,
sis and for radiation treatment-planning purposes. The and preferences should be considered in making the
treatment-planning MRI is ordered 2 to 4 weeks after final treatment decisions. Nursing staff is essential
excision. By then, the postoperative cavity would have to ­ensure that the patient understands of the plan
reduced in size and would be timed close to the actual of care and to address potential complications in a
radiation treatment-planning scans. One important con- timely manner. Together with the patient, the entire
sideration when administering radiotherapy is the tim- medical team can ensure that patients with melanoma
ing of r­adiation with systemic therapy. Radiation may have the best outcome possible.

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required a course of steroids. Active surveillance of
Patient Commentary the patient permitted the identification of new dis-
ease, while surgical intervention both provided a diag-
“When I first met with Dr. Kudchadkar in the fall of nosis and offered potential therapeutic benefit. NCCN
2017, she was forthright and honest about my situ- guidelines and trial options are both noted in this seg-
ation, which I greatly appreciated. She understood ment as is the evidence supporting decision making
the gravity of a melanoma diagnosis to a person by the multidisciplinary team.
with 2 small kids and a life-partner and took all of
that into consideration when she explained the pro-
posed treatment path, with all of its potential pitfalls Disclosures
and successes. She also put things into perspective:
that, if I had walked into her office a couple years Merck & Company provided funding for clinical trials
beforehand with the same diagnosis, I would’ve
­ and basic science related to radiation and immuno-
been sent home and told to get things in order, therapy combinations. Ragini R. Kudchadkar reports
since I probably had 6 to 9 months to live. Gratefully, grants from Merck & Company, grants and per-
we are now over 24 months into this process. sonal fees from Regeneron, and personal fees from
Bristol-Meyers Squibb, Novartis, and Immunocore
during the conduct of the study. Michael C. Lowe,
A lot of frustration could Mohammad K. Khan, and Stephanie M. McBrien made
have been avoided if there no disclosures.

was a mutual understanding

of how the key components References
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had until later in the process.” domised, open-label, phase 2 trial. Lancet Oncol.
—William E. Vogelson, III 2016;17:976-983.
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