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  • Dr. Robert A. Nagourney, MD

A NEW TARGET, A NEW DRUG AND A CHILD IN NEED

In 2015, I was contacted by colleagues in Campo Grande in southwestern Brazil. We met

during my lecture tour and I became friends with their medical and pediatric oncologists.

The pediatric oncologist contacted me to discuss a child with sarcoma. We arranged

tissue transport and processed the tumor in our laboratory.


The results revealed activity for several drugs but I was puzzled by activity for a targeted

agent known as Crizotinib that inhibits genetic changes that include ALK, ROS1, and

more recently NTRK.


The patient at first responded to chemotherapy, but then progressed.

In late 2018, I was again contacted when the physician. The child had brain metastases

and was rapidly deteriorating. They inquired whether I could obtain the new drug

Larotrectinib, an agent related to Crizotinib with very good brain penetration.


The brain lesion was biopsied and a genomic analysis revealed an NTRK gene re-

arrangement. Suddenly our original 2015 findings came into focus. Crizotinib has activity

for NTRK. With our findings and the genomic results I knew these drugs held the key.

The child had an extremely large and rapidly growing mass in the center of her brain. She

required intubation in the ICU. Her prognosis was extremely grave.


The child's father contacted me to ask whether we could procure the drug here in the US.

Quite by chance, Larotrectinib for NTRK had just received FDA approval in November

of 2018 and here barely a month later we had our first candidate.


The problem: Larotrectinib had never been used in South America and was not approved in Brazil.


Undeterred we forged ahead, wrote the prescription and arranged for delivery to a

specialty pharmacy in Santa Monica, California. We reasoned that the father could fly to

LA, buy the drug and bring back to his daughter as she remained on a respirator in Sao

Paulo.


But the father did not speak English. He had never been to the US and felt hesitant to

undertake the trip. How might we get this potentially life-saving drug to this young girl?

As many of you may be aware, we have ongoing collaborations with Brazilian

investigators and our post-doctoral fellow, Dr D’Amora learning of the desperate

situation, offered to travel to the US to procure the drug on behalf of the family.

We arranged his travel. He arrived in LA, drove to the pharmacy purchased the drug and

got back on the plane to Brazil.


The child was in desperate straits, unresponsive on a respirator in the ICU. The

medication was fed through a nasogastric tube.


She improved immediately. I mean immediately! The father contacted me to ask if a

second month’s supply could be procured and Dr D’Amora again traveled to LA to

return with the second month’s drug.


By now the response was dramatic. She came off the respirator, was transferred to the

pediatric ward and began to eat.


Recognizing the miraculous response, the Government of Sao Paulo crafted a special

dispensation and the pharmaceutical company provided the medication free of charge.

Several months later she began first grade.


Every several months thereafter the family sent photographs. First of her in a hospital

bed, then at home with her family, then on her way to her first day of school and finally a

video of her dancing. We approached the pharmaceutical company and suggested that

this miraculous story should be reported.


Despite Dr D’Amora’s heroism, the efforts of referring physician and the family’s

dedication, they would not allow us to discuss the case and non-disclosure agreements

were required, the breech of which would compromise her capacity to have the drug

provided.


Recently I was apprised of a Case Report published in the Journal of Clinical Oncology

and Research about a young girl in Sao Paulo who received this therapy. It was our

patient. But, there was no mention of the referring physician who made the diagnosis nor

the efforts of Dr. D’Amora who procured the drug, nor the heroic efforts of the family.

For this case report, it was their football and they were captain.


Now, three years later, the child has recurred. I was again approached by the family and

we have initiated efforts to procure a 3rd generation NTRK inhibitor to save her life.

If we are fortunate she may have a chance. Working with colleagues at a new

pharmaceutical company we hope we can apply for compassionate use.


The story is interesting as it was the unexpected activity for Crizotinib in our laboratory

that triggered the success. Once again, human tissue studies provided critical insights.

With confirmation of the target at a genomic level and sensitivity to this class of drugs in

our lab, response was nearly assured. With 3 years of benefit and the chance of further

response, this confirms the important role of phenotypic analyses in treating rare and

refractory tumors.

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