In September of 2013, I was asked to see a patient with metastatic adenocarcinoma of the lung.
Treatment with Chemotherapy
Biopsies did not reveal any “driver” mutations (e.g. EGFR, ALK or ROS) but our laboratory did identify a novel triplet of Platinum, Taxol and Irinotecan. With this, the patient achieved a rapid remission and was then changed, per standard practice, to Pemetrexed maintenance.
Unfortunately, some months later her disease progressed.
Treatment with Immunotherapy
As immunotherapy for lung cancer remained investigational in 2014, I referred the patient to a medical center in Los Angeles for accrual to a “checkpoint inhibitor” trial with Pembrolizumab (Keytruda). Her response was dramatic with resolution of virtually all measurable disease. She commuted faithfully to Los Angeles every two weeks with the principal toxicity being, it seemed, the gridlock traffic she had to confront.
In October, 2015, the FDA approved Pembrolizumab for lung cancer allowing her to continue therapy closer to home. All went well until the summer of 2016 when her disease again progressed.
At over 2 years, with such excellent response to initial assay-directed therapy, I recommended a repeat biopsy to examine her options. A superficial lymph node provided a source of tissue. The assay findings were surprising with a profile of clear and unequivocal sensitivity to 2 drugs.
Treatment with Targeted Agents
The first, Vemurafenib (Zelboraf), is a highly selective inhibitor of the melanoma- associated oncogene BRAF V600E. The second, AZD 6244, is an experimental agent that targets another gene (MEK/ERK) found downstream in that pathway.
Although this pattern is found in two-thirds of patients with metastatic melanoma, it only occurs in 0.5% of lung cancers. A circulating DNA analysis did not reveal any actionable targets but I felt certain that a BRAF mutation was present and I requested a second gene profile, this time using the cell block from the original biopsy.
The result confirmed the rare BRAF V600E mutation, just as our assay had predicted.
With clear concordance between our EVA/PCD (phenotypic) and the DNA (genomic) profiles, I was convinced that targeting this pathway at the BRAF and MEK/ERK level, like we do in malignant melanoma, was the right approach.
After some effort to get insurance authorization, she started the 2 drug combination.
Complications and a New Diagnosis
No sooner did she begin however, but she returned with new symptoms of headache, nausea, malaise, fatigue and gastrointestinal distress. I was puzzled for I had never seen such toxicity from this treatment. I withheld the drugs but she felt even worse. Then we found clostridium difficile, a gut infection that can wreak havoc and initiated antibiotics, but this did nothing and we finally found it necessary to admit her to the hospital.
At this point all hell broke loose.
She could not eat. Bladder function ceased. Her stomach blew up like a balloon. I carefully evaluated her. As I had her stand, her vital signs deteriorated, blood pressure became un-measureable and she collapsed into bed. My diagnosis; a rare syndrome called paraneoplastic autonomic failure or PAF.
Neurology was consulted. An MRI was conducted. A lumbar puncture was performed and I began the patient on IV steroids and intravenous immunoglobulin, the treatment of choice. But her condition worsened with the onset of profound confusion and delirium. Concerned that the steroids had caused it, I stopped them but she didn’t improve.
Now with the high likelihood of impending limbic encephalopathy (the worst and most irreversible form of PAF), I initiated extremely high doses of steroids and intravenous immunoglobulin.
Day by day her mental status improved. Her blood pressure normalized and her bladder and gastrointestinal functions returned. She sat up and began to converse lucidly. By the fifth day she was quite well. Recognizing that her symptoms had not been from the two-drug cocktail, I re-challenged her with the oral medications and she tolerated them without difficulty.
Two months later the patient is the picture of health.
Her CEA level is normal as are all the parameters of her disease. She is eating well, gaining weight and feeling fine. Interestingly she has virtually no recollection of the confusion or the hospitalization.
Three Years Later
Here we are 39 months since the diagnosis of metastatic adenocarcinoma of the lung - an absolutely lethal disease. The patient has responded to chemotherapy, immunotherapy and now to a combination of targeted agents selected in our laboratory.
She’s an example of something that I have written about before; the convergence of genomic (DNA) and phenotypic (cell culture) analyses to forge uniquely effective treatments. I was so impressed upon her recent visit to my clinic that I penned this blog to commemorate her exquisite response.
It seems that this patient has 9 lives and, by my count, she has 5 more to go.
As always, I appreciate your thoughts and comments.