Uncertainty is the state of being alive

We were certain that Jake would be dead within a few months. Then, a clinical trial drug gave us the gift of wondering: what if he lives?

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When Jake was first diagnosed with squamous cell carcinoma (SCC) of the tongue in Oct. 2022, his surgeon, Dr. Hinni, leaned forward, clapped Jake on the shoulder in a very fatherly gesture and said in a firm, reassuring voice, “Don’t worry! This won’t be what kills you.” I felt firmly reassured: when Dr. Hinni said that, Jake’s initial surgery to remove the tumor was only two weeks away. I figured the tumor would be removed and we’d move on. We’d start that family. Buy that house. Co-write that book. Jake and I left the Mayo Clinic figuring that the SCC was a speed bump, not a cliff face. If our lives were a novel, that scene with Dr. Hinni would be deleted for being too obvious. Chekov’s malignant gun. Of course, this will kill Jake.

Jake and I have written in detail elsewhere about the journey from Oct. 2022 to today, but, in brief, Jake has failed[1] all conventional treatments—including radiation, chemotherapy, immunotherapy, having part of his tongue removed, and having his entire tongue removed; he’s given up literal and figurative parts of himself trying to stay alive and yet I’m pretty sure that, if I listen closely enough, I can hear his tumors chuckling to themselves.

What’s left? Finding the right clinical trial and getting him into it is the difference between a shot at life, however tenuous or improbable, and certain premature death. I spent the entirety of July to September trying to identify and get him into that trial, a process I describe in “Please be dying, but not too quickly,” which is an epic saga (that shouldn’t be an epic saga) about the mechanical aspects of the clinical trial process. “Mechanical aspects” is an understatement: identifying and then getting Jake into the right clinical trial involved hundreds of phone calls, emails, appointments, and Excel spreadsheets. Let me thank publicly all the oncologists I pestered with questions. You’re great.

What Jake and I now call “the clinical trial essay” is designed most to help other families like mine, and to encourage policymakers to create a more humane clinical trial process, but it doesn’t capture the feeling of hope generated by the clinical trial hunt—and of anticlimax and fear. It doesn’t show the rollercoaster ride of certainty and uncertainty that my life, and more realistically our lives, have been for a year.

The last, desperate hope turns out to be an experimental medication called petosemtamab / MCLA-158, and that antibody will, out of the hundreds of treatments give Jake the best possible shot at some longevity. “Likely” is the key word: there’s good preliminary data showing that petosemtamab works in some capacity for about two-thirds of SCC patients who receive it. Jake and I, however, have heard many times before that the odds are in his favor, only for his cancer to thrive and beat the odds. Despite months of continuous effort, I know, intellectually, that I’m likely to fail at keeping him alive over the long term. Here’s the thing, though: I can’t yet be certain. In a phase one petosemtamab clinical trial, one patient in forty-three had what’s called in the business “complete response”—meaning that their cancer disappeared altogether.

It's not impossible that the same could happen to Jake. It’s just ridiculously unlikely. Jake’s cancer is, as one oncologist friend described it, “a real asshole of a tumor, even by head and neck standards.” Head and neck squamous cell carcinoma (HNSCC) standards are already low: the average patient with recurrent metastatic head and neck cancer lives a year, and it’s already been six months since Jake’s recurrence.

When I get word on Sept. 20 that Jake is officially in the petosemtamab trial at the University of California San Diego Medical Center, I feel relief and dread. There’s no better possible outcome of all the hard work, yet the fantasy that all the hard work to find the “right” trial will be positively correlated with Jake’s length of quality survival is suddenly up against the reality that the petosemtamab trial is a trial (something to try) and might not succeed at all. There’s no more project. There’s only one last what-if: What if it works? We’ve earned a little more uncertainty to enjoy before the crushing reality of Jake’s impending death arrives.

There’s a peculiar comfort in not knowing. Like the days before Jake’s biopsy that confirmed the cancer, when we were anxious to find out what was happening inside him but could still enjoy wondering: “What if it’s not the bad thing?” Or the days before the August re-staging CT scans, when we could wonder if the tumors had grown, but wonder equally if they’d shrunk from chemo and cling to that hope. Clinging to that hope was fun, before the CT scans showed tumor progression.

There’s exactly a week between confirmation that Jake’s in the clinical trial and the infusion itself. On Sept. 25 we drive from Arizona to San Diego. On Sept. 26 Jake gets preliminary bloodwork. The morning of Sept. 27, we walk to the UCSD infusion center in a grey fog that suffuses in an opaque glow the pretty, succulent lined pathway from our rented room in the La Jolla Family House hospital housing to the hospital. It’s wet but not cold, and we try to ignore the sense of nervous anticipation and focus on a few small pleasures: Jake’s headache isn’t too bad this morning, the weather is nice, the campus is pretty. Will he be like one of the 80% of phase 1 participants who had a moderate to severe allergic reaction to the infusion? We’ll find out. Jake takes my hand, and I take a deep breath of the floral air.

“I don’t want to take the study medication,” he says and pauses for a while, considering: “But I also want it very badly.”

I think he’s saying that, while certain death within months (at best) is scary, the possibility of anaphylaxis while being pumped full of an experimental medication within the hour is too. What if death comes today? What if he stops breathing during the infusion? What if his blood pressure bottoms out? What if the tumors just keep growing? Those are some possible outcomes. But what if it all goes smoothly? What if he responds and his tumors shrink? What if he’s like the one white-crow patient from phase 1 who saw a complete response, their tumors melting away like butter on a hot skillet? Those are other possible outcomes. We don’t know and, in this moment, I’m okay with not knowing. All these possibilities exist right now, including the good ones. His grip tightens on my hand.

When we get to the infusion center, we see Dr. Sacco, his oncologist at UCSD, and she gives the go-ahead. The moment of truth itself is anticlimactic. Jake changes into a hospital gown and we learn his dose: another uncertain variable that has been recently thrown into the mix. Although the initial petosemtamab study dose was 1500mg, the FDA requested that 1100mg also be tested, to see if a lower dose might produce similar results with fewer allergic reactions and side effects.

Might. My hope lives in that single word. What does it mean if Jake gets the lower dose? I don’t know. Neither do they. That’s why they’re testing the question on the man I love. I know intellectually that in medicine, “more” is not always “better” and can frequently be worse. Two Tylenol will alleviate some pain, but twenty might destroy your liver. The death is horrible and painful, which I know better than most because I’ve seen Tylenol suicides in the ICU, who’d been talking and seemingly well-appearing in the ER hours before. Will 1100mg of petosemtamab lead to a horrible, painful death that 1500mg might have prevented or delayed?

There it is again, the anxiety, the gulf between what I want to happen and what hasn’t happened yet. I want Jake to get the full dose, despite understanding that the “full” dose is a somewhat arbitrary designation, determined during phase 1 trials. I also want him to have an easy infusion, which might be more likely with a lower dose. But is it less effective? Might it be more effective?  I want to know which dose is most likely to give a positive outcome, so that I can be reassured Jake is randomized to the best treatment available, but we can’t know, because that’s what the trial is measuring.

Testing it on patients, on Jake, is how that question gets resolved. The trial isn’t for Jake, not really—it’s for the patients who come after. But while I feel a physician’s nebulous, generalized responsibility to those future patients, I don’t feel an elemental connection to them. I love this patient. I love this man. I want Jake to respond quickly. I want him to respond fully. I can’t stop wanting, even though nothing I’ve wanted yet has come to pass regarding Jake’s HNSCC. I want guarantees, but only if they’re good.  Otherwise, I don’t want certainty. Don’t come near me with it.

The bag—a 250mL clear plastic sack filled with what looked like water—is brought with the label: 1100mg.

The nurse hangs the study drug from the IV pole. She pushes Benadryl into Jake’s port, to further mitigate the risk of an acute allergic reaction. He’s sensitive to sedatives and before she’s done giving him the dose, he looks seasick and disoriented. I sit on the bed beside him, gently stroking his bald head and slip an eye mask over his eyes, letting the drugs lull him into a sticky, anticholinergic sleep. Dr. Sacco and Crystal, the study coordinator, seem surprised by how rapidly he sleeps, and how long. He’s asleep for the better part of six hours. He wakes up groggy, still under the thrall of the sedative. We take an Uber back to La Jolla House, even though it’s maybe a ten-minute walk and we like to walk. Walking and talking is a baseline activity for us, and a common way we generate ideas. We took a walk on our first date and kept adding to the odometer for fifteen years.  

Jake slings an arm around my shoulder, and I hold him around the waist as the elevator takes us upstairs to our temporary but friendly apartment. He leans against me, as if the weight of the decision to pin all our hopes on this study drug is equivalent to the weight of his entire body, though he’s a mere 135 lbs (down from 175). In bed upstairs, I watch him sleep, looking at him as if he’s a crystal ball for signs of a response which it’s obviously too soon for, trying to divine the future by examining the pattern of shallow creases at the corner of his eyes, which, in a way, is a sort of view of the future. If I can imagine them etched deeper and maybe a few across his forehead, I can imagine what he’d look like in twenty years. Then I stop, and don’t let myself think of twenty years or two or even tomorrow. Let’s make it through the night.

The day after the infusion, Jake feels basically okay, by the standards of a dying man. He doesn’t break out in the rash characteristic of EGFR inhibitors like petosemtamab until a week after his infusion. The rash is itchy and unpleasant, but not unbearable. Jake’s experience of petosemtamab is, so far, much better than the brutality of chemotherapy, though he’d combine both if he could. I want the rash to be a sign that the petosemtamab is working. It’s a positive sign in some cancers, but there’s less of a correlation in head and neck cancers. We won’t find out how Jake is responding until his first set of follow-up CT scans in late November, or more likely the second set in late January.

Here's what the possibility and probability of petosemtamab is getting us: in the Phase 1 trial, 30% of patients saw disease stabilization and another 35% saw their tumors shrink. That’s a majority of patients responding positively, by advanced cancer standards, to the medication. The average duration of response was six months, but some outliers responded longer. A lot can happen in six months—Moderna, for example, has a personalized cancer vaccine being trialed for melanoma that had early phase data in head and neck cancer suggesting remarkably positive responses. Maybe there’ll be a Phase 2 trial. Maybe Jake and I just get six months more of “bonus time” from petosemtamab, and we can finish our joint memoir before Jake’s end. It’s not listed online yet, but we’re told that Merus (the drug company making petosemtamab) and UCSD are testing petosemtamab and pembrolizumab (Keytruda—an immunotherapy, referred to as “pembro”) together. Pembro works in about 20 – 30% of HNSCC patients, and Jake isn’t in that group, but it’s conceivable that petosemtamab will convert some people into pembro responders. These slender hopes keep me, well, hopeful.

Although uncertainty can be a source of anxiety, it’s become, surprisingly, one of the great comforts of Jake’s illness. Before the tumors recurred but after Jake’s massive surgery we could ask ourselves, “What if the pembro he’s receiving and the clean surgical margins mean it’ll never come back?” and imagine that that future was still open. Then, on July 21 when we found evidence that Jake’s cancer had recurred, and only palliative options remained, we didn’t know if he had mere weeks left. Our conversation focused on preparing for his death and what I’d do after. But the clinical trial means we’re able to ask: “What if it works? What if we have more time?” It almost certainly won’t. But the chance is not zero.

Until the November CT scans, we don’t know what petosemtamab is doing to Jake other than giving him that impressive rash; Jake thinks he looks like a smallpox victim. We’ll see one of three things: the tumors are stable, shrinking, or growing. If they’re stable or shrinking, then Jake and I get to wonder how much and how long he’ll he respond. Will we have to move because we have the incredibly wonderful problem of him being on it long term? Will we be able to manage something as anodyne as the itching from the rash? Will we figure out what work looks like? Will we have to move to San Diego? Will he be here to meet his first child? When will that be? These

would be high-quality problems. I’d give anything for these problems. Uncertainty is the messiness of life. As long as we’re not certain of the outcome? Jake’s alive.

Death is the only real steady state. For the human body to maintain homeostasis, it has to be engaged in dynamic equilibrium, which means that it’s constantly adjusting and changing to conditions, adapting to uncertainties in the environment. We’ll have certainty when Jake’s pulse stops.

Despite my anxiety, I want the not knowing to linger: I want to wander in it like the cool, sweet fog of the morning of Jake’s first infusion, unable to see more than a few feet in front of our faces, my hand in Jake’s hand. Jake might not live long, but maybe he will. Though no one is promised a future, for now we’ve been given the incredible gift that a future might exist for us. In a universe where it’s amazing we exist at all, being mortal means being uncertain. In the space where nothing is certain and nothing is sure, Jake and I can exist together a while longer.

If you’ve gotten this far, consider the Go Fund Me that’s funding Jake’s ongoing care. You can also read Jake’s perspective (and I highly recommend that you do!) at JakeSeliger.com

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[1] Doctors are given too many exams over the years, so everything and everyone is subconsciously assigned a grade. What we should be saying is that chemo failed Jake. Radiation failed Jake. Surgery failed Jake (though don’t equate this with Dr. Hinni failing Jake: sometimes in life, you do everything right and get the wrong outcome). I have a list of treatments and people who have failed Jake. Jake, on the other hand, continues to amaze me.

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