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Comment by hiddencost | Hacker News Reader

I'm struggling to figure out what is being reported. They were mostly able to stop progression in 37% of their test cohort?

"At a data cutoff of February 1, 2023, efficacy-evaluable patients treated with petosemtamab (n = 43) experienced an overall response rate of 37.2%"

They discussed "progression free" survival, which seems to mean the condition didn't worsen.

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Efficacy usually drops off a cliff after first line (first therapy) treatment in many cancers. The best chance of being cured is typically the first therapy.

This is a population who has already been treated with a PD-1 (or PDL-1) therapy and platinum chemotherapy, which is pretty much the best treatment available, and their cancer has come back.

ESMO (European) guidelines suggest "Taxane or methotrexate or cetuximab or BSC (best supportive care)" for these patients.

Median OS for this drug was 11.5 months while the KEYNOTE-048 trial had the current standard of care at 10.7 months. So this drug is at least as good as current therapy which is very promising in such a small trial and difficult to treat population.

Which is good numbers in the cancer treatment arena.

>> “We look forward to continued constructive conversations with the FDA as we move forward in our plan to initiate a phase 3 trial in previously treated HNSCC mid-2024 and prepare for a potential phase 3 trial evaluating the combination of petosemtamab and pembrolizumab [Keytruda] in previously untreated patients."

I understand the caution, but I firmly believe oncologists need to get more aggressive with multi-line treatments.

The problem here is the potential toxicity of this combination. In lung cancer for example, the combination of anti-EGFR therapy + pembrolizumab led to deadly pneumonitis (lung inflammation). We want to cure more patients, but we don't want to kill them before their cancer.

I’m not sure I agree that conservatism treatment by oncologists is holding back cancer cure. Maybe in some cases but in others… eg multi-drug regimes like FOLFIRINOX, where cancer patients routinely choose hospice over treatment because of its toxicity and meager benefit. Or even more cutting edge drugs like ENHERTU, which has shown striking benefits for some, but something like 15% of patients have to be pulled off treatment due to intolerable toxicities, and twice that amount have serious adverse events and occasional patients die (“grade 5 to x”) I agree there is much work to do in cancer, and oncologist behavior is included in that. Simply getting more aggressive may help some but isn’t necessarily a magic bullet and has risks. (please pardon my emotional reaction to this) .

Maybe I can help. Progression is usually defined by radiological endpoints (RECIST 1.1 criteria) meaning that at timepoint x the tumor stayed the same size, got smaller, or grew less than 20%. Radiological measurement is very subjective so most of these trials centralize measurement of 'target lesions' (some patients have many tumors but not all are measured in clinical trials). It is worth nothing that inside PFS not only progression is an event but also death. So if you progressed and/or died, you count as an event.

The overall response rate is a combination of complete response (tumor not measurable radiologically) and partial response (>20% reduction in size). That is a common trial endpoint.

As someone else said the Breakthrough designation is common and does not necessarily lead to efficacious drug approvals.

Yeah that’s all correct. It’s particularly notable because the study was a third line treatment. These patients had already progressed after taking a platinum based chemotherapy, which is a standard first treatment, and they also progressed after taking a PD-L1 immunotherapy. So these patients had very advanced and difficult to treat cancer. This represents a real improvement for them as they probably didn't have many options left outside very invasive surgeries or lots of radiation to the head and neck.

Also the treatment targets two cancer genes at the same time. The first is EGFR, which is a very well known therapeutic target. The second is LGR5, and I’m not as familiar with that one, but I think it might be a novel target for cancer. So that's important in that more drugs might target this gene or combinations of LGR5 and others and they might be more effective than this first effort.

> which seems to mean the condition didn't worsen.

That is indeed what it means. The other metric you'll see is Overall Survival, which also is what it sounds like it is.

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