Medical progress this week
25 May - 1 June
This week it was the American Society of Clinical Oncology conference, so the major progress was in cancer - with one other major trial in obesity.
Here are my picks:
Exercise increases survival in colon cancer
Targeted therapy increases survival in BRAF-mutant colorectal cancer
The first phase 3 trial for a GLP1-glucagon receptor agonist in obesity
The first phase 3 trial for a PROTAC in cancer
The first RCT of CAR-T cells in a solid cancer
1. Exercise increases survival in colon cancer
The background
This is the first large, randomized trial (phase 3) to test whether exercise can improve cancer outcomes
Patients had surgery to remove stage 3 or high risk stage 2 colon cancer, followed by chemotherapy, and were then randomized either to a structured exercise program or health advice alone
The advance
Patients in the exercise group had less cancer recurrence, fewer new cancers, and better overall survival
Patients in the exercise group didn't lose weight - suggesting weight loss-independent benefits to the exercise
The magnitude of benefit from the exercise program was equivalent to adding another cancer drug - without the side-effects
The limitations
This exercise program is unlikely to help frail patients
It’s only proven here in colon cancer - whether this extends to other cancer types isn’t known
The future
This provides the high quality evidence needed to roll out this approach as widely as possible
Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2502760
2. Targeted therapy increases survival in BRAF-mutant colorectal cancer
The background
The BRAF V600E mutation drives ~10% of metastatic colorectal cancer
Encorafenib (a BRAF inhibitor) plus cetuximab (an EGFR-blocking antibody) +/- chemotherapy has accelarated FDA approval - this trial provides the mature data
Blocking both EGFR and BRAF (which are in the same pathway) anticipates resistance mechanisms
The advance
This is a phase 3 trial in patients with untreated BRAF V600E–mutated metastatic colorectal cancer
Encorafenib plus cetuximab, with chemotherapy, increased overall survival vs. standard care
The limitations
Serious side effects were common
Open label design and industry-sponsored
The future
Test this regimen with different chemotherapies, as well as with immunotherapies, to broaden the benefit
Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2501912
3. The first phase 3 trial for a GLP1-glucagon receptor agonist in obesity
The background
GLP1 receptor agonists are blockbuster drugs, but can they be improved? And can side-effects be reduced?
Glucagon receptor agonism increases fat breakdown
Combining them theoretically amplifies weight-loss and metabolic benefits
The advance
The GLP1-glucagon receptor agonist, Mazdutide, achieved ~15% weight loss at 48 weeks in this phase 3 trial
This compares to ~20% with Tirzepatide and ~15% with Semaglutide (though the populations are quite different)
Mazdutide lowered blood pressure, triglycerides, LDL cholesterol, systemic inflammation and liver enzymes
The limitations
Gastrointestinal side-effects were common
The only patients in this trial were Chinese adults, which limits generalisability
The future
Head-to-head comparison vs. other GLP1s needed
Trials in type 2 diabetes and fatty liver disease
Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2411528
4. The first phase 3 trial for a PROTAC in cancer
The background
The estrogen receptor (ER) drives ~70 % of breast cancers
Vepdegestrant is a PROTAC that produces deep destruction of the the ER - including of mutant versions - by directly triggering ubiquitin-dependent degradation
Here it was compared to fulvestrant, an earlier-generation ER degrader whose binding affinity is susceptible to ER mutation
The advance
This is a phase 3 trial in patients with ER-positive, HER2–negative advanced breast cancer who’d had multiple previous lines of therapy
Vepdegestrant increased progression-free survival vs. fulvestrant - but only in patients with mutations in the ER gene (ESR1)
Side-effects were more common with vepdegestrant
The limitations
The benefit was restricted to those with mutations in the estrogen receptor gene (ESR1)
Whether there’s a benefit on overall survival isn’t yet known
The future
Test vepdegestrant alongside other therapies, to broaden efficacy beyond ESR1 mutants
There are more phase 3 trials with PROTACs to come
Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2505725
5. The first RCT of CAR-T cells in a solid cancer
The background
CLDN18.2, a tight-junction antigen, is expressed in ~40 % of gastric or gastro-oesophageal junction cancers
CLDN18.2 is the target of approved and emerging therapies
CAR-T cells are edited T cells that target and kill cancer cells
The advance
This is a phase 2 trial of a CLDN18.2-targeting CAR-T therapy in gastric or gastro-oesophageal junction cancer
It was tested as third-line therapy vs. the physician’s choice of therapy
CAR-T therapy extended progression-free survival
The limitations
Some patients couldn’t receive CAR-T therapy because their disease advanced during the 4-week manufacturing window
Serious adverse events were common, with cytokine-release syndrome in 95 % of CAR-T recipients
The future
Test this CAR-T therapy in earlier lines of therapy
Shorten CAR-T manufacturing time and develop off-the-shelf (and even in-vivo editing) approaches
Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(25)00860-8/abstract
Thank you for reading!