At this year’s Best of ASCO Symposium hosted by Advent Health Cancer Institute in Orlando Florida, the CheckMate-8HW phase III trial was presented — a large, randomized study that enrolled 839 patients with metastatic, mismatch repair–deficient (dMMR) or microsatellite instability–high (MSI-H) colorectal cancer. Patients were randomized to receive either:
- Dual checkpoint blockade with nivolumab + ipilimumab,
- Nivolumab monotherapy, or
- Investigator’s choice of chemotherapy.
The results were striking — both nivolumab-based arms outperformed chemotherapy, but the dual checkpoint regimen appeared to deliver deeper and more durable responses. At three years, progression-free survival (PFS) was about 67% with nivolumab + ipilimumab compared with 51% with nivolumab alone.
This was enough to propel dual checkpoint therapy into the NCCN guidelines as a reasonable treatment recommendation, alongside PD-1 monotherapy, for first-line treatment of MSI-H/dMMR unresectable metastatic colorectal cancer.
On the surface, that sounds like a clear win. But as I listened to the data and thought about how this plays out in clinic, I kept coming back to one uncomfortable question:
👉 Are we overtreating by giving everyone Ipi/Nivo upfront?
Half of Patients Are Cured with PD-1 Alone
Let’s not lose sight of the fact that half of patients (51%) were progression-free at three years with PD-1 monotherapy alone. For these patients, ipilimumab added nothing except potential toxicity and financial burden.
The benefit from dual therapy was really concentrated in about 15–20% of patients — those who likely would not have responded as well to PD-1 monotherapy but derived additional benefit from the combination. That leaves roughly an additional 30% of patients exposed to ipilimumab/nivolumab without meaningful added benefit.
In other words, ipi/nivo may be helping one subset, but it’s not rescuing everyone.
Could a “Delayed-Add” Strategy Be Just as Effective?
Here’s the clinical trial I wish we had:
- Start with PD-1 monotherapy.
- Assess early response — both radiographically and with circulating tumor DNA (ctDNA) clearance at 6–8 weeks.
- If the patient shows response and ctDNA clearance → stay the course.
- If not → “reflex” to dual checkpoint therapy at that 6-8 week time point… preferably NOT waiting til they progress?
Many of us in clinical practice will just switch to ipi/nivo if progression on prior PD1 mono therapy, in line with NCCN guidelines. Yet CheckMate-8HW didn’t test either approach (delayed addition of ipilimumab if ctdna does not clear or if progressive disease). In fact, 90% or so who progressed on nivolumab went on to receive non-immunotherapy drug options — raising the question of whether the study overstated the absolute benefit of giving dual therapy upfront?
Would a delayed-add-on design have shown a big difference? My feeling today… I doubt it.
Why PD-1 Monotherapy Still Makes Sense
I’m not against dual checkpoint therapy — far from it. For health fit young patients who want to optimize their best chances or those with bulky, high burden disease or those unlikely to get a “2nd chance”, Ipi/Nivo up front is a very reasonable choice. For patients with bulky rapid progressive symptomatic disease, I would argue potentially chemotherapy first with or without PD1 to reset the clock and hopefully switch to dual checkpoint therapy.
But for many patients, monotherapy is not only reasonable, it may be preferable. Here’s why:
- Lower toxicity burden – Immune-related adverse events (irAEs) with PD-1 alone typically occur in 10–15% of patients at grade 3–4, compared with 20–30% for dual checkpoint. Rare but devastating toxicities — myocarditis, pneumonitis, neurologic syndromes — are almost always seen with dual therapy. “If you give enough dual checkpoint therapy, it’s not a question of if — it’s a question of when — you’ll see life-threatening toxicity.” Although, I’ll readily admit if you give PD1 monotherapy like its water.. it’s also when.
- Better for frail or elderly patients – Many of our “real world” patients aren’t the ECOG 0–1, trial-eligible population. They may have comorbidities, autoimmune disease, or simply less physiologic reserve.
- Simplicity and quality of life – PD! monotherapy can be given every 4-6 weeks as a short infusion or subcutaneous treatment, sparing patients the extra drug and side effects and the extra chair time.
- Financial toxicity is real – Why expose every patient to the cost of two checkpoint inhibitors if half of them don’t need it? Half were progression-FREE by PD1 monotherapy at 3 years.
- Better assessment tools – My experience and the IO ctdna studies clearly demonstrate to me the clearance of ctdna to be a significant indicator of long term outcomes. Now it appears there are nay-sayers for ctdna’s utility in informing treatment choices. I respectfully disagree when it’s properly ordered to inform your choice. But if it’s indiscriminately ordered without any rational decision tree for the results to inform… then agree… that it is a waste of resources.
A Personal Reflection: Have We Swung Too Far?
I can’t help but think back to the early days of immunotherapy in colorectal cancer. When the first small phase II study showed that PD-1 blockade worked in MSI-H tumors, there were a few old analytical guys who argued we “needed a randomized phase III trial” to prove it against chemotherapy.
At the time, I remember thinking: that’s like running a randomized trial of parachutes vs. no parachutes. The benefit was obvious.
Now, fast forward, and it feels like the pendulum has swung the other way. Dual checkpoint therapy is excellent, but are we at risk of declaring it the universal standard — when in fact, half of patients are already looking like they are “cured” with PD-1 alone? Again.. 51% progression free at 3 years.
Where I Stand
I’ll say this clearly:
- I’m not against Ipi/Nivo. In fact, for the right patient, it’s absolutely the right choice.
- But PD-1 monotherapy remains a very reasonable option. Especially for patients with low-volume disease, frailty, autoimmune conditions, or those who value a lower-risk path.
- Shared decision-making matters. Patients deserve to understand both the potential benefits and the trade-offs.
If you tell me every MSI-H metastatic colorectal cancer patient must get dual checkpoint therapy upfront, I’m going to respectfully disagree with you. That’s not what the data show, and it’s not what guidelines mandate.
Closing Thought
For me, this isn’t about being “for” or “against” Ipi/Nivo. It’s about being rational, objective, and patient-centered. If half our patients are potentially cured with PD-1 monotherapy alone, we should celebrate that — and reserve dual therapy for where and perhaps when it’s truly needed.
That, to me, feels like the most responsible path forward.
About the author
Dr. Sajeve Thomas is a distinguished medical professional and a compassionate guide in the field of oncology. With over a decade of dedicated experience as a board-certified medical oncologist/internal medicine specialist, Dr. Thomas has become a trusted expert in the treatment of melanoma, sarcoma, and gastrointestinal conditions. He brings a wealth of expertise to the complex and challenging world of oncology.
Disclosures:
Dr. Thomas serves as a speaker for Bristol Myers Squibb (BMS), Merck, Ipsen, Natera, Immunocore, Pfizer, and SpringWorks. He also receives industry grants in support of numerous clinical trials.