How are you approaching patients with early-stage NSCLC who progress on neoadjuvant chemo-immunotherapy and are no longer surgical candidates?

This is a good question, and we are seeing it too often these days. This question cites progression as the reason for not proceeding to surgery after neoadjuvant chemo-IO. We are also seeing patient refusal and ineligibility (i.e. N3 disease that didn't respond) as reasons. I think it's very important that these neoadjuvant chemo-IO patients see a surgeon and that both patient and surgeon agree to this treatment pathway. It's also important to recall the eligibility for these trials, specifically up to non-bulky (<3 cm) single station N2 disease. We all love the significant progress being made in lung cancer, from early-stage through metastatic disease, but let's stick to the settings these trials laid out to produce these results. The perioperative trial curves shown for the trials are of the patients who had surgery. The 20% or so who don't proceed to surgery had a very poor outcome. To answer the question posed above, the ideal situation would be to give definitive chemoradiation if they've had chemo-IO, are not having surgery, and do not have metastatic disease on restaging. 

When surgery is not an issue due to progression on neoadjuvant chemo-immunotherapy, then definitive chemoradiation would be my preference as it could offer the prospect of long-term survival and response. In this case, the neoadjuvant treatment serves as induction therapy. It is not optimal, though, and the impact of neoadjuvant immunotherapy on outcomes with chemoradiation is not clear. We know by press release that concurrent durvalumab with chemoradiation followed by durvalumab did not improve PFS over chemoradiation alone. When selecting neoadjuvant therapy, it is important that patients are felt to be candidates for surgery at that moment - both operable and resectable - and for the time being (outside of a trial), chemo-immunotherapy should not be used as a means to covert inoperable to operable. Ongoing studies will provide more insight here.

My management of an early-stage NSCLC patient who progresses on chemo-IO and is no longer a surgical candidate depends on the degree of progression, updated staging after induction, and performance status after induction. If the patient has progressed to develop nodal disease (but not distant metastatic disease), I would manage them as an unresectable locally advanced patient. I favor concurrent chemoradiation with conventionally fractionated radiation in this setting. However, if the medical oncologist feels that the patient cannot tolerate additional chemotherapy, I would offer hypofractionated radiation alone, typically to 60 Gy in 15 fractions. Occasionally, an early-stage patient who is no longer a surgical candidate may still be a candidate for SBRT, though this is less common, as this degree of progression will rarely preclude surgery (though patients may have a drop-off in performance status during induction that precludes surgery).

It depends a bit on why they are no longer a surgical candidate (locoregional progression making unresectable vs worsening of medical comorbidities/PS vs distant progression of disease) but assuming we are talking about the former, I would proceed with concurrent chemoradiation followed by consolidation immunotherapy. On CM816, 15.6% of patients did not make it to definitive surgical resection on the chemoIO arm (6.7% for disease progression, 1.1% for AEs, and 7.8% for other reasons including patient refusal, unresectability, and poor lung function). I think in a real-world setting, these numbers are going to push higher as I've anecdotally seen the use of neoadjuvant IO in "borderline resectable/borderline surgical candidates" which would have otherwise been excluded in the more rigorous trial setting. There's a question of whether adjuvant immunotherapy is going to be beneficial if the response wasn't observed in the neoadjuvant setting, however, radiation modulates the local immune environment and may modify the response to adjuvant IO in an otherwise previous IO non-responder.

This question is a current dilemma in the management of locally advanced lung cancer. The rate of patients falling out of the surgical pathway in randomized trials, a highly selected population having seen the surgeon before any therapy was given, is in the range of 15-20%. In the real world, the numbers are probably closer to 25-30% because the patients are not as highly selected. I find that the radiation +/- chemotherapy decision is highly dependent on the patient’s post-chemo IO cancer status and the performance status. If the patient is doing well and their blood counts can handle it, then I would favor pursuing a PACIFIC-style approach like MDT-Bridge. However, 4 cycles of chemoimmunotherapy can be toxic as well. If they don’t respond to it, and/or their blood counts drop to the point where additional chemotherapy is risky, is it worth it? In those cases, another choice is hypofractionated radiation therapy using something like 54-60 Gy in 15 fractions. If their cancer progressed during chemoIO, that’s a bad sign, and I lean more towards a shorter course of radiation therapy alone. MDT-Bridge was a single-arm study providing a template for a PACIFIC-style regimen for the patients who do not proceed to surgery. It certainly gives a framework for those patients healthy enough to qualify for MDT-Bridge. However, it remains open to interpretation without a comparator arm.

One of the biggest issues we see is a lack of appreciation for what defines progression. To address this reality, either thoracic surgery or radiation oncology sees the patient periodically during the course of induction systemic therapy and with this re-assessment in place, there is a lower likelihood of meaningful tumor progression. In this current algorithm of induction systemic alone therapy, it is critical to avoid the opportunity for salvage.