Timing of Immunotherapy Administration Is a Key Question to be Answered in Lung Cancer

Luis Raez, MD

Determining the ideal timing of neoadjuvant, adjuvant, or perioperative immunotherapy administration in lung cancer is a key next step for the field, according to Luis Raez, MD.

“There are a lot of positions for/against [certain approaches] but unfortunately, we need to wait for a cooperative study which may take us some time to get the answer of which approach is better, neoadjuvant, adjuvant, or [both],” Raez said in an interview with OncLive®.

In the interview, Raez detailed how there is uncertainty in terms of whether a complete response (CR) or pathologic complete response (pCR) affects administration of an adjuvant therapy, as a molecular response is also crucial. In a concurrent interview, Raez highlighted several potential biomarkers in the lung cancer space under investigation. Raez is medical director and chief scientific officer of Memorial Cancer Institute in Pembroke Pines, Florida.

Onclive: What updates in the neoadjuvant and perioperative lung cancer treatment landscape have impacted your practice?

Raez: Everyone is familiar with the new neoadjuvant studies [including] the phase 3 CheckMate 816 study [NCT02998528] with chemotherapy and nivolumab [Opdivo] and the phase 2 NADIM [NCT03081689] Spanish Lung Cancer Group study which is the same [regimen of] chemotherapy with nivolumab. Now we have the perioperative studies.

The discussion [on perioperative regimens] is more like a controversy. What we are going to do [treatment wise with immunotherapy is questionable] because we have neoadjuvant, adjuvant, and now perioperative data. If you’re a physician in general practice, you [may] ask, ‘what do I do, which one is better—neoadjuvant, adjuvant, or [both]?’

This is multidisciplinary [decision-making because] you need the surgeon, radiation oncologist, pulmonologist, and medical oncologist to decide which patients benefit from neoadjuvant immunotherapy, only from adjuvant immunotherapy because it may be better to go straight for surgery, or from both.

How would you select between neoadjuvant, adjuvant, or perioperative therapies for patients?

The [data that would provide us] answers are not there yet. We do not have a study to compare these 3 modalities. It may take us 3 or 4 years to [create] a study. NCI Cooperative Groups are planning a study to answer [the question of] which one of the 3 approaches is better—neoadjuvant, adjuvant, [or both]—but it’s going to take time. In the meantime, we need to discuss patient by patient [treatment approaches] in a multidisciplinary way to decide which one is better.

For example, if you have a patient who receives a neoadjuvant approach, has a CR during surgery [and] there is no evidence of a tumor, one of the controversies today is [the idea] that maybe they don’t need more therapy. Instead of doing another year of adjuvant therapy, perhaps we don’t do any other treatment. Or maybe we should still do [adjuvant therapy] because despite the fact that when we look at CR [and] pCR, meaning that the pathologists cannot see the tumor anymore, [that] doesn’t mean [there is a] molecular response—it doesn’t mean that the microscopic cells are gone, [and] we don’t know that. That’s why we have a lot of interesting controversies that we must resolve in the years to come.

How do you foresee the role of adjuvant and neoadjuvant therapies shifting in the overall management of lung cancer?

That’s a very difficult question because until recently the standard of care [SOC] was adjuvant chemotherapy, which was the only SOC. We didn’t use neoadjuvant chemotherapy [often] because it didn’t offer any extra benefit, but then adjuvant immunotherapy was approved [several] years ago. We have 2 drugs approved, atezolizumab [Tecentriq] and pembrolizumab [Keytruda], for patients following surgery and there is a benefit in progression-free survival with both of them.

[However], then we developed neoadjuvant immunotherapy, and it was amazing to discover that tumors can significantly decrease in size and [patients can] even [experience a] pCR. When we used to give neoadjuvant chemotherapy before, the pCR rate was very low in the 5% or less [range]. That is why we never liked that approach much—[patients] wouldn’t see any benefit to the latest surgery because of that. Now we’re reaching pCR rates of 20% to 30% because we gave 3 or 4 cycles of neoadjuvant immunotherapy. That is amazing. It’s very appealing for us to use neoadjuvant chemotherapy/immunotherapy [when] there is a tumor [present].

Adjuvant immunotherapy is more controversial because we already did surgery and there is a chance that the patient is cured, [but then] we put them on adjuvant treatment just in case. The survival data are not there yet. Some of us like the neoadjuvant approaches more than adjuvant ones, but now that we have the perioperative approach, it becomes more controversial because some people may say, ‘we don’t know what to do, so we’ll do everything.’ That also increases the cost for the patient and is a burden because the patient may not need the adjuvant part of therapy.

Could a pCR indicate that adjuvant therapy is not needed?

Some of my colleagues say with a neoadjuvant approach, surgery, [and] a pCR, we don’t have to give patients adjuvant therapy because, if you look at the data, if patients achieved a pCR in CheckMate 816 and other studies, there is a chance that they were cured. That may be [an] answer, but we learn about CRs and stopping therapy from colleagues who practice bone marrow transplant, and for the last 20 years for them the pCR [has] not [been] enough to stop therapy.

They only stop therapy when there is a molecular response, and that’s what we’re missing here. It’s very exciting that we have a lot of industry partners [who prioritize] testing for molecular response, and that is why we’re looking for minimal residual disease. The day that we can prove that a patient is cured is the day that we say, ‘we don’t need anything else, and now we only have to do half [of this regimen with the] neoadjuvant approach’.