Nivolumab Plus Chemotherapy Moves Into Neoadjuvant Setting in NSCLC

Adult patients with resectable non–small cell lung cancer (NSCLC) gained a new neoadjuvant treatment option with the March 4, 2022, FDA approval of the anti–PD-1 antibody, nivolumab (Opdivo), in combination with platinum-doublet chemotherapy.¹ The approval was based on data from the phase 3 CheckMate 816 trial (NCT02998528).

Results from the study showed that patients treated with nivolumab plus chemotherapy (n = 179) achieved a median event-free survival (EFS) of 31.6 months (95% CI, 30.2–not reached) compared with 20.8 months (95% CI, 14.0-26.7) among the 179 patients who received chemotherapy alone (HR, 0.63; 97.38% CI, 0.45-0.87; P = .005). The pathological complete response (pCR) rate was also much greater in the group that received the combination compared with the chemotherapy arm, 24.0% (95% CI, 18.0%-31.0%) vs 2.2% (95% CI, 0.6%-5.6%), respectively (odds ratio, 13.94; 99% CI, 3.49-55.75; P < .001).^2,3

In an interview with OncologyLive^®, Mark Awad, MD, PhD, discussed how the approval opens the door for this regimen to become a backbone for future treatment strategies. Awad is the clinical director of the Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Institute and an associate professor of medicine at Harvard Medical School in Boston, Massachusetts.

OncologyLive^®: What was the clinical rationale for evaluating nivolumab plus chemotherapy in this patient population and disease setting?

Awad: We know that in early-stage [NSCLC], even after surgical resection, chemotherapy, or standard radiation therapies, many of these patients have a high risk of recurrence after definitive therapy or surgical resection. There is a huge clinical need to develop improved curative therapies for patients with earlystage NSCLC. The rationale for this study was to bring the successes we’ve seen with immunotherapy in stage IV NSCLC, unresectable stage III NSCLC, and many other tumor types, and apply it to the early-stage disease setting to see [whether] we can increase the cure rate.

What did you find noteworthy about the efficacy data that led to this approval?

What was extremely notable was that when you add immunotherapy to standard platinum-doublet chemotherapy, the pCR rate was significantly higher. It was [approximately] 10 times higher vs using standard chemotherapy alone. Among patients in this trial who [received] chemotherapy before surgery, approximately 2% had a pCR at the time of surgery. But in patients who had chemotherapy plus nivolumab, the pCR rate was approximately 24%. That is quite meaningful, as a primary or surrogate end point.

What we don’t have a lot of information about yet is how well that pCR rate translates into the next end point, which we typically talk about: disease-free survival. Does that mean there is going to be less recurrences? Does that then translate to improvements in overall survival or decreases in deaths from lung cancer?

We saw data presented [in 2021] about the potential surrogate end point of pCR rate, [and] it does seem that [benefit] translated into an improvement in EFS. Hopefully, in the long run, that will also translate to improved overall survival. It is a practice-changing trial and practice-changing approval.

What new directions in research does this approval influence in NSCLC?

There are [several] outstanding questions, because the trial did enroll patients with different [disease] stages. [This included] stage II and stage III, [as well as] patients with or without lymph node involvement or lymph node metastasis. It also enrolled patients regardless of PD-L1 expression level.

The questions for us are: Are there certain subgroups that benefited more so than others with the addition of immunotherapy to chemotherapy? Does this approach and regimen work regardless of the subgroups of stages [and/or] the subgroups of patients with different PD-L1 levels? Does it work as well in [individuals] who have never smoked vs [those] who have smoked?

We still need to see the details of the trials to understand [whether] this regimen can be used across the board in all-comers with resectable lung cancer, [whether] there are subgroups that have an even greater benefit, and [whether there are] other individuals [for whom] this regimen may not be as effective. Hopefully, this will change the treatment paradigm for resectable lung cancer in that there will be more multidisciplinary discussions between medical oncologists, thoracic surgeons, and radiation oncologists to discuss the best overall treatment approach for patients with potentially resectable lung cancer. I believe [the results of] this trial will [lead to] incorporating more use of immunotherapy with chemotherapy prior to surgery.

What adverse effects (AEs) should clinicians be aware of when prescribing this regimen?

From the data that have been presented, it seems [AEs are] reasonably manageable and this is a well-tolerated regimen. But the immunotherapy can cause rare but potentially serious immune-related AEs. There can be rare complications such as pneumonitis, colitis, dermatitis, endocrine disorders, or other rare toxicities that can be serious for patients. As we do for patients with metastatic lung cancer, where we use immunotherapy or for other cancers, we [must] diligently monitor for the development of these AEs.

What does the future hold for nivolumab plus chemotherapy in NSCLC and beyond?

Prior to this approval, we already had an approval [based on results of] the IMpower010 [NCT02486718] study, which [evaluated] adjuvant atezolizumab [Tecentriq]. One question is: Should we be using immunotherapy with chemotherapy before surgery, after surgery, or both? There are some trials that are looking at that question of this sandwich approach of giving immunotherapy both before and after surgery.

As I mentioned, [there are] outstanding questions about subgroups. Of course, predicting toxicity is an important question that we don’t know how to [answer] yet, with immunotherapy and [in] any cancer. Then there are many patients who still do not benefit from immunotherapy or chemotherapy. There are many additional approaches trying to use novel immunotherapies, targeted therapies, or other novel therapeutics in patients with metastatic lung cancer, as well as many other tumor types.

There are already several trials being launched that are combining novel agents with these standard regimens. I believe this will become a new backbone regimen, from which we can hopefully build upon and develop additional improved therapies.

References

1. FDA approves neoadjuvant nivolumab and platinum-doublet chemotherapy for early-stage non-small cell lung cancer. News release. FDA. March 4, 2022. Accessed April 7, 2022. bit.ly/3jxsnoF
2. Opdivo. Prescribing information. Bristol Myers Squibb; 2022. Accessed April 6, 2022. bit.ly/3DO8NgW
3. Forde PM, Spicer J, Lu S, et al; CheckMate 816 Investigators. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N Engl J Med. Published online April 11, 2022. doi:10.1056/NEJMoa2202170