Over the years, investigators have sought to identify different ways of combining therapies with ICIs to optimize outcomes. From melanoma to lung cancer to rectal cancer, each tumor type has a slightly different theme. In renal cell carcinoma, VEGF inhibition plus ICI therapy is an important combination. In advanced non–small cell lung cancer (NSCLC), ICI therapy plus chemotherapy or dual PD-1 and CTLA-4 checkpoint blockade without chemotherapy may be utilized. Everyone is trying to determine where immunotherapies are best placed, and work is ongoing to see if the tumor microenvironment can be modified to really enable robust antitumor immune responses. The challenge lies in figuring out ways to personalize therapies, since each patient’s tumor and immune system behaves differently.

Chemotherapy plus ICI therapy is a common combination in lung cancer. The addition of chemotherapy does increase the response rate, but I would say that the ICI carries the long-term disease control, both in NSCLC and in SCLC. At the 2022 ASCO Annual Meeting, researchers from the US Food and Drug Administration presented pooled data from 12 trials of anti–PD-(L)1 regimens with or without chemotherapy for the first-line treatment of advanced NSCLC (abstract 9000). In patients with PD-L1–high disease (PD-L1 score ≥50%), the addition of chemotherapy to anti–PD-(L)1 therapy increased the overall response rate and the progression-free survival, but the overall survival benefits were not statistically significant compared with the benefits observed with ICI therapy. There are nuances that depend on the histology and the patient subgroups. For example, in some patients who are 75 years of age and older, ICI-only regimens might be preferable, as this group seems to do well without the chemotherapy.

Dual PD-1 and CTLA-4 checkpoint blockade is another treatment paradigm for patients with EGFR/ALK-negative NSCLC. In our update of the CheckMate 227 study, the 5-year overall survival in patients who were receiving nivolumab plus ipilimumab was 24% compared with approximately 14% for those who were receiving chemotherapy alone (abstract LBA9025). These were previously untreated patients who had PD-L1–positive disease (tumor PD-L1 ≥1%). Treatment stopped at 2 years, and, among the 5-year survivors, approximately two-thirds did not require treatment for more than 3 years. This is a significant achievement for that subgroup of patients, and the hope is that they will never need treatment again. There was also a subgroup of patients who were PD-L1–negative (PD-L1 <1%) who achieved benefit from nivolumab plus ipilimumab with a 5-year overall survival of 19% compared with 7% for chemotherapy, and, similar to the PD-L1–positive group, almost two-thirds of the 5-year survivors were treatment free at 3 years after stopping therapy. 

In the CheckMate 9LA study, the investigational regimen adds chemotherapy to nivolumab and ipilimumab. As reported at the recent ASCO meeting, the 3-year survival in CheckMate 9LA (abstract LBA9026) was very similar to that of CheckMate 227 at the earlier time point, and it will be interesting to see if the 2 cycles of chemotherapy, while continuing the nivolumab plus ipilimumab up to 2 years, will also result in a similar 5-year survival. Importantly, at the 3-year time point, the survival rate in CheckMate 9LA was quite similar in groups with higher vs lower PD-L1 expression (ie, approximately 33% in patients with PD-L1 of ≥50% and 26% in those with PD-L1 of 1% to 49%).

Results from the NADIM II trial in patients with resectable stage IIIA disease were also presented at the conference (abstract 8501). Patients were randomized to nivolumab plus paclitaxel and carboplatin or paclitaxel plus carboplatin as neoadjuvant treatment, followed by surgery. Rates of pathological complete response (36% vs 7%) and definitive surgery (91% vs 69%) were higher with the triplet than with paclitaxel plus carboplatin. I think that the NADIM II study gives us more data to talk about with our patients. Those with otherwise resectable disease who have mediastinal lymph node involvement can opt for definitive chemotherapy and radiation followed by durvalumab, or we may consider the opportunity to try chemotherapy and immunotherapy and then go to surgical resection.

Regarding the newer checkpoints, novel engineered ICIs, and some of the other approaches in early phase trials, I think that additional data are needed, and the key is probably going to be discovering ways to implement precision immunotherapy. The combination of an ICI plus an antiangiogenic is interesting in the advanced NSCLC setting. In the S1800A trial, the combination of the anti-VEGFR2 antibody ramucirumab plus pembrolizumab was compared with investigators’ choice of standard-of-care therapy in patients with NSCLC who had progressed on prior ICI therapy (abstract 9004). The results indicated a statistically significant improvement in overall survival for ramucirumab plus pembrolizumab compared with standard second-line therapy (15 months vs 11.6 months), so I think that this is an important combination to watch going forward. In the ARTISTRY-1 phase 1/2 trial, the combination of pembrolizumab plus the engineered interleukin-2 variant nemvaleukin demonstrated promising activity in ICI-experienced patients with advanced melanoma or renal cell carcinoma and preliminary activity in lung cancer (abstract 2500). 

There are also several interesting new bispecific antibodies that are under investigation, including a PD-1 x CTLA-4 bispecific antibody (abstract TPS5097) and an anti–PD-1/VEGF bispecific antibody (abstract 9019). The challenge will be to incorporate these agents into precision immunotherapy regimens.