The immune system is highly efficient and complex, and that is probably why it so often keeps us from dying from infections. This complexity also makes it very difficult to focus on any one particular component when trying to modify immunity to achieve a desired therapeutic result. The analogy that I like to use is that the immune system is like a symphony, where there are dozens of musicians and instruments, with many subtle things going on. Consider an ensemble that includes 30 violins and 7 violas. If this composition is suddenly changed so that 25 violins and 9 violas are now playing, the effect may not be very dramatic or even detectable. However, changing any one instrument might affect the whole symphony on some level, and some instruments have more of an effect than others. 

There is the concept of hot and cold tumors. Immune escape may be crucial for some tumors to thrive, but the growth and proliferation of other tumors may not depend on the evasion of the immune system. Non–small cell lung cancers (NSCLCs) that have co-opted PD-1/PD-L1 and/or CTLA-4 do respond to immune checkpoint inhibitor (ICI) therapy with nivolumab and ipilimumab. This was reported in the update from the CheckMate 227 study by Brahmer et al at the 2022 ASCO Annual Meeting (abstract LBA9025). Although nivolumab and ipilimumab can be very effective in many advanced NSCLCs, this treatment is generally not used in patients with EGFR/ALK-positive NSCLCs because those cancers largely do not rely on immune escape as an important mechanism for initiation and growth. We talk about turning a cold tumor into a hot tumor, but this is not feasible if the cancer cell is driven by other factors.

It is also important to distinguish between patients with cold tumors and patients with tumors that did respond to ICI therapy initially but then their response was lost. One way in which we are trying to counteract suboptimal responses and/or the loss of response is to add a different type of ICI. Various immune-related targets are being investigated, including TIM-3 (abstract 3547), TIGIT (LBA8507), LAG3 (abstract 9003), as well as VEGF (abstract 1070). At the meeting, we saw many effective agents with good pharmacokinetics and solid activity against all of these targets. Of course, when a second drug is added, such as an anti-VEGF agent, we are adding a toxicity and an uncertain degree of benefit. Thus, more data are needed to determine the risk-benefit profile for each of these approaches.

Regarding irAEs, there are several points to emphasize. First, there is a general consensus that having some irAEs signifies the ability of an ICI to activate the immune system, which can be a sign of efficacy. It is often useful to convey to patients that having irAEs may portend a better result in controlling their cancer. 

Additionally, multispecialty care can be extremely valuable in the management of irAEs. Hypophysitis is a serious irAE, but one that becomes very manageable when recognized and dealt with promptly. I would urge oncologists to enlist the help of colleagues in endocrinology to help manage those cases, to be ready for that side effect, and to take care of it promptly, but not to let the fear of hypophysitis dissuade them from using immunotherapy, as many patients with advanced NSCLC have been cured with nivolumab and ipilimumab. 

Finally, we are moving toward the use of specific biologically targeted agents to counteract irAEs to treat them in a most precise way. At many institutions, individual clinicians have become specialized in treating irAEs and can be called upon to help with these cases. This includes using mycophenolate for ICI-induced hepatitis or an anti–tumor necrosis factor agent such as infliximab for colitis and different dermatologic side effects. The field is moving away from reliance on corticosteroids because we achieve better results with the use of biologically targeted agents such as infliximab than we do with corticosteroids—and we avoid the serious AEs of corticosteroids.