Immune checkpoint inhibitors have emerged as a treatment option for several types of recurrent or metastatic cancers.1 The most widely used agents presently are anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and anti-programmed death-1 (PD1) antibodies. Anti-CTLA4, widely studied for melanoma, acts to block the inhibitory signal involving the CTLA4 molecule between antigen-presenting cells and T lymphocytes.2 Anti-PD1 compounds analogously block the inhibitory signal involving the PD1 receptor.3 In both cases, diminishing tumor-mediated immune-attenuating effects results in more robust T-cell activation and immune-mediated neoplastic destruction.4

These effects may be augmented by radiation therapy (RT), especially stereotactic body radiation therapy (SBRT), which can enhance antigen release for immune recognition and modulate the tumor stroma to facilitate immune cell infiltration.5 6 RT can also lead to responses in out-of-field (unirradiated) tumors, also known as the abscopal effect. Despite emerging evidence regarding favourable interactions between immunotherapy and RT (combined radiotherapy and immunotherapy (iRT)), whether the various immunotherapeutic compounds lead to different outcomes in combination with radiation is currently unknown. Optimizing the efficacy of immunotherapeutics used in iRT is critical not only because several compounds are available to treat metastatic cancers but also because enhancing treatment efficacy could affect the cost-effectiveness of these agents.7 8

To address these gaps in knowledge, we retrospectively analyzed two single-institution prospective clinical trials to evaluate whether combining SBRT with anti-CTLA4 versus with anti-PD1 leads to different response and survival outcomes for patients with metastatic non-small cell lung cancer (mNSCLC).

From September 2014 through August 2016, 241 patients were enrolled in either trial; after exclusions, 33 patients were the subject of this analysis: 17 in the SBRT+CTLA4 group and 16 in the SBRT+PD1 group (figure 1). Median follow-up times were 19.6 months (CTLA4) and 19.9 months (PD1) (p=0.212). Baseline characteristics were generally well balanced between groups, although patients in the CTLA4 group seemed to have had more systemic therapies before receiving iRT (mean 2.12 vs 1.13, p=0.157) (table 1).

RT has been found to interact with immunotherapeutic compounds so as to augment the immune response; however, whether that interaction depends on the particular type of immunotherapeutic agent has not been well studied. In this novel comparison of two prospective trials of iRT for mNSCLC, both anti-CTLA4 and anti-PD1 compounds led to similar in-field and out-of-field response rates; however, the global response may have been higher for the anti-PD1 cohort along with PFS. Although these findings came from prospective trials, they should nevertheless be considered hypothesis-generating and require verification in other, larger prospective trials of patients with mNSCLC.

There are multiple reasons to explain the equivocal in-field (irradiated existing lesions) and out-of-field (unirradiated existing lesions) response rates in this study. First, it is unlikely that immunotherapy (regardless of agent) would appreciably increase in-field control relative to RT alone, given that SBRT has shown high rates of local control.9 Second, the abscopal effect remains clinically uncommon (regardless of the agent used),10 implying that another mechanism may underlie the PFS and OS findings in the current study. In addition to higher global ORR, the reduced development of new out-of-field lesions could have driven our PFS findings. This notion seems to be supported by the results of an aforementioned trial of a CTLA4 inhibitor versus a PD1 inhibitor, hinting that the distant control of micrometastatic disease may be enhanced by PD1 inhibitors.11 12 However, there are other possible causes of the PFS results, such as biological factors (activation of distinct immune-galvanizing pathways that produce different degrees of immune response, especially when optimally timed with RT). Moreover, there was a trend toward higher performance status in the anti-PD1 cohort and more prior courses of systemic therapy in the anti-CTLA4 cohort (which may imply therapy-resistant disease and/or being further into the disease course than the anti-PD1 group).

Notably, the ORRs (especially in-field) in this study were high, roughly two to three times the ORRs in another study of patients given anti-PD1 alone and five times to anti-CTLA4 alone.13 This could suggest that the immune priming provided by radiation may be an integral component to augment the system responses to checkpoint therapy. The response rate to anti-PD1 alone in NSCLC is about 19%, whereas the response rate to anti-CTLA4 in NSCLC is about 4.8%.14 According to these results, the addition of RT can enhance the response rate in NSCLC by about 98% for PD1 agents and by about 389% for anti-CTLA4 compounds. These notions are corroborated by preliminary results of the PEMBRO-RT study, which randomized patients with previously treated NSCLC (although, like the present study, patients were not stratified by PD-L1 status) to receive a PD1 inhibitor with or without preceding ablative RT (24 Gy in three fractions).15 Whereas PD1 without preceding RT led to an ORR of 19%, the addition of RT led to an ORR of 41% as well as longer PFS times (1.8 months vs 6.4 months, p=0.04) with no increase in rates of toxicity (22% vs 17%). Although these results show promise for combined-modality therapy, they should also be viewed cautiously because of the small numbers of patients (n=64), short follow-up (reported ORRs were at 12 weeks), and lack of PD-L1 stratification (given that higher PD-L1 cutoffs are associated with higher ORR). As to the high response rate in anti-CTLA4 and SBRT combination, it could be interpreted not only by the immune priming provided by radiation but also by the effect from anti-CTLA4 to block radiation-induced high Tregs.16 Our data could be confirmed by another CTLA4-RT study, and the objective response rate in their NSCLC cohort was 18%.17

Even though this study was based on prospectively collected data, several limitations must be addressed. First, this was an unspecified secondary analysis of prospective trials, which does not constitute the same level of evidence as a prespecified secondary analysis. The sample sizes were also relatively small, which could be why a doubling of the grade ≥3 toxicity rate with anti-CTLA4 seen here was not statistically significant. Notably, however, our study had very low lung toxicity rates that were numerically comparable to RT alone.18 Second, no intertrial comparison can adequately balance all baseline factors. In this study, the group given anti-CTLA4 had a numerically (but not statistically) higher incidence of previous systemic therapy (since they came from our phase I group), which could result in patients with more resistant tumors, greater number of metastatic sites, and reduced lymphocyte counts. Third, in any study of immunotherapy, quantification of response remains an inexact science; we chose to use RECIST to facilitate comparisons with other work,15 19 although the immune-related response criteria are now in common use as well. Also, radiographical response may not necessarily equate to continued cellular viability or further metastatic potential, especially at early time points. Fourth, this study (like others)19 did not stratify patients by PD-L1 status, tumor mutational burden, or other biological variables that could influence response and outcomes. Fifth, the high ORRs in this study may have stemmed from exclusion of patients who may have rapidly deteriorated and not been able to obtain their first imaging evaluation; this could have been a selection bias, although good responders with immature follow-up may have been excluded for this reason as well. Sixth, in the current study, PFS and OS were measured from the date of applied radiotherapy. Five patients in the ipilimumab cohort received two cycles of ipilimumab before SBRT, which seemed to produce a survival disadvantage compared with the patients with concurrent treatment. However, our previous study showed that there was no obvious difference between SBRT followed by the ipilimumab cohort and concurrent SBRT+Ipi cohort.20 Finally, this study cannot rule out effects of concurrent versus sequential iRT because all patients given anti-CTLA4 received sequential iRT, and all subjects given anti-PD1 underwent concurrent iRT. These shortcomings underscore the need to consider this study to be hypothesis-generating and not a substitute for randomized data.

This novel study of two prospective trials of mNSCLC shows that both anti-CTLA4 and anti-PD1 agents prompt a similar degree of in-field and out-of-field responses after iRT, although the global response rate and PFS after iRT were statistically higher in the PD1 cohort. Although our findings were derived from prospective trials, these data should be considered hypothesis-generating and require verification by dedicated randomized studies, as well as biological mechanistic assessment.