How should we combine radiotherapy and immunotherapy in advanced non-small cell lung cancer?

Immune checkpoint inhibitor (ICI) immunotherapy has been one of the most consequential recent advances in cancer management. This has been especially true for patients with non-small cell lung cancer (NSCLC) in both localized and advanced-stage settings. For patients with advanced non-oncogene driven NSCLC, ICI therapies, either alone or in combination with chemotherapy have been associated with significant improvements of progression-free survival (PFS) and overall survival (OS) (1,2). Rare individual patients have experienced remissions in excess of 5 years and there is optimism that for some patients “cure” may even be within reach (3).

There is increasing evidence that, in curative-intent settings, combinations of ICI with definitive local treatments, including surgery plus neoadjuvant chemotherapy, or definitive radiotherapy plus radiosensitizing concurrent chemotherapy, can improve disease control and improve survival in NSCLC. The success of combining ICI and local treatments in curative-intent patients could have implications for the management of more advanced disease. Several clinical trials have established that in the neo-adjuvant setting that pre-operative chemo immunotherapy is associated with an increased rate of pathological complete response and with improvements in survival. For example, the CheckMate 816 trial showed that, in patients with resectable NSCLC, neoadjuvant nivolumab plus chemotherapy resulted in significantly longer event-free survival and a higher percentage of patients with a pathological complete response than chemotherapy alone (4). Combinations of platinum-based radiosensitizing concurrent immunotherapy and definitive high-dose radiotherapy have also been associated with improved survival. In the PACIFIC trial, patients with stage III NSCLC had superior OS when adjuvant durvalumab, a programmed death-ligand 1 (PD-L1) inhibitor, was added to standard chemoradiation (5). This trial has changed international practice and chemoradiotherapy (chemoRT) followed by ICI therapy is an effective standard of care in countries with access to these expensive drugs. The very recently published stereotactic ablative radiotherapy with immunotherapy (I-SABR) randomized phase 2 trial, of SABR with or without nivolumab, demonstrated that in patients with stage IA-IIB, NSCLC that SABR plus 4 cycles of nivolumab improved 4-year event-free survival from 53% with SABR to 77%, hazard ratio: 0.38, P=0.0056 (6). These studies establish the principle that local therapies, combined with immunotherapy (with or without chemotherapy), can improve outcomes in patients with local and locoregionally advanced disease. An effective combination of radiotherapy, the most effective non-invasive local therapy and immunotherapy could prove to be a valuable approach in metastatic NSCLC.

Whilst ICI and combinations of ICI and chemotherapy are associated with superior survival compared to standard chemotherapy in patients with very locally advanced and metastatic NSCLC, long term results remain poor. Most patients do not respond to ICI-containing therapy and most of those who do respond ultimately experience progressive disease and die from lung cancer. Novel strategies are clearly needed to improve outcomes for patients with advanced NSCLC. There is an intense international research effort to find more effective combinations of immunotherapy, other systemic therapies and local therapies to build on the promising but inadequate results achieved so far with immunotherapy or chemoimmunotherapy. Combinations of radiotherapy and immunotherapy without chemotherapy are attractive in the advanced disease setting, both because they are likely to be more tolerable and because they avoid the immunosuppressive effects of cytotoxic chemotherapy. The absence of the systemic cancer killing effect of chemotherapy could potentially be offset by the immune stimulus provided by radiotherapy.

The combination of radiotherapy and ICI-based systemic therapies is especially promising for two main reasons:

• Local radiotherapy is independently effective as a single modality for local disease control of metastatic lesions, especially when given in the form of SABR (7). The burden of disease to be overcome by systemic therapy can be reduced by irradiation;
• Radiotherapy can release neoantigens and induce a local immune response (8) that can enhance the systemic response to immune based therapies (9), including ICI (10).

Local radiotherapy alone can rarely induce systemic regression of metastatic lung cancer, the so-called abscopal effect (11). Researchers have attempted to build on this phenomenon by amplifying the immune effects of radiotherapy with ICI therapies (9). To date, combinations of single agent ICI and radiotherapy have not proven to be successful in advanced NSCLC in reliably inducing enhanced systemic therapeutic responses compared to immunotherapy alone, despite promising results in melanoma (10). However, a combined analysis of two phase I/II trials suggested that higher than expected response rates may be seen (12) and it has been reported that combinations of radiotherapy and ICI can be safely administered in metastatic NSCLC (13). The reasons for the lack of strong evidence of efficacy to date for radiotherapy immunotherapy combinations in advanced NSCLC are poorly understood. However, it is important to consider the effects of previous treatment in NSCLC patients treated with salvage ICI-based therapies for advanced NSCLC as a cause of treatment failure. One reason for the observed high levels of efficacy for neoadjuvant immunotherapy in early-stage disease is that these patients have not previously received immunosuppressive systemic therapies and therefore can mount an effective response.

Combinations of more than one immunotherapy drug with radiation may be more successful in building a therapeutic immune response than the use of single agents. It has been clearly established that combinations of immunotherapeutic agents with different mechanisms of action, e.g., an anti-programmed death 1 (PD1) or PD-L1 agent combined with anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) agent, can attain higher response rates in malignant melanoma compared to single agent immunotherapy, albeit at the expense of increased toxicity (14). Dual ICI therapy has also been successfully combined with chemotherapy in NSCLC (15). Combinations of dual immune checkpoint blockade and radiotherapy represent an attractive strategy for evaluation in NSCLC, in the hope that the local and systemic immune effects of radiotherapy will boost the efficacy of combined immunotherapy to a greater extent than has been so far observed in trials of radiotherapy plus single agent ICI. This approach has shown promise in preclinical studies (16).

When designing a study of radiotherapy plus immunotherapy in advanced NSCLC, there are many variables to consider with respect to the radiotherapy component. The ideal target volume is unknown. For example, should an attempt to comprehensively irradiate all sites of disease to a high dose? Unfortunately, high-dose comprehensive tumor site irradiation is not suitable for patients with multiple sites of disease or with very locoregionally advanced tumors and is generally confined to patients with oligometastases.

If the radiation approach is not comprehensive, should the primary site be targeted and if so, should the entire tumor be treated or should one or more metastatic lesions be treated instead? There is evidence that there can be important differences in mutation status between primary tumors and secondary deposits in NSCLC (17). Mutations within the primary tumor compared to its metastases can be categorized as “ubiquitous, shared and private” between different biopsy sites. Ubiquitous “trunk” mutations are found in the primary tumor and its metastases whereas private “branch” mutations may be found in metastases only. An immune response initiated by irradiating a metastasis may not be effective in targeting all disease sites, whereas an immune response targeted at the primary site could potentially be more effective at all distant sites. Having decided to target the primary tumor. A further decision needs to be made; to irradiate the whole tumor or just a portion of the tumor, because the intention of radiotherapy is to induce an immune response, not cause the tumor to regress? Targeting just a portion of the tumor with a high radiation dose may cause enough local cell death and antigen release to provide a sufficient immune stimulus. Because the volume of normal tissue irradiated to a high dose is the main predictor of radiation toxicity, this approach would be expected to be associated with a low risk of additional adverse events compared to immunotherapy alone, especially of the region targeted is in the center of a tumor. Fluorodeoxyglucose (FDG)-positron emission tomography (PET) can be used to target the highest radiation dose to viable tumor regions as in the PET-boost trial (18). Tubin and colleagues have suggested that FDG-PET can be used to help deliver partial tumor irradiation, targeting the hypoxic segment of bulky tumors [stereotactic body radiation therapy (SBRT)-PATHY] in an effort to exploit bystander and abscopal effects (19).

There is an intermediate strategy in locally advanced NSCLC between treating the entire tumor to a low dose and treating a smaller tumor region to a highly-immunogenic high-dose. This involves the deliberate application of a heterogeneous dose distribution across the tumor. Menon and colleagues reported that the incidental delivery of lower dose radiation (1–20 Gy) to nearby tumor regions appeared to modulate their responsiveness to immunotherapy when combined with high dose SABR (20). Such treatments, combining auto-vaccination and immune modulation, can be delivered in a small number of fractions or even a single fraction.

The ideal dose of radiation to induce an effective immune response has not been established and may vary widely between different diseases and even between different patients with apparently (11) the same disease. For example in lung carcinomas, reports of rare abscopal regressions have been associated with much higher doses, including ablative doses with SBRT (11). In mice with carcinomas, various approaches have been tried. Single fractions of low dose irradiation (0.5–2 Gy) can cause limited tumor cell killing (21) and induce reprogramming of the tumor microenvironment (22). Some of the most promising preclinical approaches have generally been with large radiation doses given in single or small numbers of fractions, with an influx of immune effector cells commonly about observed 14 days after irradiation (23). Two studies reported that more fractionated schedules (8 Gy per fraction or less) were more effective than single 20 Gy fractions in inducing tumor regressions outside the irradiated volumes when combined with immune checkpoint blockade (24,25). The disparate range of data available from animal studies and the significant differences that exist between animal models and human subjects highlight the need for well conducted studies of combinations of radiotherapy and immunotherapy in patients with cancer.

This brings us to the interesting preliminary paper by Kievit and colleagues from Groningen (26), which has contributed new information relevant to the search for an effective combination of radiotherapy and immunotherapy in NSCLC. For the immunotherapy component of the trial, they selected the human immunoglobulin G1 (IgG1) monoclonal antibody directed at PD-L1, durvalumab, and the human IgG2 monoclonal antibody directed against CTLA-4, tremelimumab, as their immunotherapeutic agents. These agents target different immune checkpoints and as discussed above, these classes of drugs have demonstrated both enhanced efficacy and increased toxicity when combined with each other. The combination of these agents with radiotherapy is a rational approach to for investigation in humans with NSCLC but requires careful trial design to avoid unexpected severe toxicity.

In their phase I SICI trial, Kievit et al. investigated the safety and tolerability of stereotactic radiotherapy combined with durvalumab with or without tremelimumab in advanced NSCLC, either metastatic or locoregionally advanced (26). The main novel features of the study was the combination of double immunotherapy with SBRT and the use of two different sequences of combined therapy. Eligible patients had stage IIIB or IV NSCLC and were experiencing progression on chemotherapy. In three sequential cohorts, immunotherapy regimes combined with high dose SBRT confined just to a part of the primary tumor (1×20 Gy to 9 cc) were studied. The target was selected using FDG-PET. The first cohort (n=3) received single agent durvalumab and the second (n=6) received a combination of tremelimumab and durvalumab followed by durvalumab monotherapy. The third cohort (n=6) was similar to the second cohort except that the sequence of the combination was reversed. The potential long-term toxicity risk of combined immunotherapy was attenuated by dropping one of the immunotherapy agents after local therapy. The immunotherapy doses were fixed at durvalumab 1,500 mg and tremelimumab 75 mg. The study was too small to assess efficacy but provided data on the tolerability of the combinations. The study also explored the use of electronic nose (eNose) technology applied to exhaled breath as a surrogate marker of response.

Of the 15 patients recruited to the trial, 73% had adenocarcinoma and PDL-1 expression was <1% in 10 (67%), 1–49% in 3 (20%) and >50% in 2 (13%). Sites of metastasis were varied, including brain liver and bone and 5 patients (33%) had no metastases at these sites. Overall, the combinations of radiotherapy and immunotherapy appeared safe in this trial. There was a single dose limiting toxicity in cohort 3 (durvalumab before SBRT, followed by tremelimumab) of colitis. A single grade 2 pneumonitis episode occurred in cohort 1 (SBRT plus durvalumab). Although not powered to assess efficacy, the authors reported some outcome data. Median PFS was only
2 months, with a median OS of 10 months. Two patients had confirmed partial responses but one of these had a single target lesion that was irradiated and therefore was not eligible for assessment by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. The objective response rate was 13%. The eNose method did not provide useful information.

In their discussion, the authors concluded that the combinations explored in their study were indeed safe with comparable toxicity profiles to immunotherapy combinations without radiotherapy. An increased rate of pneumonitis was not observed. The study did not show any promising evidence of efficacy however. Apart from the obvious possibility that this particular approach is not effective, there were confounding factors to consider. The cohort was varied in terms of disease extent and histology and previous therapies. The authors concluded that a larger study would be safe to conduct and would be warranted to exclude a possible therapeutic benefit in a clinically significant proportion of patients. This is certainly the case, but it would have been more encouraging had the authors observed more than a single case of regression of a non-irradiated target lesion.

Other workers have tried similar approaches. For example, Schoenfield et al. reported the results of a randomized phase 2 study durvalumab, tremelimumab alone or in combination with low-dose or hypofractionated targeted radiotherapy in metastatic NSCLC refractory to prior PD(L)-1 therapy in Lancet Oncology (27). Radiotherapy was delivered as either 0.5 Gy delivered twice per day, repeated for 2 days during each of the first four cycles of therapy or 24 Gy total delivered over three 8-Gy fractions during the first cycle only. Although these authors found that combined immunotherapy might be a promising approach for salvage therapy, they concluded that radiotherapy did not increase responses to combined PD-L1 plus CTLA-4 inhibition in patients with NSCLC resistant to PD(L)-1 therapy.

Kievit and colleagues are to be congratulated for their well conducted and innovative trial. They have demonstrated that high dose SBRT to small tumor volumes can safely be combined with sequential dual agent ICI. Although they have not excluded the possibility of a therapeutic benefit from this approach, the low response rate overall is not immediately encouraging. However, all patients in this cohort had progressive disease after chemotherapy and most of the patients had PD-L1 expression <1%. It is possible that this regimen could actually be effective in treatment naïve patients, or in cohorts of patients selected on the basis of biomarkers, such as a significant level of PD-L1 expression detected on biopsy or imaging (28), or without evidence of T-cell exhaustion. It is easy to be wise in retrospect, but this trial could have been improved by the application of more stringent eligibility criteria. Less heavily pre-treated patients, should ideally have been recruited. Similarly, although a primary target for this study was the PD1/PD-L1 axis, two-thirds of the patients had PD-L1 <1%! Had a minimum level of PD-L1 expression been mandated, e.g., 50%, more tumor responses may have been observed.

Further studies, with more selective eligibility criteria are certainly warranted, especially as the dual checkpoint durvalumab-tremilimumab combination and concurrent radiotherapy has demonstrated an impressive ability to improve pathological response rates in the neoadjuvant setting in the recently presented preliminary results of the INCREASE study (29), again suggesting that the immune response to radiotherapy must be seen in the context of the whole patient, and the effects of other therapies taken into account. In NSCLC patients who have progressed after first-line cytotoxic therapy both the immunosuppressive effect of treatment, and the evolution of resistant clones are obstacles to response.

Tantalizing evidence is emerging that blood based biomarkers may provide useful prognostic information to guide patient selection (30) and we anticipate a future where the combination of blood based biomarkers to identify the evolution resistant clones and imaging biomarkers, such as novel PET tracers (28) that can identify lesions that may benefit from radiotherapy either to change their immunophenotype or for ablation will help us develop optimal and individualized combined modality radiotherapy-immunotherapy treatment regimens. Although this paper has contributed important new information, the optimum combination of radiotherapy and immunotherapy for NSCLC remains elusive. Better biomarkers and more individualized combinations of therapies may help improve on the dismal survival results that are currently reported in advanced NSCLC.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-23-54/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-23-54/coif). M.P.M. has received lecture and travel reimbursement paid to institution from venue Varian Healthcare Systems. F.H.J. has received clinical trial drug supply (to institution) and funding, speaker’s honoraria and advisory board fees from Astra Zeneca. She also serves as Co-Chair of the WCLC 2023, Communications Committee unpaid roles of International Association Study of Lung Cancer, Board Director and Lung Working Party Chair of Trans-Tasman Radiation Oncology Group. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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