Emerging Immunotherapy Combos Seek to Capitalize on the Powers of RT

A growing appreciation of the immunomodulatory properties of radiation therapy (RT) and their role in the rare, but highly sought-after “abscopal effect”—whereby localized RT elicits systemic antitumor effects—is fueling excitement in the radiation oncology field.

Accumulating evidence suggests that RT may make an ideal therapeutic partner for immunotherapy, potentially expanding its reach by turning up the heat in immunologically cold tumors while also extending the curative potential of RT into the metastatic setting^1-5 (Figure³).

Figure. Radiation Therapy Can Prime Immune Response³ (Click to Enlarge)

In recent years, a number of prospective clinical trials have evaluated the safety and efficacy of RT combined with immune checkpoint inhibitors (ICIs) targeting CTLA-4 and the PD-1/PD-L1 pathway, and additional studies are planned. Findings from one of these trials were highlighted at the 2019 American Society for Radiation Oncology (2019 ASTRO) Annual Meeting,⁷ and several others were recently published.^8,9

So far, the results of only 2 randomized phase III trials evaluating combinations of RT and ICIs have been published. The PACIFIC trial, which evaluated the use of durvalumab (Imfinzi) as consolidation therapy following chemoradiation therapy (CRT) in patients with advanced non—small cell lung cancer (NSCLC),¹⁰ prompted regulatory approval in this setting.¹¹ In the CA184-043 trial, however, patients with metastatic prostate cancer did not receive any overall survival (OS) benefit from the combination of ipilimumab (Yervoy) and RT.¹²

The discrepancy between the results of these clinical trial findings highlights a limited understanding of the effects of combined immunotherapy and RT. Ongoing studies aim to address this limitation and some of the as-yet unanswered questions that may be critical to patient outcomes.

The Abscopal Effect

Since the discovery of x-rays in the late 1800s, ionizing radiation has been an effective tool for cancer treatment.^13,14 Estimates suggest that approximately half of all patients with cancer can benefit from RT in the management of their disease.¹⁵

The anticancer role of RT is related to its capacity to induce DNA damage and trigger various forms of cell death (predominantly apoptosis and mitotic catastrophe), exploiting the reduced DNA repair capabilities of tumor cells.^13,14

In the early-disease setting of many cancer types, RT can be curative. When cancer is more advanced and metastasizes, however, RT plays mainly a palliative role, helping to reduce the tumor burden, prolong survival, and improve quality of life.^1,2,5

Advances in the guidance and delivery of RT have permitted oncologists to administer ablative doses in the setting of oligometastatic disease, which were recently shown in the phase II SABR-COMET trial to be associated with improved survival.¹⁶ Nonetheless, patients ultimately experience distal metastases.²

Published reports have documented a rare event occurring with RT in some patients with distal metastases. This phenomenon is dubbed the abscopal effect, from the Latin meaning “away from the target.”¹⁷ First noted in the 1950s, it describes regression seen in tumors outside the irradiated field.¹⁸

As investigators sought to understand the molecular mechanisms underlying the abscopal effect, they discovered that it is most likely mediated by the immune system.¹⁹ In mouse models, RT was shown to drive the generation of a tumor-specific immune response. The ability of RT to inhibit tumor growth was significantly reduced in immune-deficient mice compared with those with a proficient immune system and was shown to be highly dependent on interferon gamma expression and the presence of effector T cells.^3,4,19-23

In Situ Vaccination?

Table. Ongoing Phase III Trials of RT + Immunotherapy (Click to Enlarge)

Investigators have proposed that irradiation of a tumor induces immunogenic cell death, which creates an in situ vaccination effect: The dying cells release tumor-associated antigens that provoke an adaptive immune response.^4,6,25

Presentation of these tumor-derived neoantigens causes cytotoxic T-cell activation, leading to immune-mediated tumor destruction. RT has been shown to promote this process by upregulating the expression of major histocompatibility complex I molecules²⁶ on the surface of tumor cells and by upregulating prophagocytosis signals while downregulating signals that inhibit phagocytosis of tumor cells by macrophages. RT-induced cell death also leads to increased release of danger-associated molecular patterns that stimulate the innate arm of the immune response.^4,6,25,27,28

Furthermore, RT can remodel the immunosuppressive tumor microenvironment by promoting the release of proinflammatory cytokines, chemokines that attract immune effector cells, and other immunostimulatory factors. Because RT eliminates many of the immune cells around the tumor, it can generate a blank slate on which the tumor microenvironment can be repopulated more favorably.^4,6,25

Overall, RT is thought to help unmask the tumor, making it visible to the immune surveillance machinery so it can elicit an effective antitumor immune response. Importantly, however, RT could be a double-edged sword, as it can also have immunosuppressive effects. Whether an immunostimulatory or immunosuppressive environment prevails may depend on the radiation dose, the fractionation schedule, and other factors.^4,6,25,29

Harnessing Synergy

Despite clear evidence of the immunemediated effects of RT, the abscopal effect is rare, and relapse is common, suggesting that RT-induced antitumor immunity is not sufficient to completely eliminate the tumor. With the advent of immunotherapyhave come suggestions of synergistic activity when the 2 treatment modalities are combined and more frequent reports of abscopal responses.^4,5

The key to this synergy is that combining RT and immunotherapy could translate the localized effects of RT into a systemic response—a theory that has been borne out, to some extent, by increased reports of abscopal responses—and the potential for long-term immunological memory, which could help to prevent recurrence.^2,4,25,29

The synergistic effects might also work in reverse, with RT acting to reduce the tumor burden, which could boost the effects of immunotherapy. According to the tumor burden hypothesis, a reduction in tumor burden would reduce inhibitory signaling by tumor-infiltrating lymphocytes (TILs) and reinvigorate their antitumor activity. In addition to having other immunostimulatory effects, this could allow RT to prime the immunologic response of cold tumors, which are typically unresponsive to immunotherapy, by reinvigorating exhausted T-cell populations.^2,3,29

The most substantial body of evidence to date has come from the combination of RT with ICIs. Preclinical trials have demonstrated synergy between RT and ICIs targeting CTLA-4 or the PD-1/PD-L1 axis, with the triple combination of RT and both types of ICIs especially beneficial for helping to stem the development of resistance.^30,31

Clinical evidence has come mostly from case reports and retrospective studies.^32-38 An example of the latter is a secondary analysis of the KEYNOTE-001 trial, in which patients with locally advanced or metastatic NSCLC were treated with pembrolizumab (Keytruda). Patients who had received prior RT had significantly longer progression-free survival (PFS) and OS than those who had not.³⁹

A number of prospective studies have been completed in recent years. Although many have been nonrandomized and involved small cohorts, they have generally lent support to the idea that RT and ICIs can be safely combined, with some evidence of synergistic activity and abscopal responses. A variety of ICIs have been tested in combination with different types of RT and different treatment sequencing, dosing, and fractionation schedules.

The abscopal effect has been reported to be positively correlated with the biologically effective dose of radiation, with greater likelihood of abscopal response with increasing doses in preclinical models.⁴⁰ In a recent phase II study, the results of which were presented at 2019 ASTRO, investigators sought to determine whether the abscopal effect would occur when high-dose radiation administered to a single site was combined with pembrolizumab in patients with metastatic NSCLC.

Among 56 patients, 22 were candidates for stereotactic body radiotherapy (SBRT) as a result of progression on pembrolizumab (6 had already progressed on immunotherapy; 16 were immunotherapy naïve and began pembrolizumab during the trial, then subsequently progressed). After a median follow-up of 15.2 months, the disease control rate was 57.14% among the 21 patients who completed both treatments, and investigators observed some abscopal responses. Two partial responses (shrinkage of tumors outside the irradiated area) lasting more than a year were observed, and 10 patients experienced stable disease. Patients with higher CD8-positive T-cell and TIL counts showed improved PFS, as did patients who experienced immune-related adverse events.⁷

Another phase II trial explored this combination in the reverse sequence, evaluating the addition of pembrolizumab after locally ablative therapy (LAT), including RT, in patients with oligometastatic NSCLC. Patients were treated with pembrolizumab 200 mg in up to eight 21-day cycles within 4 to 12 weeks of completing LAT and had the option of an additional 8 cycles in the absence of progressive disease.

The trial included 2 primary end points, PFS-L and PFS-P (PFS from the start of LAT and pembrolizumab treatment, respectively); PFS-L was compared with historical data. Median PFS-L was 19.1 months—significantly greater than the historical median of 6.6 months (P = .005)—and median PFS-P was 18.7 months. The combination was safe, with no reduction in patient quality of life.⁸

Randomized Trials

Data from only 2 randomized phase III trials have been published to date. The PACIFIC trial demonstrated a clear benefit of ICI therapy following CRT. Patients with stage III NSCLC who had not progressed on platinum-based CRT were randomized to receive 10 mg/kg durvalumab or placebo every 2 weeks. Median PFS was significantly greater in patients who received durvalumab (16.8 vs 5.6 months), as was the objective response rate.¹⁰ Updated results published in 2018 also demonstrated an improvement in 2-year OS rate (66.3% vs 55.6%; P = .005).⁴¹

On the basis of this trial, the FDA approved durvalumab as maintenance therapy following completion of CRT in this patient population.¹¹ At 2019 ASTRO, a new analysis of the survival data from the PACIFIC trial was presented; it suggested that durvalumab and CRT significantly lessened the rates of local and distant recurrence.⁴²

Several phase II studies have recently evaluated combinations of other ICIs with concurrent CRT. In the DETERRED trial, investigators examined concurrent atezolizumab (Tecentriq) and CRT in patients with locally advanced NSCLC. In part 1 of this study, 10 patients underwent CRT followed by consolidation chemotherapy and atezolizumab; atezolizumab was then given as maintenance therapy for 1 year. In part 2, 30 patients received concurrent atezolizumab and CRT followed by the same consolidation and maintenance regimen used in part 1. One-year OS was 79% in both parts, and 1-year PFS rates were 50% and 57%, respectively.⁴³

In the HCRN LUN14-179 trial, investigators administered consolidation pembrolizumab following standard chemotherapy-based CRT to 92 patients with advanced NSCLC. The primary end point of median time to metastatic disease or death was not reached by the median follow-up of 16.4 months; this represented a substantial improvement compared with historical controls. Estimates of 1- and 2-year OS were 80.5% and 68.7%, respectively.⁴⁴

The other randomized phase III trial was CA184-043, in which patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy were randomized to receive bone-directed RT followed by either ipilimumab 10 mg/kg or placebo. Unfortunately, no significant difference in OS was observed between the 2 groups. However, the results of a prespecified subgroup analysis suggested a potential benefit for certain subgroups of patients, particularly those with favorable prognostic features.¹²

According to a recent review, more than 350 clinical trials of combinations of immunotherapy and RT had been registered on the ClinicalTrials.gov website as of May 2019, and many are randomized trials.⁶ Among them is the PEMBRO-RT trial comparing pembrolizumab alone with pembrolizumab after SBRT in patients with metastatic NSCLC. Results from this trial were recently published in JAMA Oncology.⁹

Among the 76 patients randomized, the combination of pembrolizumab and SBRT led to a doubling of overall response rate at 12 weeks compared with pembrolizumab alone (36% vs 18%, respectively; P = .07). Median PFS was 6.6 versus 1.9 months (P = .19), and median OS was 15.9 versus 7.6 months, respectively (P = .16). Despite these positive results, the study did not meet prespecified criteria to demonstrate clinically meaningful benefit.⁹

Unanswered Questions

Not all the data emerging from these studies are positive, which highlights challenges to the combined use of RT and immunotherapy. The molecular mechanisms underlying their synergy are still uncertain, and a better understanding could help to put some of the clinical heterogeneity in context, particularly the potential of RT to elicit immunosuppressive rather than immunostimulatory effects.

Beyond this, significant unanswered questions remain about the type of RT that works best and the optimal dose and fractionation schedules that elicit the greatest synergistic effect while avoiding toxicity. The sequencing and timing of administration of RT and immunotherapy is also an open question. Is it best to use RT first, use immunotherapy first, or administer them at the same time?^4-6 To date, there is little evidence to support one particular strategy, but results of one study suggest the approach may depend on the type of immunotherapy.⁴⁵

A growing number of studies are addressing the issue of a single fraction of RT versus multiple fractions, as well as optimal dosing. The results of some have demonstrated improved outcomes for single-fraction compared with multifraction doses and for hypofractionated SBRT compared with conventional daily dosing.¹⁷ The studies have yielded some conflicting results, however, suggesting that the best fractionation schedule may depend on the particular context.⁵ Numerous ongoing clinical trials are continuing to address these challenges.

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Subsequent studies have shined a light on the multifaceted immunomodulatory properties of RT and have begun to provide a more detailed picture of how RT-induced antitumor immunity mediates tumor regression. For years, the prevailing paradigm was that apoptosis was nonimmunogenic, whereas necrosis played a role in inflammation and immunity. More recently, a new model has been proposed to account for the immunostimulatory properties of some instances of apoptosis: immunogenic cell death, which describes the ability of some dying cells to elicit an immune response.²⁴

The evidence has come predominantly from preclinical studies and clinical case reports or retrospective analyses. That is set to change, however, with hundreds of ongoing clinical trials evaluating the combination of immunotherapy and RT across different tumor settings, according to the ClinicalTrials.gov website. These include many phase III studies (Table).⁶