Dissociated Responses in Patients with Metastatic Solid Tumors Treated with Immunotherapy

Tumor cells escape the immune system by turning away the immune system control pathways with the cell surface overexpression of programmed cell death ligand 1 (PD-L1) ligands that interact with the program death 1 (PD-1) receptor expressed on immune cells to prevent lymphocyte activation. Immune checkpoint inhibitors (ICIs) that target the PD-1/PD-L1 axis might therefore restore lymphocyte anergy. ICIs have been shown to improve survival in multiple tumor types.

Immune checkpoint inhibitors (ICIs) are being evaluated in combination with radiotherapy, which has an immunogenic effect via several mechanisms, including immunogenic cell death with release of new antigens, release of immunostimulatory cytokines, and increased systemic anti-tumor immunity [1]. On the opposite hand, radiotherapy might also display an immunosuppressive effect via iatrogenic lymphopenia [2], by changing the tumor microenvironment by increasing PD-L1 expression because of hypoxia [3], and by the appearance of fibrosis related to inflammation [4].

New patterns of response have been reported with ICIs, including pseudoprogression, hyperprogression, and durable responses [5]. Dissociated responses (DRs) with new lesions over time while others decrease were also reported in different histological types like melanoma (4%) and non-small cell lung cancer (NSCLC) (8%) [6, 7].

We aimed in this study to evaluate the prevalence of DRs in patients with metastatic solid tumors treated with an ICI and to identify predictive factors of DR.

DRs with at least one responding TL and one progressive TL according to RECIST1.1 were observed in 8% of patients receiving an ICI. At the TL level, a higher response rate was observed in lung metastases and lymph nodes as compared to liver metastases. Response rate was lower in the case of prior radiotherapy and higher in the case of prior biopsy. The occurrence of a DR was not associated with the site of metastases, prior biopsy, and prior radiotherapy of a TL.

The outcome of patients treated in our study was favorable, with an ORR of 22%, a PFS of 3.8 months, and an OS of 13.4 months. All patients included in our study were patients included in clinical trials. In addition, patients without any follow-up CT scan were excluded, the main reason being most likely rapid disease progression. The PFS curve in our study plateaus at 20%, corresponding to the proportion of long-responder patients, which is in line with a recent meta-analysis of 19 randomized clinical trials involving ICIs [9].

We found that 62% of patients had a DR rate in our study, including 8% of patients with at least one responding TL and one progressive TL (DR1). The 8% rate of DR1 is in line with the literature. DR were also reported in melanoma (4%) and NSCLC patients (8%) [6, 7]. In these studies, a DR was defined differently as a persistent reduction in the sum of the TLs in the presence of new lesions but not by the analysis of the different TLs.

Our study showed a different response rate depending on the site of TLs. A significantly higher response rate was observed in lymph node and lung metastases than in liver metastases. Similar results were reported in the literature [10, 11]. These differences in response may be due to stromal and immune heterogeneity of the tumor microenvironment causing a variability of sensitivity to immunotherapy. The hepatic microenvironment is therefore intrinsically immunosuppressive with an initial state of active tolerance to overcome autoimmune mechanisms due to the constant flow of antigens through the hepatic circulation [12]. The higher response rate observed in lymph nodes and lung metastases might be explained by the lymphoid nature of these organs promoting the ICI-stimulated anti-tumor response [13]. Other immunological factors may explain the heterogeneity of response such as the density and variability of TLs, and the higher expression of PD-L1 and other potential biomarkers of efficacy of ICIs such as tumor mutational burden [14].

Our study showed that prior radiotherapy at least 6 months before starting ICI was associated with a lower response rate, while radiotherapy within 6 months before starting ICI was associated with a higher response rate. The lower response rate in TLs that received radiotherapy at least 6 months before starting ICI might be explained by the immunosuppressive effect of radiotherapy [3, 15]. In contrast, numerous studies support the rationale for combining radiotherapy with ICI [16]. The PACIFIC trial was the first randomized trial demonstrating the efficacy of an ICI following chemoradiation in NSCLC patients [17]. Interestingly, the outcome of patients who started durvalumab in that study within 2 weeks after the end of radiotherapy had a better outcome than those who started between 2 and 6 weeks after the end of radiotherapy [17].

A higher response rate was observed in biopsied TLs in our study. The biopsy itself might induce inflammation, trigger a danger signal with increased cytokine concentration, and release tumor antigens that stimulate adaptive anti-tumor immunity [18‐20]. Such an immune stimulation might therefore induce a priming of the anti-tumor immunity locally or even generate systemic effects thanks to the circulation of anti-tumor immune cells [21]. However, these results need to be interpreted with caution since biopsied TLs were mostly lung metastases (31%) and lymph node TLs (10%), which were associated with a higher response rate, and less frequently liver metastases (19%), which were associated with a low response rate. A larger sample size would be needed in order to integrate the sites of metastases into the multivariate analysis.

The occurrence of DRs raises the question of local treatments of oligoprogressive lesions. Catching DRs is key since local treatments of progressive lesions in the case of oligoprogressive disease might improve patients’ outcome [22, 23]. The treatment of oligoprogressive lesions has been shown to be effective and improve survival in different cancer types with chemotherapy and some targeted therapies [23‐25]. Local treatments included radiotherapy, surgery, and interventional radiology. As opposed to chemotherapy, whose hematotoxicity might hamper local therapies, ICIs can be continued during these treatments given their favorable toxicity profiles. In regard to local radiotherapy, ICIs have a synergistic effect when given sequentially or concomitantly. In a retrospective study of patients with advanced melanoma, a response rate of 45% was reported for oligoprogressive lesions under ICI with extracranial radiotherapy and/or intracranial stereotactic radiosurgery, with no increased toxicity [26]. The combination of local radiotherapy with an ICI might be able to produce an abscopal effect [27], which is rarely observed in the case of radiotherapy alone, but that might be more important with a multisite irradiation [28].

Before considering the local treatment of oligoprogressive disease, it is necessary to confirm that the increase in size is a real progression and not in relation to an inflammatory, immunological, or infectious reaction. Granulomatous pseudo-sarcoidosis reactions with the appearance of pulmonary micronodules or mediastinal or hilar lymph node involvement have indeed been reported with ICIs [29]. A biopsy of progressive disease might be needed. There is, however, no consensus on how many progressive lesions can/should be treated with local treatments [22]. It is also important to ensure that stable lesions are also shrinking and to take non-TLs into account. Finally, the clinical condition of the patient has to be good enough to consider these treatments.

Our study has several limitations. The patient population is limited and heterogeneous, with only 100 patients and more than 18 different histological subtypes. From a radiological point of view, the tumor evaluation criteria used were RECIST1.1, which might not be the most appropriate criteria for the evaluation of patients receiving an ICI, but are those that were used in all clinical trials included. iRECIST are criteria that might be used for evaluating response to ICI [30]. iRECIST allows continuation of treatment beyond progression and therefore the continuation of an effective treatment in the case of pseudoprogression. iRECIST is also relevant for accounting for DRs. Finally, it would be interesting to compare the microenvironment and the proportion in tumor-infiltrating lymphocytes of TLs according to their response, although challenging.

In conclusion, DRs with at least a responding TL and a progressive TL according to RECIST1.1 were observed in 8% of patients with solid tumors in our study. The immunological and stromal heterogeneity of the tumor microenvironment as well as previous biopsy or radiotherapy seem to be associated with individual responses of TLs, but are not predictors of DRs. The therapeutic management of progressive lesions should be discussed in the case of oligoprogression. The feasibility and efficacy of a local ablative treatment for progressive lesions has to be confirmed in larger patient populations. Our results suggest that radiotherapy might be a technique of choice because of the synergistic effect with ICI. Finally, a consensual definition of DR is greatly needed, as well as guidelines that help handle the treatment of oligoprogressive disease.