Anti-programmed cell death protein 1 (PD-1) monotherapy has greatly reshaped the systemic treatment landscape for advanced melanoma.1 2 Emerging data demonstrate that radiological data taken at different static time points, for example, baseline, maximal response and disease progression (PD) were associated with survival outcomes of patients with melanoma under anti-PD-1 monotherapy.3–7 Specifically, patients who achieved complete remission (CR) had the most durable survival benefit.4 8 9 Therefore, in the absence of other biomarkers,10 radiological response measurement is the most reliable and available data guiding therapeutic decision-making.

During routine clinical practice, clinicians seldom make decisions solely relying on instantaneous information but rather taking disease tempo into consideration.11 At every imaging time point, the physician and patient try to determine, given the tumor response and kinetics information at hand, if the patient will benefit from ongoing anti-PD-1 therapy, and if so to what degree. Currently, there is no literature addressing the radiographic evolution of patients who achieve a partial remission (PR) or stable disease (SD). Also lacking is a description of the kinetics of growth/regression across different crucial time points aside from previous reports specifically focusing on early-on-treatment tumor growth rate,7 particularly in a small subgroup of patients, that is, hyperprogression.12 13 Although consensus has been reached for clinical definitions of types of resistance to anti-PD-1 therapy largely based on accumulating translational research data, with the hope to facilitate future clinical trial design in the post anti-PD-1 scenario,14 clinical data are limited in describing the difference between primary and secondary resistance from tumor characteristics at progression and evolving trajectory thereafter.

We hypothesize that a deep examination of radiological response dynamics, PD patterns and detailed clinical characterization of primary versus secondary resistance may provide further insight to address this clinically relevant issue and to facilitate therapeutic decision-making. To do so, we assembled a melanoma cohort from two independent melanoma centers in the USA and China and performed independent radiological re-evaluation by radiologists in a single-blind manner.

Frontline anti-PD-1 monotherapy is a standard therapy associated with significant clinical benefit. Imaging data at different time points have demonstrated constant correlations with survival outcomes.3–6 However, as part of routine clinical practice, clinicians typically consider disease kinetics (fast vs slow growth/regression) to be one essential piece of information during therapeutic decision-making. At present, there are limited available data addressing the issue of tumor kinetics based on pretreatment and on-treatment radiographic imaging, change in tumor volume, and outcome for melanoma patients treated with anti-PD-1 monotherapy. Additionally, the PD pattern has not been well described, particularly in the setting of primary/refractory versus secondary/acquired resistance, and based on maximal tumor regression.14 This report represents the first international effort incorporating melanoma patients with detailed longitudinal radiological data, specifically focusing on disease kinetics at crucial time points during anti-PD-1 monotherapy, and demonstrates for the first time that time course and disease kinetics are associated with survival outcomes.

An important consideration for treatment selection prior to the initiation of frontline therapy is the kinetics of response of any potential therapy. We demonstrate here that most tumor volume change takes place within the first 3 months after initiation of anti-PD-1 monotherapy, comprising around 70% of total tumor reduction in PR/CR patients. This is in agreement with a study showing that tumor size change at month 3 is distinctively predictive of survival.7 Another important issue is how well the timing and degree of tumor regression are associated with long-term benefit. Here we show for the first time the clinical outcomes of patients based on when they achieve CR/PR/SD. Interestingly, CR patients who experienced PR first, compared with those who achieved CR at the first evaluation, seemed to have a numerically longer duration of response. Given the small number of patients, it is possible that this difference may be an artifact. However, there are data showing that CR patients treated for more than 6 months had a lower relapse risk compared with those treated for a shorter duration.8 Presuming those treated for less than 6 months were more likely to have a CR on first evaluation, it is possible that these two sets of data are corroborating. Notably, our study demonstrated that the SD category is heterogeneous with distinct evolving patterns between patients with versus without tumor shrinkage at the initial radiological evaluation, for example, no patients without tumor shrinkage upgraded into CR/PR, whereas 44% of patients with tumor shrinkage did.

While tumor size variation has been well appreciated to be associated with outcomes when evaluated at baseline and nadir,3 5 PD pattern has generally and arbitrarily categorized as oligo and systemic.15 16 We depicted PD patterns with more granularity by viewing them as a continuous heterogeneous spectrum, characterized by different types of progression (enlargement vs new lesion vs both), numbers of involved organs, target lesion size, and tumor growth rate. By doing this, we revealed a high degree of heterogeneity. As opposed to a stochastic appearance of tumor size at different static time points, we observed that response depth, timing, PD pattern, and survival outcomes were highly correlated after adjustment for baseline tumor burden. In terms of target lesion size, the correlation between baseline measurement and response depth is complicated. Consistent with a previous finding,16 we did not observe a simple linear correlation between baseline tumor measurements and response depth. However, significantly lower tumor burden was observed in patients with CR compared with all others. This may reflect the fact that smaller tumor burden at baseline simply requires less tumor size reduction to reach CR. Additionally, we speculate that some long-lasting partial responses may indeed be complete pathologically with residual scarring/fibrosis, a phenomenon that has been observed in the neoadjuvant setting,17 but as these lesions are rarely biopsied, we are left, by convention, to calling these responses partial. However, while larger baseline tumor size precluded CR, smaller tumor size did not guarantee response. Additionally, no discrepancy is observed between PR, SD, and PD patients, consistent with an observation in ipilimumab/nivolumab-treated melanoma cohort.18 Noticeably, in different multivariate analysis using different metrics of PD pattern, response depth stayed constantly the most significantly correlated factor among different covariates, in concert with the previous observation that PD after objective response was associated with excellent clinical outcomes.15

Finally, we evaluated the resistance subtype (primary vs secondary) based on a previously reported resistance definition that emerged from the SITC Immunotherapy Resistance Taskforce.14 Of note, patients included in this study are heterogeneous, 39% had prior immunotherapy, 12% had prior targeted therapy; 16% had brain metastasis; and 29% were with acral, mucosal, or ocular melanomas which are known to be less responsive to immunotherapy. Therefore, the proportion of primary resistance observed in this cohort may be higher than in the general melanoma population with anti-PD-1 monotherapy as the first-line treatment. With those caveats, we demonstrate that primary resistance is correlated with more rapid progression tempo, that is, broader PD pattern, more involved organs, higher LDH level, and larger target lesion measurement at progression. Although patients with primary resistance were treated more intensely (exemplified by lower proportion of local/regional therapy and higher rate of systemic treatment), they had poorer PPS compared with those with secondary resistance. This may relate to the fact that patients who developed secondary resistance were more likely to have oligoprogression, thus making those patients more amenable to local/regional treatment. This suggests that anti-PD-1 therapy in these patients changed the trajectory of these patients’ disease, which is obvious since these patients had a response or prolonged SD prior to progression, and that the biology of secondary resistance is distinct from primary resistance. As such, the distinct clinical manifestations of these two resistance types implicate that specific therapeutic strategies and trial enrollment recommendations should be applied accordingly.

The analysis of different systemic therapy in the post-PD-1 setting is instructive. Although no direct comparison between first line and post-PD-1 setting could be made for MAPKis and CTLA-4 monotherapy, they both demonstrated reasonable antitumor effect, similar to prior reports.6 19–21 We also report that chemotherapy in the post-PD-1 scenario at these institutions was futile and is associated with similar lack of benefit as seen prior to the dawn of immunotherapy and targeted therapy.22

We acknowledge that the major limitation of this study resides in its retrospective nature. Although we performed independent radiological re-evaluations strictly following RECIST V.1.1 in a single-blind manner, potential selection and measurement biases cannot be entirely eliminated. Thus, further validation is required.

In summary, by describing response and progression dynamics in a large cohort of patients with advanced melanoma treated at two institutions, we provide a rationale for radiological parameter-based therapeutic decision-making by showing the drastic tumor volume change shortly after anti-PD-1 initiation and the strong correlation between response dynamics, progression patterns, and survival. We present for the first time the progression patterns of both primary and secondary resistance, which may provide data from which decisions regarding patient eligibility for clinical trials in the post-PD-1 scenario can be based.