Background: Classic therapeutic (RX) oncology principles demand radiographic response or durable stable disease as surrogates of overall survival (OS) prolongation, the ultimate metric of Rx benefit. Progressive disease (PD), however, is an undisputed indication of treatment failure. Immune Oncology (IO) trials reporting individual patient outcomes using swimmers' plot (SP) suggest substantial OS subsequent to PD, unprecedented pre-IO. Hypothesis: Unrecognized phenomenon of OS benefit in the setting of radiographic PD, is tissue-agnostic and prevalent (>15%). Methods: We conducted a retrospective review of IO monotherapy trials in 3 cancers if SP were reported. Percentage of PD patients (Pts) surviving beyond defined time landmarks is reported (Table). Results: Realizing that 3rd or subsequent Rx lines rarely provide > 6 months OS duration in most cancers, our results indicate that 2/3rd of IO-treated pts, regardless of histology, or line of therapy are performing significantly better than expected; 1/3rd surviving > 1 year beyond PD. Discussion: In IO, radiographic bulk may increase despite undeniable OS benefit (in years). We likely underestimated this phenomenon since pts with PD at 1st assessment aren't included in the SP, and with longer follow up, OS of PD pts is likely to improve with longer time to manifest it. This phenomenon–we term 'Disguised Responders' (DRs)–challenges an oncology principal. DRs needs to be considered by clinicians and future drug developers to accurately identify putative novel drugs. A plausible mechanism of DRs posits that 'virulence' of a given subclone, regardless of size or bulk, dictates Rx outcome. Virulence may operate through cachexia-induction, propensity to metastasize or metabolic adaptability, to name a few. Novel experimental approaches are desperately awaited to probe and measure virulence of different tumor subclones in future drug evaluations. Table 1. Clinical Trials of IO Monotherapy Number and (%) of pts surviving beyond clinical PD (months) Tumor Rx Line 1st Author/Yr N PD (n) <6 6-11 12-23 24-35 36-47 > 48 NSCLC* 2nd + Topalian ''19 22 12 1 2 4 1 4 1st + Fredinandus ''21 45 2 1 1 1st + Kim ''22 139 22 13 5 3 N/A Bilger ''22 18 10 3 4 3 2nd Dart ''21 7 3 2 1 2nd + Tozuka (MR) ''20 11 11 4 6 1 2nd + Tozuka (PD) ''20 51 51 29 12 7 2 1 2nd + Waterhouse ''20 39 38 16 14 4 4 Subtotal 332 149 63 (42%) 44 (30%) 28 (18%) 4 (3%) 5 (3%) 4 (3%) Melanoma 1st + Warburton ''20 70 13 1 4 3 4 1 2nd + Topalian ''19 34 21 1 2 10 4 4 2nd + Weber ''15 38 4 2 1 1 2nd + Dimitriou ''21 125 9 3 4 2 Subtotal 267 47 3 (6%) 8 (17%) 10 (21%) 17 (36%) 5 (11%) 4 (8.5%) RCC** 2nd + Topalian 19'' 10 7 1 1 2 3 7 15% 15% 30% 42% Total 609 203 33% 25% 15% 10% 6% 5.4% *Non-small cell lung cancer. ** Renal Cell Carcinoma Citation Format: Farah Mazahreh, Liyan Mazahreh, Brad Fugere, Ahmad Mazin Safar. Unprecedented tumor: immune interaction–clinical and drug-development implications. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4385.

e14528 Background: WL is an adverse prognostic factor/symptom reported in ~40% cancer (ca) patients (pts) at diagnosis agnostic to site or histologic grade. The mechanism of WL in ca, however, remains elusive. The role of energetic waste in ca WL is doubtful (it neglects likely dietary compensation). On the other hand, lymphocytic activation, a clonal, energetically demanding process is accompanied with anorexia limiting caloric intake which leads frequently to WL if protracted over months as seen in lymphoma (B-symptom) or indecisive immune engagement (Eng) with tuberculosis. WL of > 5% of body weight, was an adverse prognosticator and exclusion criterion in non-small cell lung cancer (NSCLC) chemotherapy (CT) trials, likely due to CT or steroids' abrogation of the putative, limited immune ca containment. We hypothesized that WL in ca reflects months of immune Eng, ineffective as it may be at containing the tumor, but nevertheless representing immune Eng with the ca. Such cases stand the best chance for IO benefit. Notably, IO impact in ca mirrors the 40% of WL in ca pts. Methods: Tumor registry retrieved data from all stage 4 cancers treated with monotherapy IO in our institution. We dichotomized pts to beneficiaries (B) or non-beneficiaries (NB). Bs survive longer than median survival for the respective stage/line of therapy in each ca derived from published trials. To account for missing WL data prior to IO, we reasoned that weight gain of ≥10 lbs (reliably charted over 1 year from IO infusions) is acceptable surrogate for WL and met our criteria. Results: WL in our cohort (n = 53) of Melanoma, NSCLC, renal cell carcinoma, and bladder ca was 43% of B; 10% in NB (ratio > 4:1) rejecting the null hypothesis (p < 0.05). PDL-1, Tumor Mutation Burden, both inconclusive in identifying durable benefit, were limited in our set precluding further analysis. Conclusions: Our results support, though do not prove, that WL identifies the appropriate IO pts. Improved outcome despite a historically-adverse prognosticator (WL); the fact that IO was the only ca therapy used, both support our interpretation. We hope to stimulate others to examine independent larger datasets to confirm this notion and to allow comprehensive subset analyses. For WL to be utilized properly the relevant clinical context is crucial, accounting for GI obstructing ca (esophageal ca), enzymatic anomalies (pancreatic ca), volume fluctuations (cirrhosis), catabolism (prolonged hospitalization), or dental issues, to name a few. Additionally, factors such as tumor bulk, perhaps discerned from the T of TNM staging, deserve examination since more vigorous immune activation against larger targets could produce more impact on appetite and caloric intake. Finally, available clinical trial datasets, not tumor registries, might provide a more crisp, reliable source as we continue this investigation. WL can, with confirmatory work, be clinically incorporated as a predictive factor for IO benefit.