Radiographic Disease Progression Research Articles

Abstract PD1-02: A phase I/Ib study evaluating GDC-0077 + palbociclib (palbo) + fulvestrant in patients (pts) with PIK3CA-mutant (mut), hormone receptor-positive/HER2-negative metastatic breast cancer (HR+/HER2- mBC)

Abstract Background GDC-0077 is a PI3Kα-selective inhibitor and mutant PI3Kα degrader that demonstrates antitumor activity in PIK3CAmut BC xenograft models. A phase I/Ib study of GDC-0077 alone and combined with endocrine therapy ± the CDK4/6 inhibitor (i) palbo is ongoing (NCT03006172). Data from GDC-0077 + palbo + fulvestrant in pts with PIK3CAmut, HR+/HER2- mBC are presented herein. Methods Safety (NCI-CTCAE v4), pharmacokinetics (PK), and preliminary antitumor activity (clinical benefit rate [CBR]: RECIST v1.1 stable disease for ≥ 24 weeks, partial response [PR], or complete response) of 9 mg oral once daily GDC-0077 + 125 mg palbo 21/28 days + 500 mg intramuscular fulvestrant on day 1 (and day 15 of cycle 1) of 28-day cycles were assessed in Arms E and F, until intolerable toxicity or disease progression. In Arm F, pts were obese and/or pre-diabetic (body mass index ≥ 30 kg/m2 and/or HbA1c ≥ 5.7%) and also received metformin up to 2000 mg daily starting at 500 mg in cycle 1 day 1, prior to initiating GDC-0077 at cycle 1 day 15 instead of day 1 as in Arm E. Additional key eligibility criteria included Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1, no prior PI3Ki therapy, no prior CDK4/6i, and ≤ 1 prior chemotherapy for Arm E (no restrictions on prior CDK4/6i or chemotherapy for Arm F). PIK3CAmut allele frequency was assessed in circulating tumor (ct) DNA from serial plasma collections. Results At clinical cutoff (03/20/2020), 28 pts were enrolled (13 in Arm E and 15 in Arm F). Median age was 55 years in Arm E and 65 years in Arm F. ECOG PS was 0 in 8 pts (62%) in Arm E and in 7 pts (47%) in Arm F. Three (23%) and 12 (80%) pts in Arm E and F, respectively, had received ≥ 2 prior lines of therapy for mBC. One pt (8%) in Arm E and 10 pts (67%) in Arm F received prior fulvestrant. Nine pts (60%) received prior CDK4/6i (all Arm F). Median GDC-0077 treatment duration was 7.8 months (range 0.1-13.9) in Arm E and 6.5 months (1.2-11.2) in Arm F. GDC-0077 cumulative dose intensity was 98% in Arm E and 88% in Arm F. Thirteen pts (46%) discontinued treatment: 11, due to radiographic disease progression (3 in Arm E, 8 in Arm F); 1, due to an adverse event (AE; treatment-related grade 2 panniculitis in Arm F); and 1 pt withdrew (Arm F). The most common treatment-related AEs (≥ 4 pts) were stomatitis (grouped term; 92%), neutropenia (85%), diarrhea and hyperglycemia (62% each), fatigue (38%), alopecia, nausea, and thrombocytopenia (31% each) in Arm E; and hyperglycemia (67%), diarrhea and neutropenia (53% each), nausea (47%), stomatitis (grouped term; 47%), anemia, decreased appetite, and blurred vision (27% each) in Arm F. Grade ≥ 3 treatment-related AEs (≥ 2 pts) were neutropenia (62%) and hyperglycemia (23%) in Arm E; and hyperglycemia and neutropenia (47% each), and anemia (13%) in Arm F. AEs led to GDC-0077 dose reduction in 2 pts (15%) in Arm E and 4 pts (27%) in Arm F. The PK of GDC-0077 in combination with palbo + fulvestrant was similar to single agent GDC-0077. Overall, 7/25 pts (28%) with measurable disease had a PR (5/10 [50%] pts in Arm E; 2/15 [13%] pts in Arm F, both received prior fulvestrant), of whom 6 pts (24%; 4 in Arm E; 2 in Arm F) had a confirmed PR. CBR was 61% (17/28 pts: 8 in Arm E; 9 in Arm F). PIK3CAmut allele frequency by ctDNA analysis decreased during treatment in most pts. Conclusion This study demonstrated a manageable safety profile when combining GDC-0077 at its single agent recommended phase II dose of 9 mg with palbo + fulvestrant at standard doses, similar PK to GDC-0077 alone, preliminary anti-tumor activity, and modulation of PIK3CAmut allele frequency in ctDNA. In obese and/or pre-diabetic patients enrolled to Arm F, hyperglycemia was frequent despite initiating metformin prior to GDC-0077. A phase III study of GDC-0077 + palbo + fulvestrant is enrolling currently (NCT04191499). Citation Format: Philippe L Bedard, Komal Jhaveri, Andrés Cervantes, Valentina Gambardella, Erika Hamilton, Antoine Italiano, Kevin Kalinsky, Ian E Krop, Mafalda Oliveira, Cristina Saura, Peter Schmid, Nicolas Turner, Andrea Varga, Katherine E Hutchinson, Guiyuan Lei, Stephanie Royer-Joo, Piia Thomas, Jennifer L Schutzman, Dejan Juric. A phase I/Ib study evaluating GDC-0077 + palbociclib (palbo) + fulvestrant in patients (pts) with PIK3CA-mutant (mut), hormone receptor-positive/HER2-negative metastatic breast cancer (HR+/HER2- mBC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD1-02.

Core decompression with autologous bone marrow aspirate injection in humeral head osteonecrosis in adults with sickle cell disease.

Sickle cell disease is often associated with osteonecrosis of the humeral head with a risk of progression to humeral head collapse. The aim of this study was to evaluate the clinical outcome and the effect on the necrosis evolution of humeral head core decompression with autologous bone marrow aspirate injection in these patients. Forty shoulders in 23 patients were treated with core decompression with autologous concentrated iliac crest bone marrow aspirate injection. Patients were followed for a minimum of two years (limits from 2 to 10 years). Functional outcomes metrics included the simple shoulder test (STT) and subjective shoulder value (SSV) as well as assessment of radiographic progression of disease. Shoulder function improved significantly at final follow-up. The STT improved by 2.9 points (p = 0.001) and the SVV improved by 15 % (p = 0.001). However, based on radiologic features, the intervention did not halt the radiographic progression of disease nor did it result in healing of the lesion. The benefits were mainly clinical with diminished pain and functional improvement. Improvement in shoulder function was observed following core decompression and bone marrow aspirate injection in patients with sickle cell disease and early humeral head necrosis stages. The procedure should not be considered for grade 3 or greater disease and for asymptomatic cases whatever the grade. Given the lack of radiographic improvement observed in this study, further study in the context of prospective controlled trials should be undertaken before this intervention can be widely recommended.

Efficacy of cyclophosphamide in treating connective tissue disease-related interstitial lung diseases.

Interstitial lung diseases (ILDs) are some of the first and most serious complications of connective tissue diseases (CTDs). However, the pathogenesis of CTD-related ILDs (CTD-ILDs) is still unclear and their treatment often depends on functional and radiographic disease progression as well as on patient age and comorbidities. It can be difficult to manage CTD-ILDs due to their heterogeneous nature, the lack of robust therapeutic data, and the few well-defined outcome measures. This review focuses on cyclophosphamide due to its crucial role in the treatment of systemic sclerosis-related ILD, particularly in the case of patients with progressive ILD. This narrative review was performed using PubMed, Medline, and Cochrane Library databases to retrieve English language papers published between 2000 and April 2020 concerning the treatment of CTD-ILDs with cyclophosphamide.

Real-World T790M Mutation Frequency and Impact of Rebiopsy in Patients With EGFR-Mutated Advanced Non-Small Cell Lung Cancer.

IntroductionThe T790M resistance mutation is present in about one-half of epidermal growth factor receptor (EGFR)-positive advanced non-small cell lung cancer (NSCLC) patients at disease progression. We aimed to assess the prevalence of this mutation in a real-world setting and the clinical impact of repeated biopsies in its detection.MethodsThis was a single-center retrospective cohort study of patients with EGFR-positive advanced NSCLC diagnosed between 2016 and 2018, who experienced radiographic disease progression during first-line treatment with first- or second-generation EGFR-tyrosine kinase inhibitor (TKI). The frequency of T790M detection and the number of rebiopsies were determined.ResultsA total of 88 patients were included, with a median age of 65 years (range: 38-84 years). The majority of the participants were females (63 (72%)) and non-smokers (70 (81%)). Upon disease progression, 80 (91%) patients were tested for T790M mutation, and the resistance mutation was detected in 57 (71%) cases (58% in plasma samples and 42% in tissue/cytology samples). In 14 (25%) cases, T790M mutation was only detected after rebiopsy (57% by liquid biopsy), which increased the rate of mutation detection in 17%. Subsequent treatment with third-generation EGFR-TKI was possible in 42 (74%) of T790M-positive cases. Detection of T790M mutation was more likely in patients who were less than 65 years old, with EGFR exon 19 deletions and duration of first-line treatment of more than 12 months (p < 0.05).ConclusionsThe frequency of T790M mutation in this study was higher than previously reported, suggesting that repeated biopsies after a negative result are beneficial. This allowed a greater percentage of patients to receive sequential osimertinib in our clinical practice.

Stereotactic Ablative Radiotherapy for the Management of Liver Metastases from Neuroendocrine Neoplasms

Liver metastases are common in patients with metastatic well-differentiated neuroendocrine neoplasms (WD-NEN). Given the rather indolent clinical course of WD-NEN, patients may expect to have prolonged survival even in the setting of metastatic disease. Treatment modalities must therefore maximize tumor control, maintain quality of life and minimize treatment side effects. Although commonly used to treat liver metastases for other cancer histologies, the role of stereotactic ablative radiotherapy (SABR) is not well understood in this unique patient population. The purpose of this study is to evaluate the safety and efficacy of SABR in treating well-differentiated neuroendocrine liver metastases (WD-NELM). An institutional REB approved retrospective review of patients with WD-NELM treated with SABR was performed spanning January 2015 to July 2019. Demographic, treatment details and clinical/radiographic follow-up data were abstracted from the patients’ clinical and radiation planning records. RECIST 1.0 criteria were applied to each individual target to evaluate the overall response rate to treatment. One-year survival was calculated for local control and systemic progression. All stats were calculated using R Studio version 1.1.463. Toxicity was reported as per CTCAE v 5.0 criteria. Twenty-five patients were identified that matched the search criteria with a total of 53 individual liver metastases treated with SABR. The median number of liver metastases treated per patient was 2 (range: 1-4) with a median size of 2.5 cm (range 0.7-9.7 cm). The median radiation dose delivered was 50Gy/5 fractions (range 25Gy/5 - 60 Gy/3) with a median biologically effective dose (BED10) of 100 (range 39-180). The median follow-up was 14 months (range 2-54 months). Twenty-four of the 25 patients were still alive at time of data analysis. Most patients (68%) had midgut tumors (small bowel, pancreas), were Grade II (80%) and had high volume intrahepatic and/or extrahepatic disease (76%). Almost all patients (96%) remained on systemic somatostatin analogues despite having radiographic disease progression. The best overall response was: CR = 2, PR = 13, SD = 30 and PD = 2. The best treatment response based on changes in axial diameter was -100% (median: -16%, range: -100% to 47%). The objective response rate was 32%, with initial disease improvement or stability in 96% of all lesions treated. The median time to best response was 9 months (range: 3-16 mos). The 1-year local control and PFS were 92% (CI 85-99.9%) and 44% (CI 28-70.1%) respectively. No Grade III/IV acute or late toxicity was identified. Liver SABR is a safe and effective means of providing local control for NELM. This treatment modality should be considered a care option in select patients in concert with strategies to manage systemic disease.

Does the administration of preoperative pembrolizumab lead to sustained remission post-cystectomy? First survival outcomes from the PURE-01 study☆.

Initial studies of preoperative checkpoint inhibition before radical cystectomy (RC) have shown promising pathologic complete responses. We aimed to analyze the survival outcomes of patients enrolled in the PURE-01 study (NCT02736266). We report the results of the secondary end points of PURE-01 in the final population of 143 patients. In particular, we report the event-free survival (EFS) outcomes, defined as the time from the first cycle of pembrolizumab to radiographic disease progression precluding RC, initiation of neoadjuvant chemotherapy (NAC), recurrence after RC, or death from any cause. Other end points were recurrence-free survival (RFS) and overall survival (OS). Subgroup analyses were carried out, including pathological response category, clinical complete responses (CR) assessed via multiparametric magnetic resonance imaging (mpMRI), and molecular subtyping. Cox regression analyses for EFS were also carried out. After a median [interquartile range (IQR)] follow-up of 23 (15-29) months, 12- and 24-month EFS were 84.5% [95% confidence interval (CI): 78.5-90.9] and 71.7% (62.7-82). The prognosis was favorable across all the different pathological response subgroups, with the exception of ypN+ (N= 21), showing a 24-month RFS (95% CI) of 39.3% (19.2% to 80.5%). A statistically significant EFS benefit was observed in patients with a clinical CR (P= 0.002). Programmed cell-death-ligand-1 combined positive score was significantly associated with longer EFS in multivariable analyses. Four patients refused RC after clinical evidence of CR, and none of them have recurred after a median follow-up of 10 months (IQR: 11-15). The claudin-low subtype displayed a numerically longer EFS after pembrolizumab and RC compared with the other subtypes. The EFS results from PURE-01 revealed that the immunotherapy effect was maintained post-RC in most patients. Pembrolizumab compared favorably with neoadjuvant chemotherapy, irrespective of the biomarker status. Molecular subtyping may be a useful tool to select the patients who are predicted to benefit the most from neoadjuvant pembrolizumab.

Long term inhibition of hip joint damage under tumor necrosis factor-alpha inhibitors in spondyloarthritis

The aim of this study was to assess the impact of long-term treatment with TNF blockers on the radiographic progression of hip disease in spondyloarthritis (SpA).This retrospective multicentric cohort study included 2 groups of patients with SpA and hip involvement. Patients of group 1 were treated with anti-TNF alpha for at least 2 years, whereas those of group 2 were anti-TNF-naïve patients. Clinical, laboratory and radiologic parameters were assessed at baseline and after at least 2 years.Groups 1 and 2 included respectively 48 and 46 patients. The radiological features of hip disease were comparable between the two groups at baseline. The second evaluation was performed after an average duration of 4.1 ± 2.9 years [2–10] in group 1 and 4.8 ± 2.1 years [2–14] in group 2 (p = 0.116). The absence of hip structural damage was more frequently found in group 1 (72 hips vs 52, p < 0.0001, odds ratio [OR] = 4.7, 95% confidence interval [CI] = 2.1–10.4). The better outcome in group 1 remained significant even after adjusting for BASDAI (p < 0.05, (adjusted odds ratio [aOR] = 3.3, 95% CI = 1.2–9.2), BASFI (p < 0.0001, aOR = 3.1, 95% CI = 1.1–8.9), and CRP (p < 0.01, aOR = 4.2, 95% CI = 1.8–9.8).Our finding suggests that anti-TNF therapy may inhibit hip joint damage in patients with SpA.

Natural disease progression in finger osteoarthritis: results from a 10 year follow-up cohort

Objective: Limited evidence is available about long-term natural disease progression in hand osteoarthritis (HOA). The objective is to study natural radiographic and clinical disease progression in HOA after longer follow-up (i.e. 10 years) and to identify predictors for progression. Method: At baseline (T0), 270 patients with HOA were included in the Belgian HOA register. The majority (84.8%) was female and the mean age was 62.9 years. In total, 154 (57%) and 106 (39.3%) patients consented to follow-up after approximately 5 (T1) and 10 years (T2), respectively. Clinical and functional outcome measures were collected. Hand radiographs were taken and scored according to the anatomical phase scoring system. Results: At T2, most of the patients (73.3%) showed any radiographic progression compared to T0. Remodelling was most frequently seen and new erosive joints rather rarely. Functional Index for Hand Osteoarthritis (0–30) and Australian/Canadian Osteoarthritis Hand Index function (0–90) increased over time, from 8.8 to 9.9 (p = 0.017) and 39.3 to 41.9 (p = 0.035), respectively, after T2. Visual analogue scale pain (0–100) did not change (40.2 to 38.6 from T0 to T2, p = 0.656). Univariate and multivariate logistic regression retained baseline soft-tissue swelling [odds ratio (OR) 8.20 and 8.76, respectively], higher levels of pain (OR 4.08 and 4.30), and number of baseline erosive joints (OR 31.82 and 30.02) as significant predictors for radiographic progression. Conclusions: Significant radiographic progression is seen over time in HOA. While pain remains similar after 10 years, functional status declines. Patients with soft-tissue swelling, high levels of pain, and already erosive disease at baseline are prone to progression over time.

Orbital Rosai-Dorfman disease initially diagnosed as IgG4-related disease: a case report

Inflammatory orbital lesions include a broad list of diagnoses, many of them with overlapping clinical and radiographic features. They often present a diagnostic conundrum, even to the most experienced orbital specialist, thus placing considerable weight on surgical biopsy and histopathological analysis. However, histopathological diagnosis is also inherently challenging due to the rarity of these lesions and the overlaps in histologic appearance among distinct disease entities. We herein present the case of an adolescent male with a subacutely progressive orbital mass that generated a significant diagnostic dilemma. Early orbital biopsy was consistent with a benign fibro-inflammatory lesion, but corticosteroid therapy was ineffective in halting disease progression. After an initial substantial surgical debulking, histopathological analysis revealed several key features consistent with IgG4-related disease (IgG4-RD), a systemic fibro-inflammatory process typically accompanied by multifocal tumor-like lesions. Surprisingly, within months, there was clear evidence of clinical and radiographic disease progression despite second-line rituximab treatment, prompting a second surgical debulking. This final specimen displayed distinctive features of Rosai-Dorfman disease (RDD), a systemic inflammatory disease characterized by uncontrolled histiocytic proliferation. Interestingly, certain features of this re-excision specimen were still reminiscent of IgG4-RD, which not only reflects the difficulty in differentiating RDD from IgG4-RD in select cases, but also illustrates that these diagnoses may exist along a spectrum that likely reflects a common underlying pathogenetic mechanism. This case emphasizes the importance of surgical biopsy or resection and histopathological analysis in diagnosing—and, ultimately, treating—rare, systemic inflammatory diseases involving the orbit, and, furthermore, highlights the shared histopathological features between RDD and IgG4-RD.

Bisphosphonate Use Is Protective of Radiographic Knee Osteoarthritis Progression Among those With Low Disease Severity and Being Non-Overweight: Data From the Osteoarthritis Initiative.

Antiresorptive medications have been explored for treating knee osteoarthritis (OA); however, little data exist on the effects of today's more potent nitrogen-containing oral bisphosphonates on radiographic disease-progression in patients with varying disease-severity, especially those who are not overweight. The primary objective of this cohort study was to determine if the use of bisphosphonates is protective against 2-year radiographic-progression of knee OA in Osteoarthritis Initiative (OAI) participants, stratified by baseline radiographic disease status. Secondary objectives were to examine effects in non-overweight participants (body mass index [BMI] < 25 kg/m2 ) and cumulative bisphosphonate exposure effects. We identified female OAI participants aged ≥50 years and excluded those missing baseline radiograph readings, bisphosphonate use information, or all clinical questionnaire information at baseline. Participants reporting bisphosphonate use (69% alendronate) were propensity-matched 1:1 to non-bisphosphonate users and followed until first radiographic knee OA progression (1-unit increase in Kellgren and Lawrence [KL] grade) or data were censored (first missed visit or end of 2-year follow-up). Discrete-time logistic regression models estimated hazard ratios (HRs) between bisphosphonate users versus nonusers, with an interaction term for baseline KL grade (KL <2 or KL ≥2). We identified 1977 eligible women (n = 346 bisphosphonate users). Propensity-matched results indicated that bisphosphonate users with KL grade <2 were protected against progression (HRKL<2 0.53; 95% CI, 0.35 to 0.79), while bisphosphonate use was not associated with radiographic progression in those with KL grade ≥2 (HRKL≥2 1.06; 95% CI, 0.83 to 1.35). When restricting analyses to those with BMI <25 kg/m2 , effects were strengthened (HRKL<2 0.49 [95% CI, 0.26 to 0.92]; HRKL≥2 0.69 [95% CI, 0.33 to 1.26]). Duration of bisphosphonate use had no effect on progression, though sample size was limited. Bisphosphonate therapy may be protective against radiographic knee OA progression in early-stage patients, particularly those who are non-overweight, but less so for those with more advanced disease or more weight-bearing joint stress. © 2020 American Society for Bone and Mineral Research (ASBMR).

ProCAID: A randomized double-blind phase II clinical trial of capivasertib (C) in combination with docetaxel and prednisolone chemotherapy (DP) in metastatic castration-resistant prostate cancer (mCRPC).

5520 Background: DP extends survival in mCRPC, but clinical benefit is modest. PI3K/AKT/PTEN pathway activation is common in mCRPC contributing to disease progression and DP resistance. C is a pan-AKT inhibitor. Pre-clinical data indicate activity in prostate cancer and synergism with DP. This phase II trial combined C with DP in mCRPC. Methods: Key eligibility criteria: histologically or cytologically proven measurable or evaluable mCRPC, suitable for treatment with DP for PSA and/or radiographic disease progression, ECOG performance status 0-1, no prior chemotherapy for mCRPC, not requiring insulin or &gt; 2 oral hypoglycaemic drugs for diabetes mellitus. Treatment: up to 10 cycles of DP (D: 75 mg/m2 IV, day 1; P: 5 mg bd oral, day 1 – 21) and random assignment (1:1, double blind) to oral C (320 mg twice daily, 4 days on/3 days off, from cycle 1, day 2) or matched placebo to disease progression. Primary endpoint: progression free survival (PFS; comprising PSA, radiographic or clinical progression, new cancer therapy or death; PCWG2 criteria) in the intent to treat (ITT) population. Secondary endpoints included overall survival (OS) and safety. PFS and OS were also assessed by composite biomarker (B) subgroup for PI3K/AKT/PTEN pathway activation status (NGS/IHC on archival tumour, contemporaneous ctDNA). Statistics: designed to detect a 50% increase in median PFS (6 to 9 months (mo)) between the placebo and C arms (90% power, 20% 1-sided alpha) by Cox proportional hazards model. Registration: ISRCTN 69139368. Results: 150 patients were randomised to 01/2019. Median follow up 16.77 months (IQR 12.0-26.5). PFS and OS by ITT and B status, are shown in the table (NR, not reached; CI confidence interval). Grade 3–4 adverse events (AE) were equally common between arms (62.2%). The most common AEs were diarrhoea, fatigue and nausea. Conclusions: Adding C to DP did not extend PFS. The OS secondary endpoint was significantly increased. PFS and OS results were consistent irrespective of PI3K/AKT/PTEN pathway activation status. Clinical trial information: 69139368 . [Table: see text]

Radiographic paradoxical response in patients with metastatic castrate-resistant prostate cancer (mCRPC) undergoing treatment with second-generation hormone therapy (second-HT).

5577 Background: Prostate specific antigen (PSA) has well-recognized limitations as a marker for treatment response and disease progression. A post hoc analysis of the PREVAIL trial reported 24.5% of chemotherapy naïve mCRPC patients on enzalutamide had radiographic progression on conventional imaging with non-rising PSA. In this study, we sought to retrospectively compare PSA levels with C-11 choline positron emission tomography/ computed tomography (PET/CT) images in patients with m-CRPC on 2nd-HT with prior use of chemotherapy. Methods: We identified 123 patients with mCRPC on 2nd-HT following prior use of docetaxel chemotherapy (Abiraterone, n = 106; Enzalutamide, n = 17). Patients underwent serial PSA testing and C-11 choline PET/ CTs every 3–6 months. Disease progression was defined by the increase in blood pool corrected maximum standardized uptake value (SUVmax) of the index lesion on C-11 choline PET/CT scan. Suspicious lesions were confirmed by biopsy and/or conventional imaging. Results: Approximately 43% (n = 53) of patients had radiographic disease progression while on 2nd-HT. At time of radiographic progression, 60.4% of patients showed a parallel rise in PSA (Group-A), while 39.6% showed a paradoxical response; defined as radiographic progression with stable or down-trending PSA (Group-B). Median PSA at time of progression was 3.1 ng/ml for Group-A, and 1.3 ng/ml for Group-B (p-value = 0.0176). Median SUVmax was the same (4.9 Group-A, 4.6 Group-B; p-value = 0.6072). Bone-predominance progression was more significant in Group-B (90%) versus Group-A (65%) (p-value = 0.0309). The median time for radiographic progression was 9.5 months versus 3.9 months for Group-A and Group-B, respectively (Log-Rank = 0.0063). Conclusions: Metabolic imaging is a useful tool that should complement PSA in the evaluation of treatment response and disease progression in mCRPC patients on 2nd-HT, especially considering the paradoxical response observed in our data.

Major pathologic response of EGFR mutated non-small cell lung cancer (NSCLC) on 1-3 G TKI.

e21528 Background: Despite impressive clinical efficacy in response rate, increase in PFS and sometimes in OS EGFR TKI rarely cure cancer patients, as all of them inevitably develop resistance. Small fractions of residual cells appear to be a reservoir of further clones with acquired resistance. For this moment morphological characteristics of “persister” population are not well defined. Methods: We screened hospital data-base containing &gt; 200 pts for EGFRmut NSCLC who underwent cytoreductive surgical treatment during treatment with either TKI and before radiographic disease progression. We obtained 18 pairs of pretreatment biopsy and surgical specimen. 7/18 were male, median age 60.5 yo (45-79). 15/18 had ex19del; 3/18 – L858R. 12/3/2/1 received gefitinib/erlotinib/afatinib/osimertinib before surgery. Median time from treatment initiation to surgery was 8.9 mon (0.7 – 24.3). None of the pts had evidence of increase in any dimension of tumor lesions before surgery. According to RECIST 6/18 pts had SD, 12/18 – PR. 6/18 pts had complete cytoreduction, 4/18 – partial, 8/17 – metastasectomy. All pathologic responses (MPR) were graded according to Hellmann MD et al., 2014. Results: Pathologic response with &gt; 50% of residual tumor – 2/18; 10-50% – 7/18; &lt; 10% – 4/18; pCR – 3/18. Median observation time is 15.4 mon (8.4 – 37.2+). Disease progression after surgery was registered in 6/18 pts. No significant correlations between PFS, MPR, RR, TKI generation, time to surgery were seen. Conclusions: In our serie MPR rate ( &lt; 10% of viable tumor cells according to Hellmann MD et al, 2014) for NSCLC treated with various TKI was 38%, that is higher than in other reports (10.2% in CTONG 1103 for example). Further characterization of the “persister” tumor cells may help to determine mechanisms of intrinsic resistance and direct more efficient antitumor activity.

What happens at radiographic disease progression in patients with metastatic cancer receiving immune checkpoint inhibitors? A single institution analysis.

e15157 Background: Immune checkpoint inhibitors (ICIs) are widely adopted for multiple indications across various malignancies. Despite the surge in their use, what occurs at radiographic progression (rPOD) remains poorly characterized. Herein, we describe patients at our institution that experienced rPOD on ICIs. Methods: We retrospectively reviewed charts of patients (pts) with solid tumors that received at least 2 doses of ICI at our institution from 12/01/2010 to 04/25/2017. Patients’ demographic data, medical history, ICI course, and outcomes were recorded. Characteristics at rPOD included change in tumor size by metastatic site, symptoms, and hospital utilization. Additionally, we characterized outcomes of pts who continued ICIs after rPOD. Fisher’s exact test was performed to identify potential clinical predictors of hospitalization at rPOD. Results: Of the 361 evaluable pts, 238 experienced rPOD. In this cohort, the most common primary sites of disease are: genitourinary (24%), thoracic (24%), skin (21%), and hepatobiliary (15%). At rPOD, 71 (30%) patients were hospitalized within 30 days, with infection (27%) and pain (18%) being the most common reasons. Median survival of pts with hospitalization was 2 months (mos; 95% CI: 0-4), compared to 10 months (95% CI: 8-12) for those not hospitalized (p&lt;0.001). Forty-six (19%) pts continued ICI treatment after rPOD (median duration = 2.8 mos), with eleven (5%) pts continuing for at least 6 months (median duration = 8 mos). Conclusions: In our study of real-world cancer pts treated with ICI, a higher than expected proportion was hospitalized within 30 days after rPOD, and this population had a worse overall survival compared to those that were not. A subgroup of pt with rPOD did not experience clinical progression, and thus treatment was continued, although further benefit was limited to a small subset. Further studies are needed to better understand the underlying mechanism to identify those who benefits from treatment beyond rPOD. [Table: see text]

Haemophagocytic lymphohistiocytosis (HLH) in patients with large B-cell lymphoma treated with standard of care (SOC) axicabtagene ciloleucel (Axi-cel).

8057 Background: HLH is a rare but serious complication of chimeric antigen receptor (CAR) T cell therapy, characterized by severe immune activation, and immune mediated multi-organ failure. Diagnosis is difficult in the context of cytokine release syndrome (CRS) and optimal treatment and outcomes are unclear. Methods: Retrospective, descriptive analysis of patients with relapsed/refractory LBCL treated with SOC axi-cel at MD Anderson Cancer Center between 01/2018 - 10/2019 (data cut-off 12/21/2019). Progression-free survival (PFS) defined as time from axi-cel infusion to progression/death or last follow-up. Diagnosis of HLH per HLH-2004 and CART cell therapy toxicity guidelines (Neelapu, 2018) Results: One hundred and five patients with relapsed/refractory LBCL included, 6 diagnosed with HLH. No significant difference in baseline characteristics, disease stage, international prognostic index or inflammatory markers at baseline between groups, with exception of platelet count which was lower in HLH group 116 [37-129] versus 141 [9-391] (p = 0.07). Development of HLH was early after CART cell infusion at a median 11 days [7 – 78 days] with 3 patients having bone marrow hemophagocytosis; all 6 had abnormalities in liver function tests, fibrinogen, triglycerides, and at least 1 ferritin level &gt; 10,000. CART toxicity in HLH cohort: 4 patients experienced grade 0-1 CRS, and 1 with grade 2 CRS while 3 HLH patients experienced grade 3-4 IEC-associated neurotoxicity syndrome ( ICANS), and 2 patients had grade 0-1 ICANS. Five HLH patients treated with high dose steroids, and tocilizumab; anakinra administered in 2 patients. Four of 6 patients had resolution of HLH with treatment and didn’t require escalation to HLH specific therapy however 1 patient was treated with steroids/etoposide. PFS and overall survival (OS) were significantly shorter in HLH group, PFS 1 months vs 8 months, respectively (p &lt; 0.001) and median OS 2 months vs not reached, respectively (p = 0.001) follow up 10 months (95% CI 8-12 months). One patient died of acute respiratory failure, 2 patients died of HLH and multi-organ failure without progressive disease (PD). Of 3 remaining patients, all had radiographic PD at day 30, 2 of whom died of PD. Conclusions: HLH is likely an underreported complication of CART cell therapy, and patients with HLH have significantly worse outcomes. In this series the majority of patients died of PD, not the syndrome itself. More information is necessary to design treatment strategies that won’t compromise CART outcomes.

Composite quantitative knee structure metrics predict the development of accelerated knee osteoarthritis: data from the osteoarthritis initiative

BackgroundWe aimed to determine if composite structural measures of knee osteoarthritis (KOA) progression on magnetic resonance (MR) imaging can predict the radiographic onset of accelerated knee osteoarthritis.MethodsWe used data from a nested case-control study among participants from the Osteoarthritis Initiative without radiographic KOA at baseline. Participants were separated into three groups based on radiographic disease progression over 4 years: 1) accelerated (Kellgren-Lawrence grades [KL] 0/1 to 3/4), 2) typical (increase in KL, excluding accelerated osteoarthritis), or 3) no KOA (no change in KL). We assessed tibiofemoral cartilage damage (four regions: medial/lateral tibia/femur), bone marrow lesion (BML) volume (four regions: medial/lateral tibia/femur), and whole knee effusion-synovitis volume on 3 T MR images with semi-automated programs. We calculated two MR-based composite scores. Cumulative damage was the sum of standardized cartilage damage. Disease activity was the sum of standardized volumes of effusion-synovitis and BMLs. We focused on annual images from 2 years before to 2 years after radiographic onset (or a matched time for those without knee osteoarthritis). To determine between group differences in the composite metrics at all time points, we used generalized linear mixed models with group (3 levels) and time (up to 5 levels). For our prognostic analysis, we used multinomial logistic regression models to determine if one-year worsening in each composite metric change associated with future accelerated knee osteoarthritis (odds ratios [OR] based on units of 1 standard deviation of change).ResultsPrior to disease onset, the accelerated KOA group had greater average disease activity compared to the typical and no KOA groups and this persisted up to 2 years after disease onset. During a pre-radiographic disease period, the odds of developing accelerated KOA were greater in people with worsening disease activity [versus typical KOA OR (95% confidence interval [CI]): 1.58 (1.08 to 2.33); versus no KOA: 2.39 (1.55 to 3.71)] or cumulative damage [versus typical KOA: 1.69 (1.14 to 2.51); versus no KOA: 2.11 (1.41 to 3.16)].ConclusionsMR-based disease activity and cumulative damage metrics may be prognostic markers to help identify people at risk for accelerated onset and progression of knee osteoarthritis.

Does hyaluronic acid injection prevent the progression of knee Osteoarthritis ?

Purpose: Intra-articular injection of hyaluronic acid (HA) is performed as a conservative treatment for knee osteoarthritis (OA). HA has diverse pharmacological actions. In addition to increased lubrication of joint surfaces, its actions have been reported to include inhibition of the release of inflammatory cytokines and promotion of endogenous HA production. While many reports have suggested that injection of HA is clinically effective for knee OA, the actual improvement only seems to be modest. It has also been reported that injection of HA did not prevent the progression of knee OA, but rather promoted it. Thus, there are many unanswered questions about intra-articular HA therapy. The purpose of this study is imaging evaluation of patients who received long-term treatment with intra-articular HA for knee OA was conducted. Methods: This study was conducted in accordance with all applicable requirements of our university (including IRB approval). The subjects were 42 patients/64 knees (male: 17, female: 25) who received long-term intra-articular injection of HA for knee OA at the outpatient clinic of our university. Their mean age was 74.0 years, and the mean observation period was 4 years and 7 months. Knee radiographs were assessed by the Kellgren-Lawrence (K-L) classification, and the joint space was measured on frontal and lateral views obtained with the patient in the standing semiflexion position. In addition, the height, body weight, body mass index (BMI), frequency of HA injections, and total dose of HA were evaluated. Radiographic disease progression was defined as an annual increase of at least 1 grade in the K-L score or a decrease of > 0.2 mm in knee joint cartilage thickness annually. Results: Knee OA progression was seen in 24/64 knees (37.5%), while OA did not progress or the joint space increased in 40/64 knees (62.5%) (Fig 1). Approximately half of the knees with progression of knee OA were in K-L grade 3 or higher (45.8% * χ2 test), while all grade 1 or 2 patients who showed progression were obese with a BMI ≥27 kg/m2. On the other hand, in the group without knee OA progression, more than three-fourths of the knees were K-L grade 1 and 2 (77.5% * unpaired t-test). The interval between HA injections was shorter in patients without progression of knee OA, and the total dose was larger than in patients with progression (Table 1). Conclusions: Our previous study in OA animal models indicated that intra-articular injection of HA has both symptom-modifying and disease-modifying effects. In this study, the aim was to determine whether HA has these effects in human knees, as well as to determine the long-term treatment course with intra-articular injection of HA. In the OARSI guidelines, the strength of the recommendation for intra-articular injections of HA is 64, which is lower than for intra-articular injection of corticosteroids. In the previous research, HA treatment is well tolerated and produces statistically and clinically significant improvement of symptoms in patients with mild to moderate knee OA. In this study, 37.5% of the patients showed OA progression despite continuing HA injection. Converted to the annual OA progression ratio, 7.9% of the patients were shown to have knee disease progression annually. Comparing this ratio with the natural course of knee OA, 7% was reported by the Framingham study, with 3% reported by another study. It is difficult to compare this ratio because of the different populations and study designs. However, intra-articular injection of HA may not prevent OA progression. Approximately two-thirds of patients who received intra-articular injection of HA showed no progression or improvement of knee OA. Intra-articular injection of HA may not be effective in patients with K-L grade 3 or higher or BMI ≥27 kg/m2.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Knee laxity after staircaseexercise predicts radiographic disease progression in knee osteoarthritis

Purpose: Osteoarthritis (OA) of the knee is one of the major causes of joint dysfunction and physically disabling conditions in the elderly. Joint laxity is considered one of the major factors involved in the progression as well as development of knee OA. Our group reported the increasing of knee joint laxity after stair up down exercise in knee OA patients. And we considered the knee joint laxity after exercise influences the progression of knee OA. The purpose of this study was to evaluate whether the knee joint laxity after staircase climbing produces the knee joint OA progression or not.

Dietary Patterns and Progression of Knee Osteoarthritis: Data from the Osteoarthritis Initiative

While some individual foods and nutrients have been associated with knee osteoarthritis (KOA) progression, the association between dietary patterns and KOA progression has received little research attention. The objective of this study was to determine whether dietary patterns, derived by principal components analysis (PCA), are associated with KOA progression. In the Osteoarthritis Initiative (OAI), a prospective cohort with clinical centers in Maryland, Ohio, Pennsylvania, and Rhode Island, 2757 participants with existing KOA (mean age 62 y) and diet assessed at baseline were followed for ≤72 mo. Using PCA, Western and prudent dietary patterns were derived. Radiographic KOA progression was assessed using 2 separate measures, 1 full Kellgren-Lawrence (KL) grade increase and loss in joint space width (JSW). Symptomatic KOA progression was defined as an increase in or remaining in 1 of the 2 highest classification categories of the Western Ontario and McMaster Universities Arthritis Index (WOMAC). Adherence to Western and prudent dietary patterns was significantly associated with radiographic and symptomatic progression of KOA. With increasing Western pattern score, there was increased KL-worsening risk (compared with quartile 1, HR for quartile 4: 1.30; 95% CI: 1.05, 1.61; P-trend<0.01) and increased odds of progression to higher WOMAC score (compared with quartile 1, OR for quartile 4: 1.39; 95% CI: 1.18, 1.63; P-trend<0.01) but no significant change in JSW loss. With increasing prudent pattern score there was decreased KL-worsening risk (compared with quartile 1, HR for quartile 4: 0.79; 95% CI: 0.64, 0.98; P-trend=0.02), decreased JSW loss (quartile 1: 0.46 mm; quartile 4: 0.38 mm; P-trend<0.01), and decreased odds of higher WOMAC progression (compared with quartile 1, OR for quartile 4 0.73; 95% CI: 0.62, 0.86; P-trend<0.01) in multivariable adjusted models. Adherence to a Western dietary pattern was associated with increased radiographic and symptomatic KOA progression, while following a prudent pattern was associated with reduced progression. In general, for people already diagnosed with KOA, eating a diet rich in fruits, vegetables, fish, whole grains, and legumes may be related to decreased radiographic and symptomatic disease progression.

PSA progression compared to radiographic or clinical progression in metastatic castration-resistant prostate cancer patients treated with enzalutamide.

105 Background: Enzalutamideis ahighly effective treatment in patients with metastatic castration resistant prostate cancer (mCRPC). Although Prostate Cancer Working Group Guidelines (PCWG) recommend continuing treatment until radiographic progression of disease (rPD) or clinical progression (cPD), many patients discontinue therapy for rising PSA alone. Methods: We conducted an open label, randomized phase 2 clinical trial in mCRPC patients (on testosterone suppression therapy) previously untreated with docetaxel, abiraterone, or enzalutamide, comparing enzalutamide alone or in combination with PROSTVAC, a therapeutic cancer vaccine designed to induce an anti-tumor immune response. The study discontinued accrual after a planned interim analysis indicated no difference in progression between the two arms. Patients were followed beyond PSA progression (first of three confirmed PSA rises, evaluated monthly) until rPD per PCWG (scans done every 3 months per protocol). Results: A total of 57 patients were enrolled with a median follow up time of 55.4 months. Of those, 47 (82%) patients were Caucasian and seven (12%) patients were African American. The median age of patients on enrollment was 67.2 years. 49/57 (86%) patients had PSA progression and the median time to first PSA rise for all 57 patients combined was 6.4 months (95% CI: 3.7-11.0 months) after starting enzalutamide. 38/57 (67%) patients experienced progressive disease (majority with rPD and 1/38 (3%) with cPD), with the median time to progression for all 57 patients of 23.3 months (95% CI: 16.1-27.8 months). Conclusions: Consistent with PCWG recommendations, these data suggest that a rising PSA may not be a warning of near-term clinically significant disease progression in mCRPC patients given the nearly 17-month difference between the first rise in PSA and ultimate rPD or cPD seen in this analysis. These data highlight the need to continue to educate patients and providers on PCWG criteria for progression, which were also used in original trials that led to the FDA approval of enzalutamide, so as not to substantially limit the potential efficacy of mCRPC therapies such as enzalutamide. Clinical trial information: NCT01867333.