Rarity of acquired mutations (MTs) after first-line therapy with anti-EGFR therapy (EGFRi).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3514-3514
Author(s):  
Christine Megerdichian Parseghian ◽  
Ryan Sun ◽  
Stefania Napolitano ◽  
Van K. Morris ◽  
Jason Henry ◽  
...  

3514 Background: Colorectal cancers (CRC) lacking RAS MTs treated with EGFRi are thought to evolve by a repetitive process of genetic diversification and clonal evolution. Acquired MTs in KRAS, NRAS, BRAF, MAP2K1, and EGFR are known mechanisms of acquired resistance in the EGFRi refractory population. However, the prevalence of MTs in the first line (1L) setting is not well established as most experience with EGFRi has been beyond the 1L setting. Methods: We analyzed paired plasma samples from RAS/BRAF/EGFRWT mCRC patients (pts) enrolled in 3 large randomized phase 3 trials who had been treated with EGFRi and in whom paired baseline (BL) and time of progression (PRO) plasma samples had been collected for sequencing of ctDNA on a platform optimized for very low allele frequencies (Plasma Select-R™ and Resolution Bio™). Prevalence of MTs at BL and PRO from a 1L study (‘203; FOLFOX ± panitumumab) were compared with 2 studies in the third line setting (3L; ‘007; panitumumab + best supportive care [BSC] vs BSC; and 3L; ‘763; panitumumab vs. cetuximab), to assess the frequency of acquired resistance mutations via ctDNA analysis. Results: For pts with available paired plasma samples (n = 112 for ‘203; n = 89 for ‘007; n = 274 for ‘763), acquisition of at least one KRAS, NRAS, BRAF, MAP2K1, or EGFR MT was significantly less common in post-progression samples in the EGFR containing arms of the 1L ‘203 study compared to the 3L ‘763 and ‘007 studies (6.8% vs 50.4% vs 39.6%, respectively; p < 0.001). In the non EGFR containing arms of the ‘203 and ‘007 study, the rate of acquired MTs was 7.5% and 0%, respectively (p = 1). While this difference in the rate of acquired MTs between the EGFR and non EGFR containing arms was statistically significant for the 3L study (p < 0.001) it was not significant for the 1L study. Further, pts on both 3L studies treated with EGFRi who experienced CR, PR or SD acquired more MTs than those who had PD as best response (53.6% vs 33.3%, respectively; p < 0.001). This relationship was not significant in the 1L setting (7.7% vs 0%; p = 1). Subclonal MTs (rMAF < 25%) in KRAS, NRAS, EGFR, BRAF and MAP2K1 were present at BL in 129 pts (27%). Based on the hypothesis that EGFRi is selecting for rare existing mutated cells in the tumor, we would expect expansion of any preexisting subclones in the BL samples. However, in contrast to expectations, these subclones rarely expanded to become clonal at the time of progression (12.4%). Conclusions: In contrast to expectations, acquired KRAS, NRAS, BRAF, EGFR, or MAP2K1 MTs rarely develop after 1L therapy. While selective pressure appears to increase the frequency of acquired MTs in the 3L setting, preexisting subclonal MTs do not appear to be the dominant source of acquired MTs at progression, implying that there may also be a transient mutational process driving resistance rather than expansion of preexisting clones. These findings have significant implications for ongoing and planned EGFRi rechallenge studies.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9533-9533
Author(s):  
Ines Pires Da Silva ◽  
Judith M. Versluis ◽  
Tasnia Ahmed ◽  
Douglas Buckner Johnson ◽  
Jennifer Soon ◽  
...  

9533 Background: First line IPI+PD1 induces long-term response in 36% of MM patients (pts); however, the majority of pts will progress and may require further treatment, which is yet to be established. We studied the patterns of progressive disease (PD) on 1st line IPI+PD1, and the management and outcomes in MM pts. Methods: Demographics, disease characteristics, nature of PD, subsequent treatments and outcomes were examined in MM pts with PD on 1st line IPI+PD1. Multivariable analyses (MVA) identified factors associated with patterns of PD: innate resistance (IR) = PD as best response or stable disease (SD) < 6 mo; acquired resistance (AR) = PD after initial response or SD ≥ 6 mo. Results: 310 MM pts from 14 melanoma centres were included; 208 (67%) had PD during and 102 (33%) after ceasing IPI+PD1. Overall med. progression-free survival (mPFS) was 2.8 mo (CI 95% 2.7 – 3.0); 187 pts (60%) had IR (mPFS 2.2 [2.1 – 2.5]), 112 pts (36%) had AR (mPFS 8.5 [7.2 – 10.2]) and 11 pts (4%) had pseudoprogression, i.e. PD followed by response without changing treatment (mPFS 2.7 mo [1.4 – NA]). On MVA, pts with ECOG PS ≥ 1 were more likely to have IR vs AR; and within IR pts, those with head & neck primary melanomas and lung metastases were more likely to have PD < 1.5 mo. Most pts with IR (68%) had PD in multiple sites, while 61% AR pts had PD in a single site. Brain was most common site of single organ PD; 49% of IR and 41% of AR. Med. follow-up from PD was 32.7 mo (28.1 – 36.8). After PD, 61 pts (20%) had best supportive care (26% of IR and 11% of AR pts). 259 pts (80%) received further treatment: 39% IR pts had systemic treatment (ST) only and 27% had ST + local; 31% AR pts had ST only and 39% had ST + local. Of 200 pts (65%) who had ST(+/-local), 54% had 1 line of ST and 46% had ≥ 2; 1st line ST (ST1) was BRAF/MEKi in 36% of pts, PD1 in 32%, IPI+PD1 in 7%, investigational drugs in 11%, chemotherapy in 9% and others in 5%. ORR in IR pts was lower than in AR pts for every type of ST1 (see Table). Med. OS from PD was 11.4 mo (CI 95% 9.6 – 16.1); IR 6.4 mo (CI 95% 5.6 – 10.2) and AR 26.1 mo (CI 95% 17.1 – NA). Conclusions: These data suggest longer OS from PD for AR vs IR pts independent of ST type. BRAF/MEKi, rechallenge with PD1+/-IPI and investigational drugs showed activity after PD on IPI+PD1, while chemotherapy has no role in this context.[Table: see text]


2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4043-4043
Author(s):  
Allyson J. Ocean ◽  
Michael J. Guarino ◽  
Kenneth L. Pennington ◽  
Gregory M. Springett ◽  
Seza A Gulec ◽  
...  

4043 Background: A Phase I/II trial evaluated single and repeated cycles of fractionated radioimmunotherapy (RAIT) with 90Y-labeled humanized mAb (90Y-hPAM4) plus Gem as first-line therapy in Stage 3-4 APC. Methods: Cycles of Gem once-weekly x 4 with 90Y-hPAM4 on wks 2, 3 and 4 were repeated until progression, withdrawal or unacceptable toxicity. In Part I, 90Y doses were escalated with Gem fixed at 200 mg/m2. In Part II, Gem was increased up to 1000 mg/m2, with 90Y fixed at 12 mCi/m2 for cycle 1 and lowered for retreatment. Results: Of 100 pts entered, 10 withdrew early, while 90 (73 stage IV) received 1-4 cycles. In Part I, 38 pts received 90Y-hPAM4 weekly x 3 at 6.5, 9, 12, or 15 mCi/m2, with the same cycle repeated 1-3 times in 13 pts. By CT-RECIST criteria, 6 pts (16%) had PRs and 16 (42%) had stabilization as best response (58% disease control). After cycle 1, 52% (13/25) with PET-avid images had >25% SUV reduction, and 33% (9/27) with elevated CA19-9 levels decreased by >50%. The median OS was 7.7 mo., but 11.8 mo. for retreated pts [46% (6/13) survived ≥1 yr.], and with improved efficacy at higher 90Y doses. NCI-CTCv3 Grade 3-4 platelets or ANC developed in 20/38 (53%) after cycle 1 (all reversible to Grade 1) and in all retreated pts (irreversible in 4/9 pts at 12 or 15 mCi/m2). In Part II, 52 pts received increased Gem without evidence of improved efficacy, while 13 pts were retreated with more acceptable toxicity at lower 90Y doses of 6.5 or 9 mCi/m2. Treatment was well tolerated with no infusion reactions. Infections requiring IV antibiotics occurred at a low rate and responded to appropriate coverage (bacteremia/sepsis, 7%; febrile neutropenia, 4%; ascending cholangitis, 3%; pneumonia, 2%; others 1%). One case of bleeding occurred, due to rectal tumor invasion. Anecdotal reports of good performance and decreased pain medication requirements require further validation. Conclusions: Fractionated RAIT with 90Y-hPAM4 combined with low-dose 200 mg/m2 GEM appears promising as a treatment regimen for APC. Hematologic toxicity was dose limiting. A 90Y-hPAM4 dose of 12 mCi/m2 for cycle 1 and 6.5 mCi/m2 for cycle 2 have been selected as suitable for further clinical development in the first-line setting.


2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e17500-e17500
Author(s):  
Haythem Y. Ali ◽  
Zaid Abdel Rahman ◽  
Jawad Sheqwara

e17500 Background: Metastatic head and neck cancer is a diagnosis with poor prognosis and very little in terms of available active therapy. Until recently the mainstay of therapy was chemotherapy with or without cetuximab. The regimen of cetuximab (C), platinum (P) and 5FU has a response rate(RR) of 36% in the first line setting, and a PFS of 5.6 months and OS of 10.1 months. In the setting of post first line therapy immunotherapeutic agents (IO) have average RR of 15% and median OS of 8 months. Methods: We studied all patients with metastatic or recurrent head and neck cancer who were treated with an IO at our institution between May 2016 and July 2018 evaluating their entire history of therapy. 19 patient were treated with IO at our institution in the designated period of whom 9 received nivolumab (N) and 10 received pembrolizumab ( P ). Patients treated on trials were excluded. Patients who received less than 1 cycle of therapy were also excluded. 7 of the 19 patients received an IO in the first line setting after being refractory or resistant to platinum containing definitive therapy, 7 received the IO after a cetuximab (C) containing first line regimen, 1 patient received IO in second line but was naïve to C and 4 received IO in the third line setting. Results: 3 of 19 patients treated with IO had partial response, there were no complete responses, 6 patients had stable disease as their best response and 10 patients progressed at the time of their first evaluation. 11 of 19 patients received additional therapy post IO. 10 patients received taxane based therapy 5 of whom the taxane was combined with C. Of the 5 patients who received a taxane and C combination 2 had CR, 2 had PR and one had PD. Of the 5 who received other taxane regimens, 1 had PR 1 had SD and 1 had PD, 2 expired prior to their first evaluation. The patient who received a non taxane regimen all had progressive disease. Of the 4 responding patients to C regimens 1 had SD during IO therapy and 3 had PD. The longest response duration to a C regimen post IO was 628 days. Conclusions: We observe an unusual response rate among patients treated with a combination of taxanes and cetuximab after IO therapy. This finding may relate to a modifying effect of IO on sensitivity to subsequent therapy. This observation merits further investigation.


Author(s):  
Kate El Bouzidi ◽  
Steven A Kemp ◽  
Rawlings P Datir ◽  
Fati Murtala-Ibrahim ◽  
Ahmad Aliyu ◽  
...  

Abstract Objectives HIV-1 integrase inhibitors are recommended as first-line therapy by WHO, though efficacy and resistance data for non-B subtypes are limited. Two recent trials have identified the integrase L74I mutation to be associated with integrase inhibitor treatment failure in HIV-1 non-B subtypes. We sought to define the prevalence of integrase resistance mutations, including L74I, in West Africa. Methods We studied a Nigerian cohort of recipients prior to and during receipt of second-line PI-based therapy, who were integrase inhibitor-naive. Illumina next-generation sequencing with target enrichment was used on stored plasma samples. Drug resistance was interpreted using the Stanford Resistance Database and the IAS-USA 2019 mutation lists. Results Of 115 individuals, 59.1% harboured CRF02_AG HIV-1 and 40.9% harboured subtype G HIV-1. Four participants had major IAS-USA integrase resistance-associated mutations detected at low levels (2%–5% frequency). Two had Q148K minority variants and two had R263K (one of whom also had L74I). L74I was detected in plasma samples at over 2% frequency in 40% (46/115). Twelve (26.1%) had low-level minority variants of between 2% and 20% of the viral population sampled. The remaining 34 (73.9%) had L74I present at &gt;20% frequency. L74I was more common among those with subtype G infection (55.3%, 26/47) than those with CRF02_AG infection (29.4%, 20/68) (P = 0.005). Conclusions HIV-1 subtypes circulating in West Africa appear to have very low prevalence of major integrase mutations, but significant prevalence of L74I. A combination of in vitro and clinical studies is warranted to understand the potential implications.


2011 ◽  
Vol 27 (1) ◽  
pp. 71-80 ◽  
Author(s):  
B. Chaplin ◽  
G. Eisen ◽  
J. Idoko ◽  
D. Onwujekwe ◽  
E. Idigbe ◽  
...  

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 22-23
Author(s):  
Dylan J Martini ◽  
Subir Goyal ◽  
Jeffrey M. Switchenko ◽  
Mary Jo Lechowicz ◽  
Pamela B. Allen

Introduction Sézary syndrome (SS) is an aggressive, leukemic subtype of cutaneous T-cell lymphoma (CTCL) with a median survival of 3-5 years. Approved therapies include skin-directed therapy, radiation, and systemic therapies such as chemotherapy, histone deacetylase (HDAC) inhibitors, interferon, extracorporeal photopheresis (ECP), and oral retinoids. There is no consensus first-line therapy for SS and there is limited data regarding prognostic biomarkers. We assessed treatment patterns, outcomes, and racial differences at our institution. Methods We performed a retrospective review of 62 patients at Winship Cancer Institute of Emory University from 1990-2020 with a confirmed diagnosis of SS. Clinical data collected from the electronic medical record included demographics, baseline laboratory values, disease characteristics, and therapy. Clinical outcomes were measured by overall survival (OS) and time to next treatment (TTNT). OS was measured from time of diagnosis to date of death or last follow-up. TTNT was defined as the number of months from the start of the first line of therapy until the initiation of the subsequent therapeutic regimen. Descriptive analysis was performed for each variable and a comparison between African American (AA) and white patients was performed using ANOVA for numerical covariates and chi-square test or Fisher's exact test for categorical covariates. Kaplan-Meier curves for OS and TTNT were generated for the whole cohort. A Kaplan-Meier curve was also generated to compare time from diagnosis to initiation of first systemic therapy stratified by race along with the log-rank p-value. The univariate association of baseline variables with OS and TTNT was assessed by Cox proportional hazards models and the multivariable analyses (MVA) were performed on variables that had p-value less than 0.05 on univariate analyses. Results Males made up (58.1%) of our patients and the median age at diagnosis was 65.9 years. Nearly one-half (45.2%) of patients were AA. The median Sézary count at diagnosis was 1320 cells/uL. The median time from diagnosis to first systemic therapy was 2.4 months and the median number of systemic therapies was 3.0. Information regarding systemic treatments received after diagnosis is presented inTable 1. The most common first-line systemic therapies were oral retinoids (43.5%), ECP (32.3%), and interferon (30.6%). HDAC inhibitors and total skin electron beam (TSEB) radiation were common treatments beyond first line (46.8% received HDAC inhibitors, 38.7% received TSEB), but were rarely used in the first-line setting. The median OS and TTNT were 3.1 years and 6.3 months, respectively(Figure 1). In MVA, elevated WBC and LDH were significantly associated with shorter OS (WBC HR: 1.05, 95% CI: 1.01-1.08, p=0.01; LDH HR: 1.003, 95% CI: 1.001-1.005, p=0.011) and shorter TTNT (WBC HR: 1.04, 95% CI: 1.002-1.08, p=0.041; LDH HR: 1.002, 95% CI: 1.001-1.004, p=0.048). In analysis by race, AA patients had a higher proportion of females compared to non-hispanic white patients (53.6% vs 28.1%, p=0.045). AA patients also had lower median hemoglobin at diagnosis (12.6 vs 14.3, p=0.036), higher median LDH at diagnosis (360 vs 232, p=0.002), and longer median time from diagnosis to first systemic therapy compared to non-hispanic white patients (3.17 months vs 2.14 months, p=0.039,Figure 2). Conclusions SS is an aggressive subtype of CTCL with no consensus first-line therapy and limited data on prognostic biomarkers. In our cohort, oral retinoids, ECP, and interferon were the most commonly utilized treatments in the first-line setting. Elevated WBC and LDH were significantly associated with both OS and TTNT which suggests that these may have value as prognostic biomarkers in SS. AA patients may have delayed time from diagnosis to starting systemic therapy and higher LDH at diagnosis. This data is hypothesis-generating and should be validated in larger, prospective studies. Disclosures Allen: Bayer:Consultancy, Other;Imbrium:Consultancy, Other;Research to Practice:Speakers Bureau;Clinical Care Options:Speakers Bureau;Curio Sciences:Honoraria.


2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 623-623
Author(s):  
S. Lee ◽  
J. Park ◽  
S. Park ◽  
W. Kang ◽  
H. Lim ◽  
...  

623 Background: Fluoropyrimidine-based combination chemotherapy, in combination with either oxaliplatin or irinotecan, have demonstrated efficacy and tolerability against advanced colorectal cancer (ACC). Methods: Between Jan 2006 and Dec 2007, 478 ACC patients were treated with combination chemotherapy in first-line setting: 5-fluorouracil, folinic acid plus oxaliplatin (FOLFOX, n=172), 5-fluorouracil, folinic acid plus irinotecan (FOLFIRI, n=95), capecitabine plus oxaliplatin (XELOX, n=155), and capecitabine plus irinotecan (XELIRI, n=56). FOLFOX and FOLFIRI were repeated every 2 weeks, whereas XELOX and XELIRI were repeated every 3 weeks until disease progression or unacceptable toxicity occurred or until a patient chose to discontinue treatment. Results: The median age was 58 years (range, 19-84 years) and the median chemotherapy duration for FOLFOX, FOLFIRI, XELOX and XELIRI were 4.9, 4.5, 5.7 and 5.4 months, respectively. Combination chemotherapy regimens were generally well tolerated. The estimated median PFS for all patients was 6.8 months (95% confidence interval, 6.3-7.3 months). No statistically significant difference in PFS was found each regimen used as first-line chemotherapy. Sixty-percent (n=290) of patients received second or further lines of therapy after failure. Conclusions: Fluoropyrimidine-based combination chemotherapy regimens appear to be equally active and tolerable as first-line therapy for ACC. No significant financial relationships to disclose.


2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 227-227
Author(s):  
Allyson J. Ocean ◽  
Michael J. Guarino ◽  
Kenneth Lee Pennington ◽  
Gregory M. Springett ◽  
Seza A Gulec ◽  
...  

227 Background: A Phase I/II trial was undertaken to evaluate repeated cycles of 90Y-labeled anti-mucin humanized mAb (90Y-hPAM4) plus Gem as first-line therapy in Stage 3-4 APC. Methods: Pts received Gem once-weekly x 4 with 90Y-hPAM4 on wks 2, 3 and 4, with cycles repeated until progression or unacceptable toxicity. In Part I, pts were treated in cohorts with escalating 90Y doses and Gem fixed at a low 200 mg/m2 dose for radiosensitization. In Part II, the Gem doses were increased up to standard levels, with 90Y doses fixed for first cycle, but decreased for subsequent cycles. Tumor responses were assessed by CT, FDG/PET and serum CA19-9; safety by NCI-CTCv3. Results: Of 100 untreated pts enrolled, 10 withdrew early, while 90 (73 stage IV) received 1-4 cycles. In Part I, 38 pts received 90Y-hPAM4 weekly x 3 at 90Y doses of 6.5 (N=4), 9 (N=12), 12 (N=17) or 15 (N=5) mCi/m2, with the same cycle repeated 1-3 times in 13 pts. Grade 3-4 platelets or ANC developed in 20/38 (53%) after cycle 1 (all reversible to Grade 1) and in all retreated pts (irreversible in 4/9 pts at 12 or 15 mCi/m2). There were 3 febrile neutropenias, 4 other infections treated with IV antibiotics, but no major bleeding or other AEs. By CT-RECIST criteria, 6 pts (16%) had PRs and 16 (42%) had stabilization as best response (58% disease control). After cycle 1, 52% (13/25) with PET-avid images became negative or had >25% SUV reduction, and 33% (9/27) with elevated CA19-9 levels decreased by >50%. The median overall survival was 7.7 mo., but 11.8 mo. for retreated pts [46% (6/13) survived ≥1 yr.], with improved efficacy at higher 90Y doses. In Part II, 52 pts received 12 mCi/m2 90Y-hPAM4 x 3 with Gem doses of 200 (N=17), 600 (N=8) or 1000 mg/m2 (N=27), with 13 pts now retreated at 90Y doses of 6.5 or 9 mCi/m2. Results so far indicate no advantage to giving higher doses of Gem with RAIT. Toxicity, response and survival data for this group will be presented at the conference. Conclusions: Fractionated RAIT with 90Y-hPAM4 combined with low-dose gemcitabine appears to be a manageable and active first-line therapy for APC. It may provide comparable efficacy yet less toxicity compared to other regimens.


2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e14700-e14700
Author(s):  
Tomas Salek ◽  
Peter Pichna

e14700 Background: CRC is one of the most frequent malignant diseases in Slovakia. Slovakia with approximately 5 million inhabitants is country with the highest incidence of CRC in Europe, and there is a focus on CRC treatment within Slovak healthcare system. Methods: Between March 2012 and June 2012 we made a survey in the vast majority of hospital medical oncology departments and outpatient cancer clinics /93 facilities- it comprises approximately 95 % of Slovak departments and clinics treating metastatic CRC/. Data obtained during this 4months period were then multiplied by 3, and that gave us the approximate yearly data. (We reviewed data from 532 patients during four months period.) Results: 670 newly diagnosed mCRC patients (pts) (38%) were treated with chemotherapy alone in the first line, 867 pts (48%) with chemotherapy plus biologics and 231 pts (13%) were treated with best supportive care only. 87% of our newly diagnosed mCRC pts were treated with first line therapy, 37% with second line therapy and 25% with third and later lines of treatment. 42% of pts had KRAS status examined with following results: 44% KRAS wild type, 50.4% KRAS mutated and 5.6% status unknown. Conclusions: We conclude that in Slovakia we have similar patterns of mCRC treatment like in other Middle European countries and high percentage of pts in the first line is treated with biologic therapy.


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