ASCO 2020: Key trials in breast cancer: Dr. Vishwanath S comments
M3 India Newsdesk Jun 03, 2020
Dr. Vishwanath Sathyanarayanan summarises the major breast cancer studies presented at the American Society of Clinical Oncology (ASCO) 2020 live virtual meeting this year, providing his expert take on each for Indian Oncologists.
The coronavirus pandemic has led to the temporary suspension of large gatherings all over the world. But, while the world has been in complete lockdown the past few months, there have been great strides made towards cancer research, which is why ASCO, for the very first time, transitioned to an virtual annual meeting that was conducted last week between May 29 to 31, 2020. While we as oncologists may already have access to the abstracts presented at the conference, here are a few path-breaking studies in breast cancer and how they will transform practice for Indian Oncologists.
This study is definitely practice changing. Higher risk Her2 positive EBC do not benefit with neoadjuvant anthracyclines. Moreover, the addition of anthracyclines increased the risk of febrile neutropenia and cardiac toxicity. Going forward, we may be able to omit anthracyclines in this sub-group of patients.
This phase 3 study looked at the role of NACT with/out anthracyclines in the presence of dual Her2 blockade in Her2 positive EBC. Primary end point, pCR was similar in the PTC+PTZ and the FEC-T-PTZ arms (68% Vs 67%). At a median follow up of 49 months, the 3 yr EFS was 93.5% vs 92.7%, HR 0.9 (0.5-1.63) in the PTC+PTZ and the FEC-T-PTZ respectively. There was no difference in EFS in cN0, N1 and N2 in the two arms. The 3 yr OS was 98.2% vs 97.7% with HR 0.91 (0.35-2.36).
KAITLIN (negative trial)
Replacing adjuvant taxane and trastuzumab with T-DM1 does not seem to result in improved efficacy or overall safety. Hence, HP + chemotherapy continues to be the standard of care for patients with high-risk HER2-positive patients with EBC.
This was a phase III study of T-DM1 + pertuzumab versus trastuzumab + pertuzumab + taxane, after anthracyclines as adjuvant therapy for high-risk HER2-positive early breast cancer (EBC). KAITLIN did not meet its co-primary endpoints. In LN+ patients, there was no significant difference between arms in IDFS event risk (stratified hazard ratio = 0.97; 95%CI 0.71–1.32). Three-year IDFS was 94.1% with AC-THP and 92.7% with AC-KP.
Early results have shown that interim PET seems to be surrogate marker for pCR and the BCS rates are not compromised in the chemo free strategy and also with a favourable toxicity profile. Hence, a PET-adapted approach seems to be a promising modality for escalation, de-escalation strategy.
This was a phase 2 trial which looked at chemotherapy de-escalation using PET and pathological response in Her2 positive early breast cancer. Patients who were randomized into TCHP or HP +/- ET and escalation to TCHP based on PET after 2 cycles of chemotherapy or targeted therapy. Co-primary endpoints were breast/axilla pCR rate (ypT0/isN0) among B/PET-RX patients and 3-year invasive disease-free survival (iDFS).
Based on this study, CDK 4/6- don’t find a role in the neoadjuvant setting at the current time. Further studies are required to test its role. However, what came out of this trial was an interesting concept of patients on ribociclib + letrozole achieving a complete cell cycle arrest at day 14.
Ribociclib+letrozole vs letrozole + placebo in ER+, Her2 neg EBC. It did not increase the number of women with a PEPI score of 0 (pT1,2; Ki 67 ≤2.7%, N0, Allred ER score 3-8 and but did double the proportion of patients achieving complete cell cycle arrest : Ki 67 ≤2.7% at D14C1 (92% vs 52%, p<0.0001), however this was not sustained till surgery. Clinical and imaging response of RIB + LET was similar to LET alone.
The 8.7 year median follow up data of the MINDACT was presented in ASCO 2020. The estimated gain of DMFS for chemo administration in Clinical high risk/genomic low risk is a minimal 2.6%. The difference may be more relevant in premenopausal patients (DMFS gain 5%+/-2.8%) and not clinically relevant in post-menopausal women (DMFS gain 0.2% +/-2.3%).
The long-term results of the large prospective trial testing the 70-gene signature MammaPrint as guidance for adjuvant chemotherapy in breast cancer patients was presented at ASCO. The primary DMFS endpoint at 5 years continued to be met in CT untreated C-High / G-Low risk women, confirming the trial as a positive de-escalation study.
Metronomic capecitabine in early stage TNBC (SYSUCC-001)
For 1 year after standard adjuvant chemotherapy prolonged 5 year DFS by 10% (83% vs 73%, HR 0.63; 95% CI 0.42-0.96) which was well tolerated. This is definitely a practice changing study and clinically relevant which will probably be practiced by most clinicians going forward.
In this phase III trial, patients with operable TNBC were randomly assigned to receive metronomic capecitabine (650 mg/m2 twice daily continuously for one year) as maintenance therapy or observation after standard local and systemic treatment for curative intent. The primary end point was disease-free survival (DFS). Secondary end points included distant disease-free survival (DDFS), overall survival (OS) and safety. At a median follow-up of 56.5 months, 5-year DFS was significantly better in capecitabine group than in observation group (83% vs. 73%, HR, 0.63; 95% CI, 0.42 to 0.96; p = 0.027). 5-year DDFS was also significantly better in capecitabine group than in observation group (85% vs. 76%, HR, 0.56; 95% CI, 0.37 to 0.90; p = 0.016).
This study is practice changing as the results are excellent with OS advantage as well in such a poor prognostic sub-group (brain metastases).
Oral TKI Tucartinib with Trastuzumab and capecitabine in previously treated Her2 positive MBC improved CNS-PFS (9.9 vs 4.2 months, HR 0.32) and OS (20.7 vs 11.6months, HR 0.49) vs placebo. Intracranial response rate favoured tucatinib arm (47 vs 20%).
KEYNOTE 355 trial
In untreated metatstatic TNBC, Pembrolizumab + chemotherapy improves PFS by 4.1 months (9.7m vs 5.6m) with a HR of 0.65, p= 0.0012 in CPS ≥10 and benefit across all sub groups and no new safety signals. Finally, pembrolizumab has also found its role in metastatic triple negative breast cancer (TNBC) in combination with chemotherapy.
Patients with ≥6 months DFI were randomized 2:1 to pembro + chemo (nab-paclitaxel; paclitaxel; or gemcitabine/carboplatin) or pbo + chemo for up to 35 administrations of pembro/pbo or until progression/intolerable toxicity. Pts were stratified by chemo type (taxane vs gemcitabine/carboplatin), PD-L1 status (CPS ≥1 vs <1), and prior (neo)adjuvant treatment with same-class chemo (yes vs no). Pembro combined with several chemo partners showed a statistically significant and clinically meaningful improvement in PFS vs chemo alone in pts with previously untreated locally recurrent inoperable or metastatic TNBC whose tumors expressed PD-L1 (CPS ≥10). Pembro + chemo was generally well tolerated, with no new safety concerns.
The trial fails to show superiority or non-inferiority, for fulvestrant over letrozole, in combination with palbociclib in 1st line therapy for ER+/HER2- advanced breast cancer. Moreover, there is no difference in PFS by visceral disease or disease presentation and no difference in OS. The results of PALOMA 2 are here to stay for clinicians.
The randomized, multicenter, open-label, phase II trial evaluated palbociclib in combination with fulvestrant or letrozole in endocrine-sensitive patients with estrogen receptor (ER)[+]/HER2[-] metastatic breast cancer. A total 486 patients with ER[+]/HER2[-] MBC with no prior therapy in the advanced setting and endocrine sensitive criteria (relapse > 12 months [mo] after the end of adjuvant endocrine therapy or diagnosed with “de novo” metastatic disease) were randomly assigned (1:1 ratio) to receive P (oral 125 mg/day [d]; 3 eeks on/1 week off) plus F 500 mg/d (I.M Days 0, 14, 28, and then every 28 d) or PL (oral 2.5 mg/d). At median follow-up of 32 months, median PFS was 27.9 months (95% confidence interval [CI], 24.2-33.1) with PF and 32.8 months (95% CI, 25.8-35.9) with PL (HR: 1.1; 95% CI, 0.9-1.5; P = 0.321). No differences were observed for patients with or without visceral involvement (HR: 1.3 and HR: 0.97 respectively, interaction P = 0.275), and for “de novo” or recurrent metastatic disease (HR: 1.1 and HR: 1.1 respectively, P = 0.979). The 4-year OS rate was 67.6% in PF and 67.5% in PL arm (HR: 1; 95% CI, 0.7-1.5; P = 0.986). The study was not able to identify an improvement in PFS for PF over PL in patients with endocrine-sensitive ER[+]/HER2[-] MBC.
With the availability of alpelisib on compassionate basis in India, for patients who have PIK3CA mutated HR+, Her2 negative ABC post progression on CDKi + AI, alpelicib + fulvestrant may be a reasonable option in this sub-group of patients based on BYlieve trial and SOLAR-1 results.
Phase 2, open labeled trial which demonstrated a efficacy of alpelisib with fulvestrant in PIK3CA mutated HR+, Her2 negative ABC post progression on CDKi + AI. Median PFS at 6 months was 50.4% with median PFS of 7.3 months with manageable AE profile. This study confirms date from SOLAR-1.
Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.
The writer, Dr. Vishwanath Sathyanarayan is a Medical Oncologist from Apollo Hospitals, Bangalore with a fellowship from MD Anderson Cancer Center.
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