Dr. Vishwanath Sathyanarayanan wraps up a busy year in Oncology by picking key trials in breast and gynaecological cancers and deliberating on each to help understand how they will change practice for Indian Oncologists.

MONALEESA-3: Advanced Breast Cancer (ABC)

Dr. Vishwanath S: The overall survival (OS) benefit with Ribociclib (RIB) vs placebo (PBO) was consistent across all subgroups, including first-line and early-relapse/second-line subgroup. Patients without liver and lung involvement had a greater reduction in risk of death, bone-only disease did better, elderly >65 years did as well as younger patients, and interestingly, Asians fared poorly on subset analysis. The combination was well tolerated.

The combination of CDK 4-6 inhibitors and hormonal therapy has revolutionised the management of HR+/Her2 negative advanced breast cancer. The phase III MONALEESA-3 trial evaluated the role of ribociclib (RIB) with fulvestrant (FUL) as first-line (1L) or second-line (2L) treatment for postmenopausal patients with HR+/HER2− ABC. The progression free survival (PFS) benefit was previously reported. The OS data was reported in ESMO 2019.

At median follow-up of 39.4 months, RIB + FUL demonstrated a statistically significant OS prolongation over placebo + FUL (median, NR vs 40.0 mos; HR, 0.724, 95% CI, 0.568-0.924, P = 0.00455). The reduction in relative risk of death with RIB was 28%.

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IMpassion130: Triple Negative Breast Cancer (TNBC)

Dr. Vishwanath S: Results of several studies of immunotherapy have been rather disappointing. However, this study is an exception and showed a survival advantage and can be practice changing in untreated metastatic TNBC with PDL1 positivity. With TNBC being an aggressive subset, this regimen will be a valuable addition to clinicians.

ASCO 2019 witnessed the presentation of the updated overall survival (OS) from the phase III study of Atezolizumab (Atezo) + Nab-paclitaxel (nP) in previously untreated locally advanced or metastatic triple-negative breast cancer (mTNBC). The primary PFS analysis reported previously, found that the combination significantly improved PFS in intent-to-treat (ITT) and PD-L1+ patients vs placebo + nP, with efficacy driven by the PD-L1+ population.

In the 2nd interim OS analysis, though statistical significance was not demonstrated in ITT patients, a 7.0-month improvement in median OS was observed in PD-L1+ patients (1% or higher) with Atezo + nP (25.0 months) vs placebo + nP (18.0 months; HR, 0.71 [95% CI: 0.54, 0.93]) and the combination was well tolerated.

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KEYNOTE-522: Triple Negative Breast Cancer (TNBC)

Dr. Vishwanath S: A regimen of Pembrolizumab with platinum-based chemotherapy may be the new standard of care of the neo-adjuvant setting in triple negative breast cancer (TNBC) patients.

KEYNOTE-522 was a phase III study of neoadjuvant Pembrolizumab + chemo vs. chemotherapy followed by adjuvant Pembrolizumab in patients with untreated, non-metastatic early stage triple negative breast cance (TNBC). After surgery, patients received pembrolizumab or placebo for 9 cycles or until recurrence or unacceptable toxicity (adjuvant phase).

The results which were presented in ESMO 2019 showed that the addition of Pembrolizumab to platinum-based chemotherapy led to statistically significant improvement in rate of pCR (64.8% with Pembrolizumab vs 51.2% with placebo P = .00055) independent of PDL1 status with trend in improved EFS with addition of Pembrolizumab (HR: 0.63). The reported AEs were consistent with known toxicities for each agent. Pathological complete response rate (pCR) has been shown to translate to long term better outcomes in TNBC.

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MONALEESA-7: Advanced Breast Cancer

Dr. Vishwanath S: Several trials have evaluated the role of CDK 4/6 inhibitors in post-menopausal patients and shown PFS benefit. This study represents a new standard of care in premenopausal patients and has also been the first to show OS benefit. Increased QT when added to Tamoxifen is a limiting factor and this combination should not be used by clinicians.

Evaluated Ribociclib plus endocrine therapy exclusively in peri- and pre-menopausal women with hormone receptor–positive, HER2-negative disease. It randomly assigned 672 women to endocrine therapy alone (Letrozole, Anastrozole, or Tamoxifen, by physician’s choice) or the same plus Ribociclib (600 mg/d for 3 weeks on, one week off). All women also received Goserelin.

The combination led to a 29% reduction in risk of death vs endocrine therapy alone (P = .00973). Overall survival rates were 71.9% vs 64.9% at 36 months for the combination and control arms, respectively, and 70.2% vs 46.0% at 42 months.The study is the first to show a statistically significant improvement in overall survival for a CDK4/6 inhibitor in breast cancer. However, there are safety concerns of using Ribociclib with Tamoxifen (increased QT) and hence, the combination should not be used.

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SOLO-3: Advanced Ovarian Cancer

Dr. Vishwanath S: This trial shows that Olaparib provides benefit over standard-of-care chemotherapy for certain patients with relapsed BRCA-mutated advanced ovarian cancer. With a robust patient assistance program for Olaparib in India, this may serve as a reasonable therapeutic option in this select subset of patients.

The phase 3 SOLO-3 trial results were presented at ASCO 2019. The PARP inhibitor Olaparib reduced the risk of disease progression or death by 38% versus chemotherapy in patients with platinum-sensitive, relapsed, germline BRCA1/2-mutated ovarian cancer who received at least 2 prior lines of chemotherapy.

The median progression-free survival (PFS) was 13.4 months with Olaparib compared with 9.2 months with chemotherapy (HR, 0.62; 95% CI, 0.43-0.91; P = .013). The overall response rate (ORR) was 72% with the PARP inhibitor compared with 51% with chemotherapy. Fifty percent of patients receiving Olaparib had a grade ≥3 adverse event (AE) compared with 47% of patients in the chemotherapy arm.

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PAOLA-1/ENGOT-ov25: Endometroid Ovarian Cancer

Dr. Vishwanath S: This combination is again practice-changing as a maintenance therapy in combination with Bevacizumab in newly diagnosed advanced ovarian cancer following platinum-based chemotherapy and Bevacizumab. BRCA mutation is mandatory in all newly diagnosed ovarian malignancies.

This was a randomised, double-blind, international phase III trial in patients with newly diagnosed, FIGO stage III–IV, high-grade serous or endometrioid ovarian cancer, fallopian tube, or primary peritoneal cancer. Patients in clinical complete or partial response following platinum-based chemotherapy plus Bevacizumab were randomised 2:1 to receive oral Olaparib at 300 mg twice daily for up to 24 months or placebo plus Bevacizumab at 15 mg/kg on day one every 3 weeks for 15 months, which included doses received during chemotherapy.

The patients were stratified by first-line treatment outcome and tumour BRCA mutation. The median PFS was significantly prolonged with the addition of Olaparib to maintenance Bevacizumab after frontline platinum-based CT in patients with ovarian cancer, regardless of BRCA mutation status or initial surgical outcome. Prespecified subgroup analysis suggested that patients with homologous recombination deficiency (HRD) or tumour BRCA mutation had the most significant improvement in PFS.

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KEYNOTE-146: Endometrial Carcinoma

Dr. Vishwanath S: This study has shown that Pembrolizumab can be given in microsatellite stable (MSS) as well in patients with advanced endometrial carcinoma and may well be an option in this setting.

It was a single-arm, multicentre trial in 108 patients with metastatic endometrial carcinoma who had received at least one prior systemic therapy in any setting. Patients were treated with Lenvatinib in combination with Pembrolizumab until unacceptable toxicity or disease progression.

Ninety-four had tumours that were not microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR); 11 had tumours that were MSI-H or dMMR; and in 3 patients, the tumour MSI-H or dMMR status was not known. The combination of Lenvatinib + Pembrolizumab showed clinical activity independent of MSI status, PD-L1 status, or histologic subtype. ORR at data cutoff- all patients, 38.9%; not MSI-H/dMMR, 37.2%; MSI-H/dMMR, 63.6%. Responses were deep and durable (median duration of response (DoR) in all patients: 21.2 months). Safety profile of Lenvatinib + Pembrolizumab is generally comparable to monotherapy profiles.

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 in Lymphoma & Myeloma from MD Anderson Cancer Center.