Ten Recent Landmark Trials Across Oncology – Dr Vidit Kapoor

The field of Oncology has witnessed a transformative journey over
the last decade, marked by groundbreaking discoveries and advancements that
continue to redefine the way we approach and treat cancer.

As we navigate the
ever-expanding landscape of oncology in 2023, several key trends and
developments stand out in the management of both solid tumours and
hematological malignancies.

The FLAURA 2 trial demonstrated that first line treatment with
Osimertinib plus platinum based chemotherapy achieved a statistically
significant and clinically meaningful improvement in progression free survival (PFS)
by 38% compared to Osimertinib alone in patients with advanced or metastatic
EGFR (Epidermal Growth Factor Receptor) mutated NSCLC.

This study supports
the use of Osimertinib combined with platinum based chemotherapy as a new and
promising first line treatment option in advanced/metastatic Non Small Cell
Lung Cancer (NSCLC) with an EGFR mutation.

An updated analysis of the ADAURA trial, that analysed patients
with surgically resected stage Ib to IIIa EGFR mutated NSCLC patients, revealed
that there is a statistically significant Overall Survival (OS) Benefit with
adjuvant Osimertinib.

This update enhances evidence in support of
prescribing Osimertinib to patients with resected stage Ib to IIIa EGFR mutated
NSCLC patients.

The PAPILLON trial showed that the use of amivantamab-chemotherapy
resulted in superior efficacy with a significant prolongation of PFS as
compared with chemotherapy alone as first line treatment of patients with
advanced NSCLC with EGFR exon 20 insertions. At 18 months, PFS was reported in
31% of patients in the amivantamab-chemotherapy group and in 3% in the
chemotherapy group.

The PROSPECT trial showed that in patients with locally advanced
rectal cancer who were eligible for sphincter-sparing surgery, pre-operative
chemotherapy with FOLFOX was non inferior to pre-operative chemoradiotherapy
with respect to disease free survival suggesting that it may be possible for
some patients with localized rectal cancer to forego pre-operative radiation
therapy thus avoiding added toxicity.

In the KEYNOTE-A39 randomized phase III trial, Enfortumab Vedotin
in combination with pembrolizumab (EV + P) significantly improved OS, reducing
the risk of death by 53%, as compared to chemotherapy in patients with locally
advanced/metastatic urothelial cancer.

Median OS was 31.5 months in the EV + P
group versus 16.1 months in the chemotherapy group. [5] EV + P is a new
standard of care treatment in the first line setting for locally
advanced/metastatic urothelial cancer.

The LMS-04 trial demonstrated a statistically significant
improvement in PFS with Doxorubicin plus Trabectedin as compared to Doxorubicin
alone in the first line treatment setting in patients with unresectable or
metastatic leiomyosarcoma which may be a new standard of care first line
treatment in this patient population.

The SWOG S1826 study, a phase III randomized study of Nivolumab
plus AVD (Adriamycin, Vinblastine and Dacarbazine) or Brentuximab Vedotin (BV)
plus AVD in patients with newly diagnosed advanced stage Classical Hodgkin
Lymphoma, showed a statistically significant superior PFS with reduced toxicity
in the Nivolumab AVD group as compared to the BV ABD group.

The addition of
nivolumab to AVD was associated with a 52% reduction in the risk of disease
progression or death compared with BV AVD suggesting the use of Nivo AVD as a
preferred standard of care in patients with advanced classical Hodgkin
lymphoma.

The ZUMA-7 trial of patients with early relapsed or refractory
large B-cell lymphoma who received CART (CD19 chimeric antigen receptor T cell
therapy) with Axi-cel (Axicabtagene Ciloleucel) versus standard of care
(chemoimmunotherapy +/- autologous stem cell transplant) resulted in a
significantly longer median OS with Axi-cel (not reached) as compared to
standard of care (31 months). 

Similarly, the TRANSFORM trial showed
significant improvements in event free survival, complete response rates and
PFS with Liso-cel (lisocabtagene maraleucel) CART as a second line therapy in
early relapsed/refractory large cell lymphoma.  These results support the
use of CART in patients with early relapsed or refractory large B cell lymphoma
wherever available and possible.

In the ECOG-ACRIN E1910 Randomized phase III trial, the addition
of Blinatumomab to consolidation chemotherapy resulted in a significantly
better OS in patients with newly diagnosed B-lineage Acute Lymphoblastic Leukemia
who were MRD (minimal residual disease) negative after intensive induction
chemotherapy.

This result expands the use of blinatumomab to MRD negative
patients in addition to MRD positive patients.

References

[1] Planchard D et
al; FLAURA2 Investigators. Osimertinib with or without Chemotherapy in EGFR-Mutated
Advanced NSCLC. N Engl J Med. 2023 Nov 23. PMID: 37937763.

[2] Tsuboi Met et al;
ADAURA Investigators. Overall Survival with Osimertinib in Resected EGFR-Mutated
NSCLC. N Engl J Med. 2023 Jul 13; PMID: 37272535.

[3] Zhou C et al;
PAPILLON Investigators. Amivantamab plus Chemotherapy in NSCLC with EGFR Exon
20 Insertions. N Engl J Med. 2023 Oct 21. PMID: 37870976.

[4] Deborah Schrag et al; Alliance N1048; Preoperative Treatment
of Locally Advanced Rectal Cancer; Journal of Clinical Oncology 2023 41:17_suppl, LBA2

[5] TB Powles at al; Keynote A39; Open label, randomized phase III
study of Enfortumab Vedotin in combination with Pembrolizumab (EV + P) vs
chemotherapy (Chemo) in previously untreated locally advanced metastatic
urothelial carcinoma; Annals of Oncology; Oct 2023

[6] Pautier P et al;
Doxorubicin alone versus doxorubicin with trabectedin followed by trabectedin
alone as first-line therapy for metastatic or unresectable leiomyosarcoma
(LMS-04): a randomised, multicentre, open-label phase 3 trial. Lancet Oncol.
2022. PMID: 35835135.

[7] Alex Herrera et al; SWOG S1826, a randomized study of
nivolumab AVD vs Brentuximab AVD (BV AVD) in advanced stage (AS) Classic
Hodgkin Lymphoma (HL); Journal of Clinical Oncology 2023 41:17_suppl, LBA4

[8] Westin JR et al;
ZUMA-7 Investigators; Kite Members. Survival with Axicabtagene Ciloleucel in
Large B-Cell Lymphoma. N Engl J Med. 2023 Jul 13. PMID: 37272527.

[9] Kamdar M et al;
TRANSFORM Investigators. Lisocabtagene maraleucel versus standard of care with
salvage chemotherapy followed by autologous stem cell transplantation as
second-line treatment in patients with relapsed or refractory large B-cell
lymphoma (TRANSFORM): Lancet. 2022 Jun 18; PMID: 35717989.

[10] Mark R. Litzow et al; Consolidation Therapy with Blinatumomab Improves Overall Survival in
Newly Diagnosed Adult Patients with B-Lineage Acute Lymphoblastic Leukemia in
Measurable Residual Disease Negative Remission: Results from the ECOG-ACRIN
E1910 Randomized Phase III National Cooperative Clinical Trials Network
Trial. Blood 2022; 140 (Supplement 2): LBA–1.